Podcasts about sprague dawley

Lege Sjur Even Aunmo er opptatt av å følge med på forskning. I denne episoden forteller han om problemene med å leve av planter. Planter har nemlig forsvarsmekanismer mot å bli spist. De kan dessuten stjele mineraler, trigge immunsystemet, tilføre tungmetall og gi næring til kreft. Selv foretrekker han et kosthold bestående utelukkende av animalske produkter. Han synes det er beklagelig at rådene har blitt politiske gjennom at de har tatt inn klimasaken, fremfor at de er en mest mulig sann fremstilling av hva ulike typer mat gjør med kroppen. Aunmo legger frem forskningsevidens som peker i motsatt retning av kostholdsrådene norske myndigheter har lagt frem nylig. Han har mange suksesshistorier fra pasienter med autoimmune sykdommer, diabetes og andre sykdommer, som har blitt friske etter at de sluttet å spise bestemte typer planter, produkter fra planter eller utelukket dem helt fra kosten.Sjur Even Aunmo: • youtube.com • facebook.comGrønnsaker uten noen kjent form for gluten: • hodekål, blomkål, brokkoli, paprika, rødbeter, bladbete, squash, potet, søtpotet, gulrøtter, gresskar, romano-salat, indisk bladsennep, spinat, grønnkål • Obs: Selv om disse plantene ikke inneholder gluten, finnes det andre stoffer i dem som er uheldige. Paprika, for eksempel, hører til søtvier-familien, sammen med potet og tobakk. De forsvarer seg mot mennesker, dyr og insekter med lektiner og solanin. Spinat inneholder mye oksalat som stjeler kalsium fra kroppen. Det finnes igjen i nyrestener og mistenkes for å stimulere brystkreft. Grønnsaker inneholder druesukker, som er et viktig næringsstoff for kreft. Grønnsaker som vokser over bakken inneholder ofte mindre sukker enn de som vokser under bakken. De minst usunne grønnsakene på listen synes å være hodekål, blomkål og brokkoli, på tross av at disse danner goitrin, et stoff som motvirker dannelsen av stoffskiftehormon.Diverse kilder: • Mindre kjøtt, mer plantebasert: Her kommer De nordiske ernæringsanbefalingene 2023 • Helsedirektoratets kostråd • The Seven Countries Study (søk) • Paleo diet (søk) • Keto diet (søk) • Carnivore diet (søk)› Relaterte AJP-episoder: • AJP 61 | Sjur Even Aunmo – Fikk sparken for å snakke om bivirkningerRelatert forskning:› FETT› https://doi.org/10.1136/bmj.e8707 Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis› https://doi.org/10.1136/bmj.i1246 Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)› https://doi.org/10.3945/ajcn.2009.27725 Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease› https://doi.org/10.1186/s12937-017-0254-5 The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials› https://doi.org/10.1016/j.jacc.2020.05.077 Saturated Fats and Health: A Reassessment and Proposal for Food-Based Recommendations: JACC State-of-the-Art Review› http://dx.doi.org/10.1136/openhrt-2014-000196 Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis› http://dx.doi.org/10.1136/bmjebm-2019-111180 Fat or fiction: the diet-heart hypothesis› https://www.mn.uio.no/ibv/tjenester/kunnskap/plantefys/leksikon/h/herdet-fett.html› https://doi.org/10.1046/j.1471-4159.1997.68052092.x 4-Hydroxynonenal-Derived Advanced Lipid Peroxidation End Products Are Increased in Alzheimer's Disease› https://doi.org/10.1016/j.freeradbiomed.2006.07.021 Induction of mitochondrial nitrative damage and cardiac dysfunction by chronic provision of dietary ω-6 polyunsaturated fatty acids› https://doi.org/10.1038/s41467-018-05614-6 Dietary stearic acid regulates mitochondria in vivo in humans› http://dx.doi.org/10.17140/AFTNSOJ-1-123 Oxidation of Polyunsaturated Fatty Acids and its Impact on Food Quality and Human Health› https://doi.org/10.1194/jlr.M026179 Dietary oxidized n-3 PUFA induce oxidative stress and inflammation: role of intestinal absorption of 4-HHE and reactivity in intestinal cells› https://doi.org/10.1021/jf049207s Effect of the Type of Frying Culinary Fat on Volatile Compounds Isolated in Fried Pork Loin Chops by Using SPME-GC-MS› STATINER (KOLESTEROLSENKENDE STOFFER)› http://dx.doi.org/10.1136/bmjopen-2018-023085 Statins for the primary prevention of cardiovascular disease: an overview of systematic reviews› http://dx.doi.org/10.1136/bmjopen-2014-007118 The effect of statins on average survival in randomised trials, an analysis of end point postponement› https://doi.org/10.1001/archinternmed.2010.182 Statins and All-Cause Mortality in High-Risk Primary Prevention: A Meta-analysis of 11 Randomized Controlled Trials Involving 65 229 Participants› https://www.felleskatalogen.no/medisin/lipitor-upjohn-eesv-pfizer-560999› https://www.felleskatalogen.no/medisin/zocor-organon-565655› https://www.legemiddelhandboka.no/L8.15.1/Statiner› https://www.bmj.com/campaign/statins-open-data Statins - a call for transparent data› https://doi.org/10.1001/archinternmed.2011.625 Statin Use and Risk of Diabetes Mellitus in Postmenopausal Women in the Women's Health Initiative› https://doi.org/10.1007/s40264-017-0620-4 Amyotrophic Lateral Sclerosis Associated with Statin Use: A Disproportionality Analysis of the FDA's Adverse Event Reporting System› https://doi.org/10.1001/jamainternmed.2020.6084 Evaluation of Time to Benefit of Statins for the Primary Prevention of Cardiovascular Events in Adults Aged 50 to 75 Years› https://doi.org/10.1016/j.atherosclerosis.2022.07.003 Statin therapy for the primary prevention of cardiovascular disease: Cons› http://doi.org/10.1161/STROKEAHA.121.034576 Lipid-Lowering Therapy and Hemorrhagic Stroke RiskLipid-Lowering Therapy and Hemorrhagic Stroke Risk› KJØTT› https://www.acpjournals.org/doi/full/10.7326/M19-0622 Effect of Lower Versus Higher Red Meat Intake on Cardiometabolic and Cancer Outcomes A Systematic Review of Randomized Trials› https://doi.org/10.3945/ajcn.116.142521 Total red meat intake of ≥0.5 servings/d does not negatively influence cardiovascular disease risk factors: a systemically searched meta-analysis of randomized controlled trials› https://doi.org/10.3945/ajcn.113.062638 Meat intake and cause-specific mortality: a pooled analysis of Asian prospective cohort studies› FISK› https://doi.org/10.1093/jn/nxab112 Biomarkers and Fatty Fish Intake: A Randomized Controlled Trial in Norwegian Preschool Children› https://doi.org/10.1007/s12016-013-8363-1 Fish Allergy: In Review› KOLESTEROL› http://dx.doi.org/10.1136/bmjopen-2015-010401 Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review› https://doi.org/10.1016/j.mehy.2018.09.019 Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia› PMID: 18277343 ApoB/ApoA1 ratio and subclinical atherosclerosis› https://doi.org/10.1016/0021-9150(89)90130-5 Cigarette smoking renders LDL susceptible to peroxidative modification and enhanced metabolism by macrophages› https://doi.org/10.1161/01.CIR.93.7.1346 Cigarette Smoking Potentiates Endothelial Dysfunction of Forearm Resistance Vessels in Patients With Hypercholesterolemia: Role of Oxidized LDL› https://doi.org/10.1161/01.CIR.97.20.2012 Passive Smoking Induces Atherogenic Changes in Low-Density Lipoprotein› https://doi.org/10.1016/j.atherosclerosis.2008.04.046 Smoking and smoking cessation—The relationship between cardiovascular disease and lipoprotein metabolism: A review› https://doi.org/10.1161/ATVBAHA.113.300156 Smoking and Cardiovascular Disease› https://doi.org/10.3402/fnr.v59.29240 LDL biochemical modifications: a link between atherosclerosis and aging› https://doi.org/10.1016/j.cjca.2017.07.015 Association Between Circulating Oxidized LDL and Atherosclerotic Cardiovascular Disease: A Meta-analysis of Observational Studies› https://doi.org/10.1054/plef.2000.0204 Why is glycated LDL more sensitive to oxidation than native LDL? A comparative study.› KARBOHYDRAT› https://www.helsedirektoratet.no/rapporter/anbefalinger-om-kosthold-ernaering-og-fysisk-aktivitet/Anbefalinger%20om%20kosthold%20ern%C3%A6ring%20og%20fysisk%20aktivitet.pdf/_/attachment/inline/2f5d80b2-e0f7-4071-a2e5-3b080f99d37d:2aed64b5b986acd14764b3aa7fba3f3c48547d2d/Anbefalinger%20om%20kosthold%20ern%C3%A6ring%20og%20fysisk%20aktivitet.pdf› FRUKTOSE› https://doi.org/10.1016/j.jhep.2021.02.027 Fructose- and sucrose- but not glucose-sweetened beverages promote hepatic de novo lipogenesis: A randomized controlled trial› https://doi.org/10.1093/ajcn/nqaa332 Effects of fructose restriction on liver steatosis (FRUITLESS); a double-blind randomized controlled trial› https://doi.org/10.5223/pghn.2021.24.5.483 The Relationship between Daily Fructose Consumption and Oxidized Low-Density Lipoprotein and Low-Density Lipoprotein Particle Size in Children with Obesity› KUNSTIG SØTNING› https://doi.org/10.1016/s0378-8741(99)00081-1 Effects of chronic administration of Stevia rebaudiana on fertility in rats› https://doi.org/10.1371/journal.pone.0000698 Intense Sweetness Surpasses Cocaine Reward› https://doi.org/10.1016/j.cell.2022.07.016 Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance› https://doi.org/10.1289/ehp.8711 First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats› https://doi.org/10.1289/ehp.10271 Life-Span Exposure to Low Doses of Aspartame Beginning during Prenatal Life Increases Cancer Effects in Rats› DIABETES› https://doi.org/10.1001/jama.295.6.655 Low-Fat Dietary Pattern and Risk of Cardiovascular DiseaseThe Women's Health Initiative Randomized Controlled Dietary Modification Trial – se side 661, økt hjerte/kar-risk sfa. Lavfett-diett› https://doi.org/10.3945/ajcn.110.010843 Effects of a low-fat dietary intervention on glucose, insulin, and insulin resistance in the Women's Health Initiative (WHI) Dietary Modification trial› https://doi.org/10.1007/s11745-008-3274-2 AOCS Lipids (lavranket journal) Carbohydrate Restriction has a More Favorable Impact on the Metabolic Syndrome than a Low Fat Diet› https://doi.org/10.1161/ATVBAHA.114.303284 Small Dense Low-Density Lipoprotein-Cholesterol Concentrations Predict Risk for Coronary Heart Disease- ArtThromVas prospektiv kohort› https://doi.org/10.1097/MOL.0b013e328306a057 Glycation as an atherogenic modification of LDL : Current Opinion in Lipidology› https://doi.org/10.1016/0021-9150(93)90084-8 Glycosylated low density lipoprotein is more sensitive to oxidation: implications for the diabetic patient?› https://doi.org/10.2337/diabetes.55.02.06.db05-1103 Loss of Endothelial Glycocalyx During Acute Hyperglycemia Coincides With Endothelial Dysfunction and Coagulation Activation In Vivo› https://doi.org/10.1016/S0895-7061(00)01260-7 Blood viscosity and blood pressure: role of temperature and hyperglycemia› https://doi.org/10.2337/dc13-1374 Blood Viscosity in Subjects With Normoglycemia and Prediabetes› https://doi.org/10.1007/s00592-017-1004-z Elevated 1-h post-challenge plasma glucose levels in subjects with normal glucose tolerance or impaired glucose tolerance are associated with whole blood viscosity› https://doi.org/10.1080/09674845.2010.11730293 Blood viscosity at different stages of diabetes pathogenesis.› DIABETES-DEMENS› https://doi.org/10.1212/WNL.53.9.1937 Diabetes mellitus and the risk of dementia - The Rotterdam Study› https://doi.org/10.1016/S1474-4422(05)70284-2 Lancet Neurology 2006, sysrew lavere evidensgrad. Risk of dementia in diabetes mellitus: a systematic review› https://doi.org/10.1111/j.1445-5994.2012.02758.x Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies› https://doi.org/10.1016/j.arr.2019.100944 Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies› https://doi.org/10.1177/193229680800200619 Alzheimer's Disease is Type 3 Diabetes—Evidence Reviewed› https://doi.org/10.3390/ijerph120708281 Evaluating the Association between Diabetes, Cognitive Decline and Dementia› https://doi.org/10.3390/ijms21030934 Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model› https://doi.org/10.1038/s41574-018-0048-7 Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications› https://doi.org/10.1038/s41586-020-2247-3 APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline› DIABETES NYRESYKDOM› https://doi.org/10.2337/diacare.27.2007.S79 Nephropathy-in-Diabetes Nephropathy in Diabetes› Diabetic Nephropathy: Diagnosis, Prevention, and Treatment› https://doi.org/10.1016/S0272-6386(96)90538-7 Diabetic nephropathy in type II diabetes› DIABETES ØYESYKDOM› https://doi.org/10.1016/S0140-6736(09)62124-3 Diabetic retinopathy› https://doi.org/10.1016/S2213-8587(18)30128-1 Incidence and progression of diabetic retinopathy: a systematic review› DIABETES HJERTE- OG KAR-SYKDOM› https://doi.org/10.1001/jamacardio.2020.7073 Association of Lipid, Inflammatory, and Metabolic Biomarkers With Age at Onset for Incident Coronary Heart Disease in Women› PLANTE-ANTINÆRINGSSTOFF, VERN OG GIFT› https://doi.org/10.1016/j.foodchem.2008.01.056 Food Chemistry 2008 Bioaccessibility of Ca, Mg, Mn and Cu from whole grain tea-biscuits: Impact of proteins, phytic acid and polyphenols› https://doi.org/10.1002/mnfr.200900099 Phytate in foods and significance for humans: food sources, intake, processing, bioavailability, protective role and analysis.› https://doi.org/10.1046/j.1440-6047.1999.00038.x Oxalate content of foods and its effect on humans› https://doi.org/10.1104/pp.109.2.347 Lectins as plant defense proteins.› https://doi.org/10.1016/j.taap.2009.03.012 Effects of wheat germ agglutinin on human gastrointestinal epithelium: Insights from an experimental model of immune/epithelial cell interaction› https://doi.org/10.1038/s41531-018-0066-0 Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat› https://doi.org/10.1016/S0140-6736(05)79894-9 Identification of intact peanut lectin in peripheral venous blood› https://doi.org/10.1136/bmj.318.7190.1023 Do dietary lectins cause disease?› https://doi.org/10.1016/S0015-0282(16)54596-8 Lectin binding of endometrium in women with unexplained infertility› https://doi.org/10.1016/S0271-5317(88)80133-7 Changes in organs and tissues induced by feeding of purified kidney bean (Phaseolus vulgaris) lectins› https://doi.org/10.3390/molecules20022014 Insecticidal Activity of Plant Lectins and Potential Application in Crop Protection› https://doi.org/10.1210/endo-113-6-1921 Bound Lectins that Mimic Insulin Produce Persistent Insulin-Like Activities› https://doi.org/10.1042/BJ20071137 Contribution of leptin receptor N-linked glycans to leptin binding› https://doi.org/10.1111/j.1365-2249.2007.03368.x Potato lectin activates basophils and mast cells of atopic subjects by its interaction with core chitobiose of cell-bound non-specific immunoglobulin E› https://doi.org/10.1002/(SICI)1521-4141(199903)29:03 Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils› https://doi.org/10.1016/j.ekir.2018.07.020 Secondary Oxalate Nephropathy: A Systematic Review› http://dx.doi.org/10.1136/gut.16.3.193 The effect of tea on iron absorption.› PMID: 1862 Disler PB, Lynch SR, Torrance JD, et al. The mechanism of the inhibition of iron absorption by tea. The South African Journal of Medical Sciences. 1975 ;40(4):109-116.› https://doi.org/10.1016/0887-2333(95)00113-1 Effects of saponins and glycoalkaloids on the permeability and viability of mammalian intestinal cells and on the integrity of tissue preparationsin vitro› https://doi.org/10.1079/BJN2002725 The biological action of saponins in animal systems: a review› http://doi.org/10.1093/carcin/bgp082 Lung tumor promotion by curcumin› https://doi.org/10.3945/ajcn.2009.26736M Cancer incidence in vegetarians: results from the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford)› https://doi.org/10.3382/ps.0550716 Antithyroid Activity of Goitrin in Chicks› https://doi.org/10.1016/s0278-6915(82)80294-9 Hepatic effects of R-goitrin in in Sprague-Dawley rats› https://doi.org/10.1002/ana.24448 Vagotomy and subsequent risk of Parkinson's disease --> https://doi.org/10.1038/s41531-018-0066-0› Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat› http://doi.org/10.1056/NEJMra2010852 Salicylate Toxicity› https://doi.org/10.1021/jf0113070 Relationship between Cyanogenic Compounds in Kernels, Leaves, and Roots of Sweet and Bitter Kernelled Almonds› https://doi.org/10.1179/146532810X12637745451951Cyanide poisoning caused by ingestion of apricot seeds› https://doi.org/10.3390/toxins11060324 Ricin: An Ancient Story for a Timeless Plant Toxin› https://doi.org/10.1016/j.taap.2009.03.012Effects of wheat germ agglutinin on human gastrointestinal epithelium: Insights from an experimental model of immune/epithelial cell interaction› GLUTEN› https://doi.org/10.1080/00365520500235334 Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines› https://doi.org/10.1053/j.gastro.2008.03.023 Gliadin Induces an Increase in Intestinal Permeability and Zonulin Release by Binding to the Chemokine Receptor CXCR3› https://doi.org/10.1016/j.jprot.2017.03.026 A curated gluten protein sequence database to support development of proteomics methods for determination of gluten in gluten-free foods› https://doi.org/10.1111/jgh.13703 What is gluten?› https://doi.org/10.1186/s41043-015-0032-y The opioid effects of gluten exorphins: asymptomatic celiac disease› https://doi.org/10.1016/j.peptides.2015.07.013 Bioactive peptides derived from natural proteins with respect to diversity of their receptors and physiological effects› SOYA› https://doi.org/10.1271/bbb.70516Soymorphins, novel μ opioid peptides derived from soy β-conglycinin β-subunit, have anxiolytic activities.› TILSETNINGSSTOFFER› https://doi.org/10.3233/NHA-170023 A randomized trial of the effects of the no-carrageenan diet on ulcerative colitis disease activity› https://doi.org/10.1053/j.gastro.2021.11.006 Randomized Controlled-Feeding Study of Dietary Emulsifier Carboxymethylcellulose Reveals Detrimental Impacts on the Gut Microbiota and Metabolome› https://doi.org/10.1002/ijc.21925 Processed meat consumption, dietary nitrosamines and stomach cancer risk in a cohort of Swedish women› KETOGENISITET/KREFT› https://oslo-universitetssykehus.no/behandlinger/pet-undersokelse› https://stanfordhealthcare.org/medical-tests/p/pet-scan/what-to-expect.html› https://www.sciencedirect.com/topics/medicine-and-dentistry/warburg-effect› https://doi.org/10.1016/j.tibs.2015.12.001 The Warburg Effect: How Does it Benefit Cancer Cells?› https://doi.org/10.1080/01635581.2019.1650942 Feasibility, Safety, and Beneficial Effects of MCT-Based Ketogenic Diet for Breast Cancer Treatment: A Randomized Controlled Trial Study› https://doi.org/10.1093/jnci/djs399 Dietary Glycemic Load and Cancer Recurrence and Survival in Patients with Stage III Colon Cancer: Findings From CALGB 89803› https://doi.org/10.18632/aging.101382 Ketogenic diet in cancer therapy› IATROGENISITET› https://doi.org/10.1111/eci.12834 How to survive the medical misinformation mess› https://doi.org/10.1111/jlme.12068 Institutional Corruption of Pharmaceuticals and the Myth of Safe and Effective Drugs› https://doi.org/10.1136/bmj.f3830 Why we can't trust clinical guidelines› https://doi.org/10.1016/S0140-6736(15)60696-1 Offline: What is medicine's 5 sigma?› https://apjcn.nhri.org.tw/server/apjcn/procnutsoc/1990-1999/1995/1995%20p1-10.pdfLast ned episodenInnspilt: 2023-07-18Publisert: 2023-07-28Støtte Antijantepodden?Liker du arbeidet vi gjør, og vil bidra til at vi lager flere episoder?Finn ut hvordan du kan gi noe tilbake ved å gå til antijantepodden.com!Meld deg på vårt nyhetsbrev

A new research paper was published in Aging (Aging-US) Volume 15, Issue 7, entitled, “Effect of deferoxamine and ferrostatin-1 on salivary gland dysfunction in ovariectomized rats.” Xerostomia can be defined as a subjective sensation associated with reduction of lubrication and dehydration of the oral mucosa. Xerostomia is known to be common in elderly people, especially women, and its prevalence is thought to range from 5.5% to 46%. The mechanism underlying xerostomia after menopause has not yet been fully elucidated. In this new study, researchers Yong-Il Cheon, Ji Min Kim, Sung-Chan Shin, Hyung-Sik Kim, Jin-Choon Lee, Gi Cheol Park, Eui-Suk Sung, Minhyung Lee, and Byung-Joo Lee from Pusan National University and Sungkyunkwan University School of Medicine aimed to investigate the mechanism of xerostomia and the effect of the ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (FER) on salivary gland dysfunction in a postmenopausal animal model. “Recently, it was reported that ferroptosis in the salivary gland may be related to the xerostomia that occurs after menopause [30]. However, no studies to date have used anti-ferroptosis drugs to investigate the mechanisms underlying postmenopausal salivary gland dysfunction.” Twenty-four female Sprague–Dawley rats were randomly divided into four groups: a SHAM group (n = 6, sham-operated rats), an OVX group (n = 6, ovariectomized rats), an FER group (n = 6, ovariectomized rats injected intraperitoneally with FER), and a DFO group (n = 6, ovariectomized rats injected intraperitoneally with DFO). GPX4 activity, iron accumulation, lipid peroxidation, inflammation, fibrosis, and salivary gland function were analyzed. Recovery of GPX4 activity and a decrease in iron accumulation and cytosolic MDA + HAE were observed in the DFO group. In addition, collagen I, collagen III, TGF-β, IL-6, TNF-α, and TGF-β levels were decreased in the DFO group compared to the OVX group. Recovery of GPX4 activity and the morphology of mitochondria, and reduction of cytosolic MDA + HAE were also observed in the FER group. In addition, decreased expression of inflammatory cytokines and fibrosis markers and increased expression of AQP5 were observed in both the DFO and FER groups. Postmenopausal salivary gland dysfunction is associated with ferroptosis. This is the first study to investigate the effect of ferroptosis inhibitors (DFO and FER) on the salivary glands of ovariectomized rats. DFO and FER are considered promising treatments for postmenopausal xerostomia. “In the absence of a standard treatment for postmenopausal dry mouth, this study is expected to be helpful in understanding the mechanism of postmenopausal salivary gland dysfunction and developing a treatment for postmenopausal dry mouth.” DOI: https://doi.org/10.18632/aging.204641 Corresponding author - Byung-Joo Lee - voicelee@pusan.ac.kr Keywords - aging, menopause, ferroptosis, xerostomia, deferoxamine, ferrostatin-1 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.24.538086v1?rss=1 Authors: Maxwell, N. D., Smiley, C. E., Sadek, A. T., Loyo-Rosado, F. Z., Giles, D. C., Macht, V. A., Woodruff, J. L., Taylor, D. L., Wilson, S. P., Fadel, J. R., Reagan, L. P., Grillo, C. A. Abstract: Leptin is a homeostatic regulatory element that signals the presence of energy stores -in the form of adipocytes- which ultimately reduces food intake and increases energy expenditure. Similarly, serotonin (5-HT), a signaling molecule found in both the central and peripheral nervous systems, also regulates food intake. Here we use a combination of pharmacological manipulations, optogenetics, retrograde tracing, and in situ hybridization, combined with behavioral endpoints to physiologically and anatomically identify a novel leptin-mediated pathway between 5-HT neurons in the dorsal raphe nucleus (DRN) and hypothalamic arcuate nucleus (ARC) that controls food intake. In this study, we show that microinjecting leptin directly into the DRN reduces food intake in male Sprague-Dawley rats. This effect is mediated by leptin-receptor expressing neurons in the DRN as selective optogenetic activation of these neurons at either their ARC terminals or DRN cell bodies also reduces food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing leptin receptors that send projections to the ARC. Finally, by utilizing in vivo microdialysis and high-performance liquid chromatography, we show that leptin administration to the DRN increases 5-HT efflux into the ARC. Overall, this study identifies a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, utilizing 5-HT as a mechanism to control feeding behavior. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior, as well as opens alternative routes for the treatment of eating disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.18.537371v1?rss=1 Authors: Ellison, S. P. Abstract: FC-12738, a retro-inverso pentapeptide developed by Neurodegenerative Disease Research, Inc., is currently under investigation for treating neuroinflammation associated with amyotrophic lateral sclerosis (ALS). This study aimed to evaluate the pharmacokinetic properties of FC-12738, including absorption, distribution, metabolism, excretion, and drug-drug interactions. Pharmacokinetics were assessed in Sprague-Dawley rats and beagle dogs following intravenous and subcutaneous administration. Our findings suggest that FC-12738 demonstrates many favorable pharmacokinetic properties, although further optimization may be required to improve CNS penetrance. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.12.536625v1?rss=1 Authors: Huckleberry, K. A., Calitri, R., Li, A. J., Mejdell, M., Singh, A., Bhutani, V., Laine, M. A., Nastase, A. S., Morena, M., Hill, M., Shansky, R. M. Abstract: Increasing evidence suggests that the neurobiological processes that govern learning and memory can be different in males and females, and here we asked specifically whether the endocannabinoid (eCB) system could modulate Pavlovian fear conditioning in a sex-dependent manner. Systemic (i.p.) injection of CB1R antagonist AM251 in adult male and female Sprague Dawley rats prior to auditory cued fear conditioning produced a female-specific increase in freezing that persisted across extinction and extinction retrieval tests but was prevented by co-administration of TRPV1R antagonist Capsazepine. Notably, AM251 also produced robust freezing in a novel context prior to auditory cue presentation the day following drug administration, but not the day of, suggesting that CB1R blockade elicited contextual fear generalization in females. To identify a potential synaptic mechanism for these sex differences, we next used liquid chromatography/tandem mass spectrometry, Western Blot, and confocal-assisted immunofluorescence techniques to quantify anandamide (AEA), TRPV1R, and perisomatic CB1R expression, respectively, focusing on the ventral hippocampus (vHip). Fear conditioning elicited increased vHip AEA levels in females only, and in both sexes, CB1R expression around vHip efferents targeting the basolateral amygdala (BLA) was twice that at neighboring vHip neurons. Finally, quantification of the vHip-BLA projections themselves revealed that females have over twice the number of neurons in this pathway that males do. Together, our data support a model in which sexual dimorphism in vHip-BLA circuitry promotes a female-specific dependence on CB1Rs for context processing that is sensitive to TRPV1-mediated disruption when CB1Rs are blocked. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.23.533930v1?rss=1 Authors: Sandini, T. M., Onofrychuk, T. J., Roebuck, A. J., Hammond, A., Udenze, D., Hayat, S., Herdzik, M. A., McElroy, D. L., Orvold, S. N., Greba, Q., Laprairie, R. B., Howland, J. G. Abstract: Due to the recent legalization of Cannabis in many jurisdictions and the consistent trend of increasing THC content in Cannabis products, there is an urgent need to understand the impact of Cannabis use during pregnancy on fetal neurodevelopment and behavior. To this end, we repeatedly exposed female Sprague-Dawley rats to Cannabis smoke from gestational days 6 to 20 (n=12; Aphria Mohawk; 19.51% THC, less than 0.07% cannabidiol) or room-air as a control (n=10) using a commercially available system. Maternal reproductive parameters, behavior of the adult offspring, and gene expression in the offspring amygdala were assessed. Body temperature was decreased in dams following smoke exposure and more fecal boli were observed in the chambers before and after smoke exposure in those dams exposed to smoke. Maternal weight gain, food intake, gestational length, litter number, and litter weight were not altered by exposure to Cannabis smoke. A significant increase in the male-to-female ratio was noted in the Cannabis-exposed litters. In adulthood, both male and female Cannabis smoke-exposed offspring explored the inner zone of an open field significantly less than control offspring. Gestational Cannabis smoke exposure did not affect behavior on the elevated plus maze test or social interaction test in the offspring. Cannabis offspring were better at visual pairwise discrimination and reversal learning tasks conducted in touchscreen-equipped operant conditioning chambers. Analysis of gene expression in the adult amygdala using RNAseq revealed subtle changes in genes related to development, cellular function, and nervous system disease in a subset of the male offspring. These results demonstrate that repeated exposure to high-THC Cannabis smoke during gestation alters maternal physiological parameters, sex ratio, and anxiety-like behaviors in the adulthood offspring. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.22.533834v1?rss=1 Authors: Meckel, K. R., Simpson, S., Godino, A., Peck, E. G., George, O., Calipari, E. S., Hofford, R. S., Kiraly, D. Abstract: Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an FR1 schedule. However, microbiome-depleted subjects exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.02.530889v1?rss=1 Authors: Yu, V., Hernandez-Morato, I., Brenner-Morton, S. L., Pitman, M. J. Abstract: Proprioception plays a crucial role in laryngeal function. Further, dysfunctional proprioception likely contributes to disorders such as laryngeal dystonia, dysphagia and vocal fold paresis. Despite this, the physiology of laryngeal proprioception is not well-understood. Controversy remains over whether canonical proprioceptive organs, like muscle spindles (MS) even exist in the intrinsic laryngeal muscles (ILM). Vesicular Glutamate Transporter 1 (VGLUT1) expression has been described in the sensory afferents of MS. This study's primary aim is to determine whether the ILM contain MS using VGLUT1. This is a novel approach, as prior studies have relied on morphology and myosin composition to study this question. Secondarily, we describe the pattern of VGLUT1 expression in the rat larynx, Larynges of 62 Sprague-Dawley rats distributed across 5 age groups (P3, P8, P11, P14-15, and adult), were sectioned and immunostained for VGLUT1 and beta-tubulin III. Other markers (S46, GNAT3, PLC{beta}2, S100b, CGRP) were used to further characterize identified afferent innervation. Of 62 rats, MS were identified in the lateral thyroarytenoid muscles of just three P8 rats, and no golgi tendon organs (GTO) were seen. VGLUT1-positive intramuscular receptor-like entities were observed ILM, and VGLUT1-positive nerve endings were observed in the laryngeal mucosa, concentrated around the arytenoid cartilage. Employing VGLUT1 immunostaining, this study shows that rat intrinsic laryngeal muscles rarely express MS and do not express GTO. This leaves open the possibility that the larynx exhibits a unique proprioceptive apparatus. VGLUT1-positive intramuscular and mucosal structures provide candidates for an alternative system. Further defining the role of these sensory organs will increase our understanding of vocal fold function and ultimately lead to better treatment of vocal fold disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.23.529774v1?rss=1 Authors: Gaulden, A. D., Tepe, E. A., Sia, E., Rollins, S. S., McReynolds, J. R. Abstract: Stress is a significant contributor to the development and progression of substance use disorders (SUDs) and is problematic as it is unavoidable in daily life. Therefore, it is important to understand the neurobiological mechanisms that underlie the influence of stress on drug use. We have previously developed a model to examine the contribution of stress to drug-related behavior by administering a stressor, electric footshock stress, daily at the time of cocaine self-administration in rats resulting in an escalation of cocaine intake. This stress-induced escalation of cocaine intake involves neurobiological mediators of stress and reward such as cannabinoid signaling. However, all of this work has been conducted in male rats. Here we test the hypothesis that repeated daily stress can produce an escalation of cocaine in both male and female rats. We further hypothesize that cannabinoid receptor 1 (CB1R) signaling is recruited by repeated stress to influence cocaine intake in both male and female rats. Male and female Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during a modified short-access paradigm wherein the 2-hr access was separated into 4-30 min self-administration blocks separated by 4-5 min drug free period. Footshock stress produced a significant escalation of cocaine intake similarly in both male and female rats. Female stress-escalated rats did display greater time-out non-reinforced responding and greater front-loading behavior. In males, systemic administration of a CB1R inverse agonist/antagonist Rimonabant only attenuated cocaine intake in rats with a history of combined repeated stress and cocaine self-administration. However, in females, Rimonabant attenuated cocaine intake in the no stress control group but only at the highest dose of Rimonabant (3 mg/kg, i.p.) suggesting that females show a greater sensitivity to CB1R antagonism. However, female rats with a history of stress showed even greater sensitivity to CB1R antagonism as both doses of Rimonabant (1, 3 mg/kg) attenuated cocaine intake in stress-escalated rats similar to males. Altogether these data demonstrate that stress can produce significant changes in cocaine self-administration and suggests that repeated stress at the time of cocaine self-administration recruits CB1Rs to regulate cocaine-taking behavior across sexes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.18.528981v1?rss=1 Authors: Sharma, M., Bhaskar, V., Yang, L., FallahRad, M., Gebodh, N., Zhang, T., Esteller, R., Martin, J., Bikson, M. Abstract: Spinal cord stimulation (SCS) evokes fast epidural Evoked Compound Action Potential (ECAPs) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recoding lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and back. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies less than 2 ms) and an additional wave (S1) starting after the N2. We verified the S1-wave was not a stimulation artifact and was not a reflection of hindlimb/back EMG. The S1-wave has a distinct stimulation-intensity dose response and spatial profile compared to ECAPs. CNQX (a selective competitive antagonist of AMPA receptors) significantly diminished the S1-wave, but not ECAPs. Furthermore, cortical stimulation, which did not evoke ECAPs, produced epidurally detectable and CNQX-sensitive responses at the same spinal sites, confirming epidural recording of an evoked synaptic response. Finally, applying 50 Hz SCS resulted in dampening of ESAPs, but not ECAPs. Therefore, we hypothesize that the S1-wave is synaptic in origin, and we term the S1-wave type responses: Evoked Synaptic Activity Potentials (ESAPs). The identification and characterization of epidurally recorded ESAPs from the dorsal horn may elucidate SCS mechanisms. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.16.528856v1?rss=1 Authors: Beitchman, J. A., Krishna, G., Bromberg, C. A., Thomas, T. C. Abstract: Aspects of glutamate neurotransmission implicated in normal and pathological conditions are often evaluated using in vivo recording paradigms in rats anesthetized with isoflurane or urethane. Urethane and isoflurane anesthesia influence glutamate neurotransmission through different mechanisms; however real-time outcome measures of potassium chloride (KCl)-evoked glutamate overflow and glutamate clearance kinetics have not been compared within and between regions of the brain. In the following experiments, in vivo amperometric recordings of KCl-evoked glutamate overflow and glutamate clearance kinetics (uptake rate and T80) in the cortex, hippocampus and thalamus were performed using glutamate-selective microelectrode arrays (MEAs) in young adult male, Sprague-Dawley rats anesthetized with isoflurane or urethane. Potassium chloride (KCl)-evoked glutamate overflow was similar under urethane and isoflurane anesthesia in all brain regions studied. Analysis of glutamate clearance determined that the uptake rate was significantly faster (53.2%, p less than 0.05) within the thalamus under urethane compared to isoflurane, but no differences were measured in the cortex or hippocampus. Under urethane, glutamate clearance parameters were region dependent, with significantly faster glutamate clearance in the thalamus compared to the cortex but not the hippocampus (p less than 0.05). No region dependent differences were measured for glutamate overflow using isoflurane. These data support that amperometric recordings of glutamate under isoflurane and urethane anesthesia result in mostly similar and comparable data. However, certain parameters of glutamate uptake vary based on choice of anesthesia and brain region. Special considerations must be given to these areas when considering comparison to previous literature and when planning future experiments. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.06.527058v1?rss=1 Authors: Sabetta, Z., Krishna, G., Curry, T., Adelson, P. D., Thomas, T. C. Abstract: Traumatic brain injury (TBI) manifests late-onset and persisting clinical symptoms with implications for sex differences and increased risk for the development of age-related neurodegenerative diseases. Few studies have evaluated chronic temporal profiles of neuronal and glial pathology that include sex as a biological variable. After experimental diffuse TBI, late-onset and persisting somatosensory hypersensitivity to whisker stimulation develops at one-month post-injury and persists to at least two months post-injury in male rats, providing an in vivo model to evaluate the temporal profile of pathology responsible for morbidity. Whisker somatosensation is dependent on signaling through the thalamocortical relays of the whisker barrel circuit made up of glutamatergic projections between the ventral posteromedial nucleus of the thalamus (VPM) and primary somatosensory barrel cortex (S1BF) with inhibitory (GABA) innervation from the thalamic reticular nucleus (TRN) to the VPM. To evaluate the temporal profiles of pathology, male and female Sprague Dawley rats (n = 5-6/group) were subjected to sham surgery or midline fluid percussion injury (FPI). At 7-, 56-, and 168-days post-injury (DPI), brains were processed for amino-cupric silver stain and glial fibrillary acidic protein (GFAP) immunoreactivity, where pixel density of staining was quantified to determine the temporal profile of neuropathology and astrocyte activation in the VPM, S1BF, and TRN. FPI induced significant neuropathology in all brain regions at 7 DPI. At 168 DPI, neuropathology remained significantly elevated in the VPM and TRN, but returned to sham levels in the S1BF. GFAP immunoreactivity was increased as a function of FPI and DPI, with an FPI x DPI interaction in all regions and an FPI x Sex interaction in the S1BF. The interactions were driven by increased GFAP immunoreactivity in shams over time in the VPM and TRN. In the S1BF, GFAP immunoreactivity increased at 7 DPI and declined to age-matched sham levels by 168 DPI, while GFAP immunoreactivity in shams significantly increased between 7 and 168 days. The FPI x Sex interaction was driven by an overall greater level of GFAP immunoreactivity in FPI males compared to FPI females. Increased GFAP immunoreactivity was associated with an increased number of GFAP-positive soma, predominantly at 7 DPI. Overall, these findings indicate that FPI, time post-injury, sex, region, and aging with injury differentially contribute to chronic changes in neuronal pathology and astrocyte activation after diffuse brain injury. Thus, our results highlight distinct patterns of pathological alterations associated with the development and persistence of morbidity that supports chronic neuropathology, especially within the thalamus. Further, data indicate a convergence between TBI-induced and age-related pathology where further investigation may reveal a role for divergent astrocytic phenotypes associated with increased risk for neurodegenerative diseases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.02.526698v1?rss=1 Authors: Carrica, L. K., Choi, J., Walter, F., Noonan, B. L., Shi, L., Johnson, C. T., Bradshaw, H. B., Liang, N.-C., Gulley, J. M. Abstract: The increase in social acceptance and legalization of cannabis over the last several years is likely to increase the prevalence of its co-use with alcohol. In spite of this, the potential for effects unique to co-use of these drugs, especially in moderate doses, has been studied relatively infrequently. We addressed this in the current study using a laboratory rat model of voluntary drug intake. Periadolescent male and female Sprague-Dawley rats were allowed to orally self-administer ethanol, {Delta}9-tetrahydrocannibinol (THC), both drugs, or their vehicle controls from postnatal day (P) 30 to P47. They were subsequently trained and tested on an instrumental behavior task that assesses attention, working memory and behavioral flexibility. Similar to previous work, consumption of THC reduced both ethanol and saccharin intake in both sexes. Blood samples taken 14h following the final self-administration session revealed that females had higher levels of the THC metabolite THC-COOH. There were modest effects of THC on our delayed matching to position (DMTP) task, with females exhibiting reduced performance compared to their control group or male, drug using counterparts. However, there were no significant effects of co-use of ethanol or THC on DMTP performance, and drug effects were also not apparent in the reversal learning phase of the task when non-matching to position was required as the correct response. These findings are consistent with other published studies in rodent models showing that use of these drugs in low to moderate doses does not significantly impact memory or behavioral flexibility following a protracted abstinence period. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Are you or a loved one dealing with depression, anxiety or mental illness? Are you looking for natural solutions? Want to know how eliminating gluten, balancing blood sugar, or going keto can help? Tune in to hear us discuss the role of inflammation in brain dysfunction and how you can use diet to support mental health   An estimated 20-30% of adults experience some form of mental illness with those numbers steadily increasing from 2020 on, especially among 18-24 year olds.  Whether you or someone you know deals with anxiety, depression or another mental health diagnosis, this episode provides practical information on how to remove inflammatory foods, balance blood sugar, and use a Mediterranean ketogenic approach to support balanced mood and beyond!   Also in this episode:  Episode 222: The Depression Immune Connection Harnessing the HPA-axis  Why inflammation drives brain dysfunction The gluten mental health connectionEpisode 74 Are You Still Eating Gluten? Is schizophrenia rare if grain is rare? Mechanisms underlying the neurotoxicity induced by glyphosate-based herbicide in immature rat hippocampus: Involvement of glutamate excitotoxicity Digestaid Why corn is not a great substitute for gluten Thoughts on dairy and mental illnessEpisode 82 Pros and Cons of Dairy | Ali Miller RD The importance of carb control and blood sugar balanceDepression in diabetic patients: the relationship between mood and glycemic control.  Ketosis for mental healthThe use of the ketogenic diet in the treatment of psychiatric disorders The Ketogenic Diet for Refractory Mental Illness: A Retrospective Analysis of 31 Inpatients The Current Status of the Ketogenic Diet in Psychiatry Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats. Anti-Anxiety Diet Bundle use code ANXIETY15 for 15% off LIVE Food-as-Medicine Ketosis Program use code KETO100 for $100 off Stress manager bundle for mental health support as initial supplement strategy Digestaid enzymes for dining out and to reduce gluten sensitivity if exposed EPA-DHA Liquid or EPA-DHA capsules for omega-3 antiinflammatory boost and to offset omega-6 ratio   Sponsors for this episode:  This episode is sponsored by Carnivore Snax, a delicious snack combining just 2 ingredients: meat and Redmond Real Salt! These melt-in-your-mouth meat pastries are like no other dehydrated meat product or jerky on the market. We love that Carnivore Snax are a pro-America brand who sources from US farmers practicing regenerative agriculture and are verified by the Savory Institute confirming their carbon sequestering status. Check out the ribeye, pork loin, brisket and leg of lamb for just a few of our favorites! Use code ALIMILLERRD to save 15% off your order and get free shipping on $125 or more at carnivoresnax.com.  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.12.523845v1?rss=1 Authors: Phillips, R. A., Tuscher, J. J., Wan, E., Fitzgerald, N. D., Zipperly, M. E., Duke, C. G., Ianov, L., Day, J. J. Abstract: Drugs of abuse increase extracellular concentrations of dopamine in the nucleus accumbens (NAc), resulting in transcriptional alterations that drive long-lasting cellular and behavioral adaptations. While decades of research have focused on the transcriptional mechanisms by which drugs of abuse influence neuronal physiology and function, few studies have comprehensively defined NAc cell type heterogeneity in transcriptional responses to drugs of abuse. Here, we used single nucleus RNA-seq (snRNA-seq) to characterize the transcriptome of over 39,000 NAc cells from male and female adult Sprague-Dawley rats following acute or repeated cocaine experience. This dataset identified 16 transcriptionally distinct cell populations, including two populations of medium spiny neurons (MSNs) that express the Drd1 dopamine receptor (D1-MSNs). Critically, while both populations expressed classic marker genes of D1-MSNs, only one population exhibited a robust transcriptional response to cocaine. Validation of population-selective transcripts using RNA in situ hybridization revealed distinct spatial compartmentalization of these D1-MSN populations within the NAc. Finally, analysis of published NAc snRNA-seq datasets from non-human primates and humans demonstrated conservation of MSN subtypes across rat and higher order mammals, and further highlighted cell type-specific transcriptional differences across the NAc and broader striatum. These results highlight the utility in using snRNA-seq to characterize both cell type heterogeneity and cell type-specific responses to cocaine and provides a useful resource for cross-species comparisons of NAc cell composition. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.04.522581v1?rss=1 Authors: Fozzato, A., New, L. E., Griffiths, J. C., Patel, B., Deuchars, S. A., Filippi, B. M. Abstract: Objectives: Brown adipose tissue (BAT) is a potent thermogenic organ, activated by the central nervous system (CNS) through direct noradrenergic sympathetic innervation. Dysregulation of signalling modules in selective CNS areas such as the nucleus of tractus solitarius (NTS) are linked with altered BAT activity, obesity and diabetes. High-fat diet (HFD)-feeding increases mitochondrial fragmentation in the NTS triggering insulin resistance, hyperphagia and weight gain. Here we sought to determine whether changes in mitochondrial dynamics in the NTS can affect BAT activity. Methods: Eight-week-old male Sprague Dawley rats received DVC stereotactic surgery to facilitate brain infusion for local administration of viruses that express mutated Drp1 genes. PET/CT scans were used to measure BAT glucose uptake using. Biochemical assays and immunohistochemistry determined altered levels of key signalling molecules and neural innervation of BAT. Results: We show that short-term HFD-feeding decreases the ability of BAT to uptake glucose and decreases catecholaminergic innervation of BAT, observed by altered intensities and pools of Tyrosine Hydroxylase (TH) labelling. HFD also increased the infiltration of enlarged white fat droplets in the BAT. We demonstrate that inhibiting mitochondrial fragmentation in NTS-astrocytes of HFD-fed rats can prevent the effects on BAT morphology and neural innervation, and increase BAT glucose uptake while lowering blood glucose and insulin levels. In regular chow-fed rats, increasing mitochondrial fragmentation in the NTS-astrocytes reduces BAT glucose uptake, TH and {beta}3-adrenergic receptor levels. Conclusions: Our data suggest that targeting mitochondrial dynamics in the NTS-astrocytes could be a beneficial strategy to increase energy expenditure and protect from developing obesity and diabetes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.20.513048v1?rss=1 Authors: Nett, K. E., Zimbelman, A. R., McGregor, M. S., Alizo Vera, V., Harris, M. R., LaLumiere, R. T. Abstract: Prior evidence indicates that the infralimbic cortex (IL) mediates the ongoing inhibition of cocaine seeking following self-administration and extinction training in rats, specifically through projections to the nucleus accumbens (NA) shell. Our own data indicate that IL activity immediately following an unreinforced lever press is critical for encoding the extinction contingencies in such procedures. Whether extinction encoding requires activity in the IL exclusively or also activity in its outputs, such as those to the NAshell and amygdala, is unknown. To address this issue, we used a closed-loop optogenetic approach in female and male Sprague-Dawley rats to silence IL-NAshell or IL-amygdala activity following an unreinforced lever press during extinction training. Optical illumination (20 s) was given either immediately after a lever press or following a 20 s delay. IL-NAshell inhibition immediately following an unreinforced lever press increased lever pressing during extinction training and impaired retention of extinction learning, as assessed during subsequent extinction sessions without optical inhibition. Likewise, IL-amygdala inhibition given in the same manner impaired extinction retention during sessions without inhibition. Control experiments indicate that critical encoding of extinction learning does not require activity in these pathways beyond the initial 20 s post-lever press period, as delayed IL-NAshell and IL-amygdala inhibition had no effect on extinction learning. These results suggest that a larger network extending from the IL to the NAshell and amygdala is involved in encoding extinction contingencies following cocaine self-administration. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.05.511027v1?rss=1 Authors: Walling, S. G., Harley, C. W., Martin, G. M., Dutton, D. O., Burke, A. T., Chirinos, E. A. Abstract: Network plasticity in the medial perforant path (MPP) of adult (5-9 mo) and aged (18-20 mo) urethane-anesthetized male and female Sprague-Dawley rats was characterized. Paired pulses probed recurrent networks before and after a moderate tetanic protocol. Adult females exhibited greater EPSP-spike coupling suggesting greater intrinsic excitability than adult males. Aged rats did not differ in EPSP-spike coupling but aged females had larger spikes at high currents than males. Paired pulses suggested lower GABA-B inhibition in females. Absolute population spike measures were larger post-tetani in female rats than male rats. Relative population spike increases were greatest in adult males relative to females and to aged males. EPSP slope potentiation was detected with normalization in some post-tetanic intervals for all groups except aged males. Tetani shortened spike latency across groups. Tetani-associated NMDA-mediated burst depolarizations were larger for the first two trains in each tetanus in adult males than other groups. EPSP slopes over 30 min post-tetani predicted spike size in female rats, but not in males. Replicating newer evidence MPP plasticity in adult males was mediated by increased intrinsic excitability. Female MPP plasticity was related to synaptic drive increases, not excitability increases. Aged male rats were deficient in MPP plasticity. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.03.509933v1?rss=1 Authors: Smiley, C. E., Pate, B. S., Bouknight, S. J., Francis, M. J., Nowicki, A. V., Harrington, E. N., Wood, S. K. Abstract: While over 95% of the population has reported experiencing extreme stress or trauma, females of reproductive age develop stress-induced neuropsychiatric disorders at twice the rate of males. This suggests that ovarian hormones may facilitate neural processes that increase stress susceptibility and underlie the heightened rates of these disorders, like depression and anxiety, that result from stress exposure in females. However, there is contradicting evidence in the literature regarding estrogen's role in stress-related behavioral outcomes. Estrogen signaling through estrogen receptor beta (ERb) has been traditionally thought of as anxiolytic, but recent studies suggest estrogen exhibits distinct effects in the context of stress. Furthermore, ERb is found abundantly in many stress-sensitive brain loci, including the central amygdala (CeA), in which transcription of the vital stress hormone, corticotropin releasing factor (CRF), can be regulated by an estrogen response element. Therefore, these experiments sought to identify the role of CeA ERb activity during stress on behavioral outcomes in naturally cycling, adult, female Sprague-Dawley rats. Rats were exposed to an ethological model of vicarious social stress, witness stress (WS), in which they experienced the sensory and psychological aspects of an aggressive social defeat encounter between two males. Following stress, rats exhibited stress-induced anxiety-like behaviors in the marble burying task, and, finally, brain analysis revealed increased ERb and CRF specifically within the CeA following exposure to stress cues. Subsequent experiments were designed to target this receptor in the CeA using microinjections of the ERb antagonist, PHTPP, prior to each stress session. Sucrose preference, acoustic startle, and marble burying tasks determined that blocking ERb in the CeA during WS prevented the development of depressive-,anxiety-like, and hypervigilant behaviors. Additionally, brain analysis revealed a long-term decrease of intra-CeA CRF expression in PHTPP-treated rats. These experiments indicate that ERb signaling in the CeA, through its effects on CRF, contributes to the development of negative valence behaviors that result from exposure to repeated social stress in female rats. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.30.510371v1?rss=1 Authors: Yagi, S., Wen, Y., Galea, L. Abstract: Estrone and estradiol differentially modulate neuroplasticity and cognition but how they influence maturation pathways of new neurons is not known. The present study assessed the effects of estrone and estradiol on various aspects of neurogenesis in the dentate gyrus (DG) of ovariectomized young adult Sprague-Dawley rats using daily subcutaneous injections of 17{beta}-estradiol or estrone. Rats were injected with a DNA synthesis marker, 5-bromo-2-deoxyuridine (BrdU), and were perfused one, two, or three weeks after BrdU injection and treatment. Immunofluorescent labelling for Sox2 and Ki67 were used to examine the density of neural stem cells and proliferating cells, respectively. Double-immunofluorescent labelling of BrdU with doublecortin (DCX) or NeuN was used to examine the attrition and maturation of adult-born neurons over time. Estradiol reduced the density of neural stem cells in the dorsal DG, whereas estrone reduced the density of neural stem cells in the ventral DG. Furthermore, estradiol enhanced, whereas estrone reduced, cell proliferation after one week but not after longer exposure to hormones. Both estrogens increased the density of BrdU/DCX-ir cells after one week of exposure but showed greater attrition of new neurons between one and two weeks after exposure. Lastly, estradiol decreased the percentage of BrdU/NeuN-ir cells in the dorsal DG after three weeks of treatment. These results demonstrate that estrogens have differential effects to modulate several aspects of adult hippocampal neurogenesis in the short term, but fewer effects after long-term exposure and that estradiol and estrone modulate neurogenesis via different pathways. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.27.509680v1?rss=1 Authors: Giuliano, C., Marti-Prats, L., Domi, A., Puaud, M., Pena-Oliver, Y., McKenzie, C., Everitt, B. J., Belin, D. Abstract: Humans greatly differ in how they cope with stress, a natural behaviour learnt through negative reinforcement. Some individuals engage in displacement activities, others in exercise or comfort eating, and others still in alcohol use. Across species, adjunctive behaviors, such as polydipsic drinking, are used as a form of displacement activity that reduce distress. Some individuals, in particular those that use alcohol to self-medicate, tend to lose control over such coping behaviors, which become excessive and compulsive. However, the psychological and neural mechanisms underlying this individual vulnerability have not been elucidated. Here we tested the hypothesis that the development of compulsive adjunctive behaviors stems from the functional engagement of the dorsolateral striatum (DLS) dopamine-dependent habit system after a prolonged history of adjunctive responding. We measured in longitudinal studies in male Sprague Dawley rats the sensitivity of early established vs compulsive polydipsic water or alcohol drinking to a bilateral infusion of the dopamine receptor antagonist -flupentixol into the anterior DLS (aDLS). While most rats acquired a polydipsic drinking response with water, others only did so with alcohol. Whether reliant on water or alcohol, the acquisition of this coping response was insensitive to aDLS dopamine receptor blockade. In contrast, after prolonged experience, adjunctive drinking became dependent on the aDLS dopamine-dependent habit system at a time it was compulsive in vulnerable individuals. These data suggest that habits may develop out of negative reinforcement and that the engagement of their underlying striatal system is necessary for the manifestation of adjunctive behaviors. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.26.509528v1?rss=1 Authors: Yi, D., Hartner, J. P., Ung, B. S., Zhu, H. L., Watson, B. O., Chen, L. Abstract: Microwire microelectrode arrays (MEAs) have been a popular low-cost tool for chronic electrophysiological recordings. Multi-MEA implantations can reveal electrical dynamics crucial to brain function. However, both the fabrication and implantation procedures for multi-MEAs on a single rodent are time-consuming and highly manual skill-dependent for quality. To enable in-house design, fabrication, and implantation of custom microwire MEAs, we developed (1) a computer-aided designed and 3D printed skull cap for pre-determined implantation locations of each MEA and (2) a benchtop fabrication approach for low-cost custom microwire MEAs. A proof-of-concept design of 32-channel 4-MEA (8-wire each) recording system was prototyped and tested through Sprague Dawley rat recordings. The skull cap design based on CT-scan of single rat conforms well with multiple Sprague Dawley rats of various size, age, and weight with minimal bregma alignment error. The prototyped 32-channel system were able to record spiking activities over 5 months. In comparison with conventional stereotactic surgeries, the skull cap system simplifies the implantation location alignment for each MEA by embedding them into the pre-printed designs, thus dramatically reducing the surgical time and effort and increasing the accuracy and repeatability. Compared to commercially available custom microwire MEAs, this in-house fabrication method enables neuroscience labs to create a custom recording apparatus with lower cost and shorter lead time for design modifications. A new methodology for neuroscience labs to fabricate and insert custom microwire MEAs has been developed and it could be easily generalized to enable low-cost highly-custom multi-region recording/stimulation studies. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.13.507749v1?rss=1 Authors: Velazquez Sanchez, C., Muresan, L., Belin, D. Abstract: Some compulsive disorders have been considered to stem from the loss of control over coping strategies, such as displacement. However, the cellular mechanisms involved in the acquisition of coping behaviors and their ensuing compulsive manifestation in vulnerable individuals have not been elucidated. Considering the role of the locus coeruleus (LC) noradrenaline dependent system in stress and related excessive behaviors, we hypothesised that neuroplastic changes in the LC may be involved in the acquisition of an adjunctive polydipsic water drinking, a prototypical displacement behavior, and the subsequent development of compulsion in vulnerable individuals. Thus, male Sprague Dawley rats were characterised for their tendency, or not, to develop compulsive polydipsic drinking in a schedule-induced polydipsia (SIP) procedure before their fresh brains were harvested. A new quantification tool for RNAscope assays revealed that the development of compulsive adjunctive behavior was associated with a low mRNA copy number of the plasticity marker Arc in the LC which appeared to be driven by specific adaptations in an ensemble of tyrosine hydroxylase (TH)+, zif268- neurons. This ensemble was specifically engaged by the expression of compulsive adjunctive behavior, not by stress, because its functional recruitment was not observed in individuals that no longer had access to the water bottle before sacrifice while it consistently correlated with the levels of polydipsic water drinking only when it had become compulsive. Together these findings suggest that downregulation of Arc mRNA levels in a population of a TH+zif268- LC neurons represents a signature of the tendency to develop compulsive coping behaviors. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.30.505941v1?rss=1 Authors: Wong, A., Bhuiyan, M. I. H., Rothman, J., Drew, K., Pourrezaei, K., Sun, D., Barati, Z. Abstract: Timely and sensitive in vivo estimation of ischemic stroke-induced brain infarction are necessary to guide diagnosis and evaluation of treatments efficacy. The gold standard for estimation of the cerebral infarction volume is magnetic resonance imaging (MRI), which is expensive and not readily accessible. Measuring regional cerebral blood flow (rCBF) with Laser Doppler flowmetry (LDF) is the status quo for confirming reduced blood flow in experimental ischemic stroke models. However, rCBF reduction following cerebral artery occlusion often does not correlate with subsequent infarct volume. In the present study, we employed the continuous-wave near infrared spectroscopy (NIRS) technique to monitor cerebral oxygenation during 90 min of the intraluminal middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats (n=8, male). The NIRS device consisted of a controller module and an optical sensor with two LED light sources and two photodiodes making up two parallel channels for monitoring left and right cerebral hemispheres. Optical intensity measurements were converted to deoxyhemoglobin (Hb) and oxyhemoglobin (HbO2) changes relative to a 2-min window prior to MCAO. Area under the curve (auc) for Hb and HbO2 was calculated for the 90-min occlusion period for each hemisphere (ipsilateral and contralateral). To obtain a measure of total ischemia, auc of the contralateral side was subtracted from the ipsilateral side resulting in {Delta}Hb and {Delta}HbO2 parameters. Infarct volume (IV) was calculated by triphenyl tetrazolium chloride (TTC) staining at 24h reperfusion. Results showed a significant negative correlation (r = -0.81, p = 0.03) between {Delta}Hb and infarct volume. In conclusion, our results show feasibility of using a noninvasive optical imaging instrument, namely NIRS, in monitoring cerebral ischemia in a rodent stroke model. This cost-effective, non-invasive technique may improve the rigor of experimental models of ischemic stroke by enabling in vivo longitudinal assessment of cerebral oxygenation and ischemic injury. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Podcast Editor, Liz McInnes, interviews author Jae-Woo Cho to discuss the article, "Implementation and Practice of Deep Learning-Based Instance Segmentation Algorithm for Quantification of Hepatic Fibrosis at Whole Slide Level in Sprague-Dawley Rats" which can currently be found in Vol 50, Issue 2, 2022 of Toxicologic Pathology. Click here to read the article

Efectos de diferentes regímenes de Entrenamiento en Intervalos de Alta Intensidad -HIIT- sobre la resistencia y la neuroplasticidad después de derrame cerebral isquemico Caroline Pin-Barre, Nicolas Hugues, Annabelle Constans, Eric Berton, Christophe Pellegrino, Jérôme Laurin Originally published1 Feb 2021https://doi.org/10.1161/STROKEAHA.120.031873 Stroke. 2021;52:1109–1114 Abstracto Traducido del Original Antecedentes y objetivo: El objetivo es comparar los efectos del entrenamiento en intervalos de alta intensidad (HIIT) con intervalos largos versus cortos sobre la resistencia y el rendimiento motor. Su influencia sobre los marcadores de neuroplasticidad se evalúa en la corteza e hipocampo ipsilesional y contralesional ya que su remodelación podría mejorar la recuperación funcional. Métodos: Las ratas realizaron un HIIT4 adaptado al trabajo (intervalos largos: 4 minutos) o HIIT1 (intervalos cortos: 1 minuto) en una cinta rodante durante 2 semanas después de la oclusión transitoria de la arteria cerebral media. La fuerza de agarre de las extremidades anteriores evaluó la función motora, mientras que las pruebas de ejercicio incrementales midieron el rendimiento de resistencia. Los marcadores clave de neuroplasticidad se evaluaron mediante Western blot. Resultados: Ambos regímenes fueron efectivos para mejorar tanto la velocidad asociada con el umbral de lactato como la velocidad máxima en D8 y D15. Los marcadores de neuroplasticidad se regularon positivamente en el hemisferio contralesional después del entrenamiento contrario al lado ipsilesional. La fuerza de agarre se recuperó por completo, pero es más rápida con HIIT4. Conclusiones: El HIIT con intervalos cortos y largos indujo mejoras tempranas en la aptitud aeróbica y la fuerza de agarre. Nuestros hallazgos revelaron que los marcadores de neuroplasticidad se regularon positivamente en la corteza contralesional y el hipocampo para promover la recuperación funcional. Resumen Sujetos En este estudio se incluyeron 42 ratas Sprague-Dawley macho adultas. Los animales se asignaron aleatoriamente a 4 grupos: los animales se sometieron a la cirugía sin isquemia cerebral (n=12); los animales se sometieron a una oclusion transitoria de la arteria cerebral media sin entrenamiento tMCAO (n=10); y dos grupos que después de oclusion arterial realizaron HIIT con intervalos largos HIIT4 (n=10) o cortos HIIT1 (n=10). tMCAO, puntuación neurológica, fuerza de agarre y pruebas de ejercicio incremental Los ratones fueron sometidos a una oclusion arterial derecha por 2 horas. La recuperación funcional se evaluó midiendo primero la fuerza de agarre de cada miembro anterior y de los miembros anteriores combinados antes y en los dias1, 3, 8 y 15 despues de la oclusion. Se les realizaron pruebas de esfuerzo incrementales en los dias 1, 8 y 15 para definir la velocidad asociada al umbral de lactato (SLT) y la velocidad máxima (Smax; rendimiento de resistencia). Se recogió una muestra de sangre de la vena de la cola después de cada nivel de velocidad para medir la concentración de lactato. HIIT4 y HIIT1 emparejados en la cinta de correr HIIT4 (intervalos largos: 4 minutos) y el HIIT1 (intervalos cortos: 1 minuto) incluyeron 10 sesiones desde el dia 2 hasta el dia 13 despues de la oclusion. Segun los autores, estos protocolos de HIIT pueden extrapolarse fácilmente a los pacientes con esquemia cerebral porque: (1) el entrenamiento se basó en parámetros fisiológicos aplicables en pacientes a partir de una prueba de ejercicio incremental, es decir, velocidad asociada al umbral de lactato y velocidad máxima. (2) la velocidad y la duración se individualizaron de una manera emparejada con el trabajo para permitir dosis de ejercicio comparables (3) el HIIT es seguro durante el período crítico de rehabilitación en pacientes médicamente estables, y (4) la velocidad se incrementó progresivamente añadiendo una prueba incremental intermedia para reevaluar la velocidad de las sesiones. Western Blot En el dia 17 se extrajeron las proteínas totales del hipocampo y la corteza ipsilesional y contralesional para detectar GFAP (proteína ácida fibrilar glial), pTrkB (la forma fosforilada del receptor de tropomiosina quinasa B) p75NTR (receptor de neurotrofina p75), FNDC5 (proteína 5 que contiene dominio de fibronectina tipo III), VEGF (factor de crecimiento endotelial vascular) y CytC (citocromo C). Hallazgos importantes Ambos regímenes de HIIT promueven los marcadores de neuroplasticidad en el hemisferio contralateral, además de un aumento sustancial del rendimiento de resistencia y de la fuerza de agarre. Las mejoras funcionales podrían estar asociadas a los cambios en el hemisferio contralesional. El aumento de la pTrkB y del FNDC5 tras el HIIT podría contribuir a los resultados beneficiosos por su papel en la supervivencia neuronal, la neurogénesis del hipocampo, la plasticidad sináptica y la recuperación funcional. La recuperación efectiva de la fuerza de agarre confirma la necesidad de superar la velocidad asociada al umbral de lactato (SLT) para mejorar la función motora. Sin embargo, una mayor velocidad (HIIT1) no induce mayores ganancias porque se observan beneficios similares entre los regímenes. Curiosamente, el HIIT4 mostró una recuperación más rápida que el HIIT1, lo que sugiere que los intervalos largos podrían ser más adecuados. Esto tiene relevancia clínica, ya que los efectos beneficiosos más tempranos se asocian con frecuencia a una mayor recuperación a largo plazo. Ambos regímenes de HIIT generan una cinética similar de dos fuertes indicadores de calidad de vida, el SLT y el Smax. El SLT está poco estudiado en los pacientes, mientras que su aumento sugiere una reducción de la fatiga inducida por el ejercicio a una velocidad determinada. Las mejoras en el Smax, fuertemente correlacionadas con el consumo máximo de oxígeno, sugieren una mejora de las capacidades aeróbicas. En cuanto a las ganancias de fuerza, el aumento temprano del rendimiento de resistencia (en D8) podría ser prometedor para la recuperación a largo plazo. Al garantizar un estímulo fisiológico suficiente durante el período de entrenamiento, la prueba intermedia también permite observar que las velocidades individualizadas pueden aumentar fuertemente durante la segunda semana. Por lo tanto, la aptitud aeróbica sigue mejorando a lo largo del entrenamiento. Por lo tanto, debería considerarse la reevaluación periódica del rendimiento para optimizar la intensidad del entrenamiento. Por último, los pacientes con ictus podrían utilizar ambos regímenes HIIT en función de sus capacidades aeróbicas/motoras y de sus preferencias de ejercicio sin reducir la relevancia del entrenamiento. Mas Episodios

Paul J. Wang: Welcome to the monthly podcast On the Beat for circulation, arrhythmia, and electrophysiology. I'm Dr. Paul Wang, Editor In Chief, with some of the key highlights from this month's issue.   Elizabeth Wang and Associates examined the relationship between acute precipitants of atrial fibrillation and long-term recurrence of atrial fibrillation, AF, from a multi-institutional, longitudinal electronic medical record database. Among 10,723 patients with newly diagnosed Afib, age 67.9 years, 41% women, the authors found that 19% had an acute AF precipitant, the most common of which were cardiac surgery in 22%, pneumonia in 20% and non-cardiothoracic surgery in 15%. The cumulative incidence of AF recurrence at five years was 41% among individuals with a precipitant, compared to 52% in those without a precipitant. Adjusted hazard ratio 0.75 P < 0.001. The lowest risk of recurrence among those with precipitants with postoperative atrial fibrillation, five-year incidence 32% in cardiac surgery and 39% in non-cardiothoracic surgery. Regardless of the initial precipitant, recurrent atrial fibrillation was associated with an increased adjusted risk of heart failure, hazard ratio of 2.74 P < 0.001, Stroke, hazard ratio 1.57 P < 0.001 and mortality, hazard ratio 2.96 P < 0.001. Thus, the authors found that atrial fibrillation after acute precipitant frequently recurs and the recurrence is associated with substantial long-term morbidity and mortality.   In the next paper, Jacob Koruth and associates examine the effect of pulse field ablation on the esophagus in a novel in-vivo porcine esophageal injury model. The authors studied 10 animals under general anesthesia while the lower esophagus was deflected towards the inferior vena cava using an esophageal deviation balloon and ablation was formed from within the inferior vena cava at areas of esophageal contact. Six animals received eight pulse field ablation applications per site and four animals received six clusters of irrigated radio frequency ablation applications at 30 Watts for 30 seconds. All animals survived to 25 days, sacrificed, and the esophagus was submitted for a pathological examination including 10 discreet histological sections of the esophagus. The authors found that zero out of six pulse field ablation animals demonstrated esophageal lesions while esophageal injury occurred in all four radio frequency ablation animals, P = 0.005. A mean of 1.5 mucosal lesions per animal, length 21.8 millimeters with 4.9 millimeters were observed, including one esophageal pulmonary fistula, and deep esophageal ulcers in the other animals. Histological examination demonstrated tissue necrosis surrounded by an acute and chronic inflammation and fibrosis. The necrotic radio frequency ablation lesions involved multiple esophageal tissue layers with evidence of arteriolar medial thickening and fibrosis of peri-esophageal nerves, abscess formation and full thickness esophageal wall disruption were seen in the areas of perforation or fistula.   In our next paper, Peter Noseworthy and associates examine whether the ability of deep learning algorithms to detect low left ventricular ejection fraction using the 12 lead electrocardiogram varies by race or ethnicity. The authors used a retrospective cohort analysis and included 97,829 patients with paired electrocardiograms and echocardiograms and used a convolutional neural network to identify patients with a left ventricular ejection fraction less than or equal to 35% from the 12 lead electrocardiogram. The convolutional neural network was previously derived in a homogeneous population, 96.2% non Hispanic white, N = 44,959 which demonstrated consistent performance to detect low left ventricular ejection fraction across a range of racial ethnic subgroups in a separate cohort of 52,870 patients (Non-Hispanic white 44,524 patients with an AUC of 0.93; Asian 557 with an AUC of 0.96; Black/African American N = 651 with an AUC of 0.937; in Hispanic/Latino N = 331 AUC of 0.937; in Native American/Alaskan N = 223 AUC of 0.938). In secondary analysis, a separate neural network was able to discern racial subgroup category, Black/African American AUC 0.84 and white non-Hispanic AUC 0.75 in a five-class classifier. In a network trained only in non-Hispanic whites, from the original derivation cohort, performed similarly well across a range of racial ethnic subgroups in the testing cohort with at least an AUC of 0.93 in all racial ethnic subgroups. The authors concluded that while ECG characteristics vary by race, this did not impact the ability of a convolutional neural network to predict low left ventricular ejection fraction from the ECGs. They recommend reporting of performance against diverse ethnic, racial, age, and gender groups for all new artificial intelligent tools.   In our next paper, Benjamin Shoemaker and associates examine the association between atrial fibrillation or AF genetic susceptibility and recurrence after de novo AF ablation, using a comprehensive polygenic risk score for AF in the 10 centers from the AF genetics consortium. AF genetic susceptibility was measured using a previously described a polygenic risk score, N = 929 snips. The overall arrhythmia recurrence rate between 3 and 12 months was 44% in 3,259 patients. Patients with a higher AF genetic susceptibility were younger and have fewer clinical risk factors for atrial fibrillation. Persistent atrial fibrillation has a ratio of 1.39, left atrial size has a ratio of 1.32, and left ventricular ejection fraction per 10% has a ratio of 0.88, were associated with increased risk of occurrence. In unit varied analysis, the authors found that AF genetic susceptibility had a hazard ratio of 1.08 P = 0.07 and in multivariate analysis hazard ratio 1.06 with a P value 0.13.   In our next paper, Mohit Turagam and associates reported the outcomes of the first inhuman value trial, which uses low intensity collimated ultrasound or LICU guided anatomical mapping in robotic ablation to isolate the pulmonary veins for atrial fibrillation ablation. In 52 paroxysmal atrial fibrillation patients, ultrasound M-mode based left atrial anatomies were successfully created and ablation was performed under robotic control along an operated defined lesion path. The operatives found that acute pulmonary vein isolation was achieved in 98% of pulmonary veins using LICU only in 77% of pulmonary veins and requiring touch-up with a standard radio frequency ablation catheter in 23% of the pulmonary veins. The touch up rate decreased to 5.8% in patients undergoing LICU ablation with an enhanced software. Freedom from atrial relational recurrence was 79.6% at 12 months or 92.3%, 12 out of 13 patients with the enhanced software. Major adverse events occurred in three patients or 5.8%. One had transient diaphragmatic paralysis, one vascular access complication and one had transient ST segment elevation from air-embolism without sequelae.   In our next paper, Miguel Rodrigo and associates mapped electrical patterns of disorganization and reasons of reentrant activity in atrial fibrillation, or AF, from the body surface using electrocardiographic imaging. The author examined the bi-atrial intracardiac electrograms of 47 patients at ablation (30 persistent, 29 males, age 63 years) obtained using 64-pole basket catheters while simultaneously recording 57-lead body surface electrocardiogram. The authors found the body surface mapping showed greater atrial fibrillation organization near intracardiac detected drivers and elsewhere, both in phase singularity density in numbers of drivers, they found that complexity defined as a number of stable AF reentrant sites was concordant between the noninvasive and invasive methods. The subset receiving targeted ablation, AF complexity, showed lower values in those in whom AF terminated than in those in whom AF did not terminate, P < 0.01. The authors concluded that AF complexity, assessed noninvasively, correlates well with organized, disorganized regions detected by intracardiac mapping.   In our next paper, Krystien Lieve and Veronica Dusi and associates examined whether heart rate reduction immediately after exercise is regulated by autonomic reflexes, particularly vagal tone and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia, CPVT. In a retrospective observational study, the authors studied 187 patients mean age 36 years, 68 or 36% symptomatic before diagnosis, pre-exercise stress test heart rate and maximal heart rate were equal amongst symptomatic and asymptomatic patients. Patients that were symptomatic prior to diagnosis had a greater delta HRR one prime after a maximum exercise, 43 versus 25, P < 0.001. Corrected for age, gender, and relatedness, patients in the upper tertile for Delta HRR one prime had an odd ratio of 3.4 of being symptomatic before diagnosis, P < 0.001. In addition, Delta HRR one prime was higher in patients with complex ventricular arrhythmias at exercise stress test, off antiarrhythmic drugs. After diagnosis, patients with a Delta HRR one prime in the upper tertile of its distribution, had significantly more rhythmic events as compared to patients and other tertiles, P=0.045. The authors concluded that CPVT patients with a larger heart rate reduction following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during first exercise stress test off antiarrhythmic drugs.   In our next paper, Balvinder Handa and associates examined whether low spatial resolution, sequentially acquired data can be used to examine the global fibrillation organization, characterizing dominant propagating patterns and identifying rotational drivers. The authors employed ranger causality analysis, an econometric tool for quantifying causal relationships between complex time series, which was developed as a novel fibrillation mapping tool and adapted to low spatial resolution sequentially acquired data. Ventricular fibrillation, or VF, optical mapping was performed and Langendorff-perfused Sprague Dawley rat hearts, N = 18. And novel algorithms were developed using Granger causality analysis to quantify causal dependence of neighboring signals and plot Granger causality analysis vectors, quantify global organization using causality pairing index, a measure of neighboring causal signal pairs, and localize rotational drivers by quantifying the circular interdependence of neighboring signals with the circular interdependence value. Granger causality analysis based mapping tools were optimized for low spatial resolution by down sampled optical mapping data validated against high resolution phase mapping analysis and further tested in previous VF optical mapping recordings of coronary perfused donor heart LV wedge preparations, N = 12, and adaptive for sequentially acquired intracardiac electric Grande during human persistent atrial relation mapping, N=16. The authors found that global VF organization quantified by causality pairing index showed a negative correlation at progressively lower resolutions in organized VF with high causality pairing index values. Ranger causality analysis vector mapping characterize dominant propagating patterns and localized stable rotational drivers with the circular interdependence value showing a significant difference in driver versus non driver regions, P = 0.0002. These findings were further confirmed in human VF in persistent atrial fibrillation, a positive correlation was found between causality peri-index and presence of stable rotational drivers. 50% of patients had rotational drivers with a low incidence of 0.9 rotational drivers per patient. In a special report, Piotr Futyma and associates report on the use of bipolar radiofrequency ablation of ventricular arrhythmias originating in the vicinity of the His bundle. Bryce Alexander and associates report in a research letter the patient acceptance of cybersecurity upgrade in ICDs.   That's it for this month. We hope that you'll find the journal to be the go to place for everyone interested in the field. See you next time.   This program is copyright American Heart Association 2020.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.17.384651v1?rss=1 Authors: Joshi, A., Faivre, F., la Fleur, S. E., Barrot, M. Abstract: Dopamine influences food intake behavior. Reciprocally, food intake, especially of palatable dietary items, can modulate dopamine-related brain circuitries. Among these reciprocal impacts, it has been observed that an increased intake of dietary fat results in blunted dopamine signaling and, to compensate this lowered dopamine function, caloric intake may subsequently increase. To determine how dopamine regulates food preference we did 6-hydroxydopamine (6-OHDA) lesions, depleting dopamine in specific brain regions in male Sprague Dawley rats. The food preference was assessed by providing the rats with free choice access to control diet, fat, 20% sucrose and tap water. Rats with midbrain lesions targeting the substantia nigra (which is also a model of Parkinson's disease) consumed fewer calories, as reflected by a decrease in control diet intake, but they surprisingly displayed an increase in fat intake, without change in the sucrose solution intake compared to sham animals. To determine which of the midbrain dopamine projections may contribute to this effect, we next compared the impact of 6-OHDA lesions of terminal fields, targeting the dorsal striatum, the lateral nucleus accumbens and the medial nucleus accumbens. We found that 6-OHDA lesion of the lateral nucleus accumbens, but not of the dorsal striatum or the medial nucleus accumbens, led to increased fat intake. These findings indicate a role for lateral nucleus accumbens dopamine in regulating food preference, in particularly the intake of fat. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.18.388132v1?rss=1 Authors: Guo, Y., Mehabian, Z., Johnson, M. A., Miller, N. R., Henderson, A., Hamlyn, J., Bernstein, S. L. Abstract: Purpose : The rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION) is similar in many of its pathophysiological responses to clinical NAION. However, little is known of the parameters associated with rNAION induction severity and if pre- or early post-induction biomarkers can be identified that enable prediction of lesion severity and ultimate loss of retinal ganglion cells (RGCs). Methods : Adult male Sprague-Dawley outbred rats were evaluated for various parameters including physiological characteristics (heart rate, respiratory rate, temperature, hematocrit), optic nerve head (ONH) appearance, pre- and post-induction mean diameter, and intravenous fluorescein and indocyanine green angiographic patterns of vascular leakage at 5 hours post-induction, performed using a spectral domain-optical coherence tomography (SD-OCT) instrument. These parameters were correlated with ultimate RGC loss by Brn3a (+) immunohistology. RGC loss also was correlated with the relative level of laser exposure. Results : The severity of ONH edema 2d, but not 5hr, post induction was most closely associated with the degree of RGC loss, revealing a threshold effect, and consistent with a compartment syndrome where a minimum level of capillary compression within a tight space is responsible for damage. RGC loss increased dramatically as the degree of laser exposure increased. Neither physiological parameters nor the degree of capillary leakage 5hr post induction were informative as to the ultimate degree of RGC loss. Conclusions : Similar to human NAION, the rNAION model exhibits marked variability in lesion severity. Unlike clinical NAION, pre-induction ONH diameter likely does not contribute to ultimate lesion severity; however, cross-sectional ONH edema can be used as a biomarker 1-2d post-induction to determine randomization of subjects prior to inclusion in specific neuroprotection or neuroregeneration studies. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.09.373993v1?rss=1 Authors: Luo, H., Wang, Q., Wang, L. Abstract: Aims In the present research, we assessed the therapeutic effects of Exendin-4 (Ex-4) on rat models with spinal cord injury (SCI). Materials and methods 36 male Sprague-Dawley rats were randomly allocated into three groups, including sham operation group, SCI group and SCI+Ex-4 group (Ex-4 treatment (10 {micro}g/rat) after SCI, i.p.). In the SCI group, a laminectomy was performed at the T10 vertebrae, followed by weight-drop contusion of the spinal cord. In the sham group, a laminectomy was carried out without SCI contusion. Key findings Our results showed that Basso-Beattie-Bresnahan scale scores were significantly decreased after SCI, and were obviously improved in SCI rats with Ex-4 administration. Additionally, the water content of spinal cord in SCI group was dramatically increased than that in sham group, and after Ex-4 treatment, degree of edema of spinal cord was remarkably reduced. And also, concentration levels of inflammatory cytokines (IL-1, IL-1{beta}, IL-6 and TNF-) in the spinal cord were significantly elevated after SCI, and were remarkably reduced in SCI rats with Ex-4 administration. Subsequently, cell apoptosis rate in the injured spinal cord was significantly increased, and after Ex-4 treatment, cell apoptosis rate was remarkably decreased. We also revealed that levels of PCBP2 mRNA and protein were significantly up-regulated after SCI, and were dramatically dropped in SCI rats with Ex-4 administration. Significance Take altogether, our findings disclosed that Ex-4 plays a role in promoting neurological function recovery and inhibiting neuronal apoptosis through effecting PCBP2 expression in SCI rat models. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.06.370023v1?rss=1 Authors: Schmidt, K. T., Sharp, J. L., Ethridge, S. B., Pearson, T., Ballard, S., Potter, K. M., Smith, M. A. Abstract: Heroin intake decreases during the proestrus phase of the estrous cycle in female, Long-Evans rats. The purpose of this study was to (1) determine if proestrus-induced decreases in heroin intake extend across rat strains and (2) determine if proestrus-induced decreases in responding extend to a nondrug reinforcer. Female rats were implanted with intravenous catheters and trained to self-administer heroin. Estrous cycle was tracked daily for the duration of the study. During testing, Lewis, Sprague-Dawley, and Long Evans rats self-administered low (0.0025 mg/kg) and high (0.0075 mg/kg) doses of heroin (Experiment 1) and then self-administered sucrose (Experiment 2) on fixed ratio (FR1) schedules of reinforcement. Heroin intake decreased significantly during proestrus in all three rat strains under at least one dose condition; however, sucrose intake did not decrease during proestrus in any strain. These data indicate that responding maintained by heroin, but not a nondrug reinforcer, significantly decreases during proestrus in female rats and that these effects are consistent across rat strain. Keywords: opioid; proestrus; reinforcement; self-administration Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.02.365841v1?rss=1 Authors: Nato, A. Q., Ata Ul Mustafa, H., Patel, R. K., Sexton, H. G., Moore, S. D., Denvir, J., Primerano, D. A., Risher, M.-L. Abstract: Introduction: Alcohol use disorder (AUD) is a complex, chronic psychiatric disease. AUD manifests as having uncontrollable drinking patterns with detrimental effects. Excessive alcohol intake in the form of binge drinking, which is common among adolescents and young adults, is associated with increased risk of developing AUD. Here, we analyze RNA-seq data from hippocampi of Sprague Dawley rats to investigate temporal changes in gene expression. We used a rodent model of binge drinking, i.e., adolescent intermittent ethanol (AIE), to identify candidate genes that may play a role in the chronic changes in brain function and contribute to the development of AUD. Methods: At postnatal day (PND) 30 (adolescence), rats received chronic intermittent ethanol (5g/kg intragastrically (i.g.) 10 times across 16 days). We extracted total RNA from rat hippocampal tissue that was collected at three time points. RNA was sequenced on an Illumina HiSeq 2000 platform. We processed RNA-seq data (TrimGalore), compiled gene counts (HTSeq), and performed differential expression analysis (DESeq2). The full rank list of genes and the differentially expressed genes (DEGs) with nominal p

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.02.364927v1?rss=1 Authors: Walker, C. D., Sexton, H. G., Risher, M.-L. Abstract: Introduction: Peer interactions are a crucial part of social and personal development, particularly during adolescence. Adolescence is characterized as a transitional developmental period between childhood and adulthood that is often associated with increased freedom, self-exploration, and new experiences that are often peer-influenced. Due to this newfound independence, there is a higher prevalence of alcohol consumption, which is in part due to the heightened social facilitating and rewarding effects of alcohol. Previous work shows that males and females that consume excessive alcohol during adolescence are at an increased risk of developing an alcohol use disorder (AUD) later in life. However, the contributions of social interaction and sexual dimorphism in alcohol consumption, two driving factors influencing AUD risk, are not fully understood. Currently, there are several rat models used to study the characteristics of alcohol use and the emergence of AUD. However, many require the addition of a sweetener to coerce them into consuming liquid ethanol, which has been proven to confound results in adolescent rats. Here we use a novel self-administration ethanol eVape system to investigate the sexual dimorphic nature of socially facilitated ethanol consumption without the use of sweeteners. Methods: Adolescent and adult male and female Sprague-Dawley rats underwent a novel voluntary chronic intermittent self-administration ethanol vapor paradigm. Nosepoke initiated self-administration eVape chambers (La Jolla Alcohol Research, Inc.) administered 20mg/L of vaporized ethanol or air (control) into the chamber in response to each nose poke. Beginning postnatal day (PND)30 or PND70 animals were placed in vapor chambers for 4 hours every other day for a total of 40 sessions. All animals underwent 10 sessions with their cagemate (social access) followed by 10 sessions in isolation (isolated access), a 10 day forced abstinence period, 10 sessions in isolation (isolated access), and 10 sessions with their cagemate (social access). Results: These data reveal that while female rats consumed more alcohol than age-matched males, male rats increase ethanol preference regardless of age. In addition, all rats regardless of sex or age consumed more ethanol during the first social access session than during the subsequent isolated access sessions. Interestingly, there was an increase in ethanol consumption in adult females during the second social access session compared to the previous isolated access session that was not observed in males. Conclusion: These data demonstrate that female and male rats, regardless of age are vulnerable to socially facilitated ethanol consumption. This is consistent with human data that show increased levels of alcohol consumption among adolescents and young adults is associated with high levels of alcohol use within their social group. However, only male rats demonstrate escalation across sessions. This may indicate that male rats are more vulnerable to escalated drinking and the emergence of ethanol dependence compared to females regardless of peer interaction. These data demonstrate that the self-administration ethanol eVape system is an effective alternative to other methods of voluntary ethanol administration for investigating factors that contribute to alcohol use and escalation. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.12.336941v1?rss=1 Authors: Mukhopadhyay, S., Chatterjee, A., Tiwari, P., Ghai, U., Vaidya, V. A. Abstract: Elevation of serotonin via postnatal fluoxetine (PNFlx) treatment during critical temporal windows is hypothesized to perturb the development of limbic circuits thus establishing a substratum for persistent disruption of mood-related behavior. We examined the impact of PNFlx treatment on the formation and maintenance of perineuronal nets (PNNs), extracellular matrix (ECM) structures that deposit primarily around inhibitory interneurons, and mark the closure of critical period plasticity. PNFlx treatment evoked a significant decline in PNN number, with a robust reduction in PNNs deposited around parvalbumin (PV) interneurons, within the CA1 and CA3 hippocampal subfields at postnatal day 21 in Sprague-Dawley rat pups. While the reduction in CA1 subfield PNN number was still observed in adulthood, we observed no change in colocalization of PV-positive interneurons with PNNs in the hippocampi of adult PNFlx animals. PNFlx treatment did not alter hippocampal parvalbumin, calretinin, or reelin-positive neuron numbers in PNFlx animals at P21 or in adulthood. We did observe a small, but significant increase in somatostatin (SST)-positive interneurons in the DG subfield of PNFlx-treated animals in adulthood. This was accompanied by altered GABA-A receptor subunit composition, increased dendritic complexity of apical dendrites of CA1 pyramidal neurons, and enhanced neuronal activation revealed by increased c-Fos-positive cell numbers within hippocampi of PNFlx-treated animals in adulthood. These results indicate that PNFlx treatment alters the developmental trajectory of PNNs within the hippocampus, raising the possibility of a disruption of critical period plasticity and the establishment of an altered excitation-inhibition balance within this key limbic brain region. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.06.327312v1?rss=1 Authors: Moore, C. F., Davis, C. M., Harvey, E. L., Taffe, M. A., Weerts, E. M. Abstract: Advances in drug vapor exposure systems utilizing e-cigarette technology have enabled evaluation of {Delta}9-tetrahydrocannabinol (THC) vapor effects in laboratory animals. The purpose of this study was to 1) establish a range of parameters of THC vapor exposure in rats sufficient to produce a behavioral dose-effect curve in a battery of tasks sensitive to THC; 2) to investigate sex differences in the effects of THC vapor exposure and THC injection (intraperitoneal, IP) on these behaviors in two strains of outbred rats. Male and female Wistar and Sprague Dawley rats (N=22, 5-6/group) received THC via IP injection (1-20 mg/kg) and passive exposure to THC vapor (200 mg/ml; 5 conditions) in a within subject design. The effects of vaped and injected THC were determined using the tail-withdrawal assay for nociception, rectal measurements of body temperature, and progressive-ratio responding for food pellets. Plasma THC concentrations were assessed after 10 mg/kg IP THC or THC vapor. THC produced dose and exposure-dependent antinociception and hypothermia. THC vapor produced inverted U-shaped effects in motivation to obtain food, while IP THC reduced PR breakpoints. Plasma THC concentrations were higher after 10 mg/kg IP THC (152 ng/mL) compared to the highest vapor exposure condition tested (38 ng/mL). THC vapor exposure produces reliable, dose-orderly effects on nociception, body temperature, and food-maintained behavior that is comparable to effects observed after IP THC. There are considerable differences between the time course of behavioral outcomes produced by these two different routes of administration. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.29.319186v1?rss=1 Authors: Kucharczyk, M. W., Derrien, D., Dickenson, A. H., Bannister, K. Abstract: Pain resulting from metastatic bone disease is a major unmet clinical need. Studying spinal processing in rodent models of cancer pain is desirable since the percept of pain is influenced in part by modulation at the level of the transmission system in the dorsal horn of the spinal cord. Here a rodent model of cancer induced bone pain (CIBP) was generated following syngenic rat mammary gland adenocarcinoma cell injection in the tibia of male Sprague Dawley rats. Disease progression was classified as 'early' or 'late' stage according to bone destruction. Even though wakeful CIBP rats showed progressive mechanical hypersensitivity, subsequent in vivo electrophysiological measurement of mechanically evoked deep dorsal horn spinal neuronal responses revealed no change. Rather, a dynamic reorganization of spinal neuronal modulation by descending controls was observed, and this was maladaptive only in the early stage of CIBP. Interestingly, this latter observation corresponded with the degree of damage to the primary afferents innervating the cancerous tissue. Plasticity in the modulation of spinal neuronal activity by descending control pathways reveals a novel opportunity for targeting CIBP in a stage-specific manner. Finally, the data herein has translational potential since the descending control pathways measured are present also in man. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.29.318204v1?rss=1 Authors: Finney, C. A., Morris, M. J., Westbrook, R. F., Jones, N. M. Abstract: Silent infarcts (SI) are subcortical cerebral infarcts that occur in the absence of clinical symptoms commonly associated with ischemia and are linked to dementia development. Little is known about the pathophysiology underlying the cognitive dysfunction associated with SI, and few studies have examined the early cellular responses and neurobiological underpinnings. We induced SI in adult male Sprague-Dawley rats using an infusion of endothelin-1 in the CA1 dorsal hippocampus. Twenty-four hours later, we assessed cognition using the hippocampal-dependent object place recognition task. We also examined whether the resulting cognitive effects were associated with common markers of ischemia, specifically cell and synapse loss, gliosis, and inflammation, using histology and immunohistochemistry. Hippocampal SI led to subtle cognitive impairment on the object place recognition task 24-hours post-injury. This was characterized by a significant difference in exploration proportion relative to a pre-injury baseline and a positive association between time spent with both the moved and unmoved objects. SI did not result in any detectable cell or synaptophysin loss, but did increase apoptosis, gliosis and inflammation in the CA1. Principal component analysis indicated the main variables associated with hippocampal SI included increased time spent with the unmoved object, gliosis, apoptosis and inflammation as well as decreased exploration proportion and CA1 cells. Our data demonstrate that hippocampal SI can lead to cognitive dysfunction 24-hours after injury. Further, this appears to be driven by early degenerative processes including apoptosis, gliosis and inflammation, suggesting that these may be targets for early interventions treating hippocampal SI and its cognitive consequences. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.23.310342v1?rss=1 Authors: Shallcross, J., Wu, L., Knackstedt, L., Schwendt, M. Abstract: Post-traumatic stress disorder (PTSD) develops in a subset of individuals exposed to a trauma with core features being increased anxiety, and impaired fear extinction. To model the heterogeneity of PSTD behavioral responses, we exposed Sprague-Dawley rats to predator scent stress (TMT) once for 10 minutes and then tested for anxiety-like behavior 7 days later using the elevated plus-maze and acoustic startle response. Rats displaying anxiety-like behavior in both tasks were classified as stress-Susceptible, and rats exhibiting behavior no different from unstressed Controls were classified as stress-Resilient. Our previous findings revealed increased mRNA expression of mGlu5 in the amygdala and PFC and CB1R mRNA in the amygdala of Resilient rats. Here, we performed fluorescent in situ hybridization (FISH) to determine the subregion and celltype-specific expression of these genes in Resilient rats. We found higher mRNA expression of mGlu5 in the BLA, IL, and PL, and CB1R in the BLA of Resilient rats relative to Controls. Using dual-labeled FISH we determined that mGlu5 and CB1R mRNA increases were limited to vGlut+ cells. To test the necessity of mGlu5 receptor activity for attenuating contextual fear, intra-BLA infusions of the mGlu5 negative allosteric modulator MTEP were administered prior to context re-exposure. MTEP increased contextual fear on the day of administration, which extinguished over the course of two additional un-drugged sessions. These results suggest that an enhanced mGlu5 expression within BLA glutamate neurons contributes to the behavioral flexibility observed in stress-Resilient animals by facilitating a capacity for extinguishing contextual fear associations. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.31.276253v1?rss=1 Authors: Blackwood, C. A., McCoy, M. T., Ladenheim, B., Cadet, J. L. Abstract: To identify signaling pathways activated by oxycodone self-administration (SA), Sprague-Dawley rats self-administered oxycodone for 20 days using short-access (ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized two hours after SA cessation and dorsal striata were used in post-mortem molecular analyses. LgA rats escalated their oxycodone intake and separated into lower (LgA-L) or higher (LgA-H) oxycodone takers. LgA-H rats showed increased striatal protein phosphorylation of ERK1/2 and MSK1/2. Histone H3, phosphorylated at serine 10 and acetylated at lysine 14 (H3S10pK14Ac), a MSK1/2 target, showed increased abundance only in LgA-H rats. RT-qPCR analyses revealed increased AMPA receptor subunits, GluA2 and GluA3 mRNAs in the LgA-H rats. GluA3, but not GluA2, expression correlated positively with changes in pMSK1/2 and H3S10pK14Ac. Our findings indicate that escalated oxycodone SA results in MSK1/2-dependent histone phosphorylation, which promoted increases in striatal gene expression. Our observations offer novel avenues for pharmacological interventions against oxycodone addiction. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.11.246165v1?rss=1 Authors: Toossi, A., Bergin, B., Marefatallah, M., Parhizi, B., Tyreman, N., Everaert, D. G., Rezaei, S., Seres, P., Gatenby, J. C., Perlmutter, S. I., Mushahwar, V. K. Abstract: The overall goal of this work was to create a high-resolution MRI atlas of the lumbosacral enlargement of the spinal cord of the rat (Sprague-Dawley), cat, domestic pig, rhesus monkey, and human. These species were chosen because they are commonly used in basic and translational research in spinal cord injuries and diseases. Six spinal cord specimens from each of the studied species (total of 30 specimens) were fixed, extracted, and imaged. Sizes of the spinal cord segments, cross-sectional dimensions, and locations of the spinal cord gray and white matter were quantified and compared across species. The obtained atlas establishes a reference for the neuroanatomy of the intact lumbosacral spinal cord in these species. It can also be used to guide the planning of surgical procedures of the spinal cord, technology design and development of spinal cord neuroprostheses, and the precise delivery of cells/drugs into target regions within the spinal cord parenchyma. Copy rights belong to original authors. Visit the link for more info

Podcast Editor, Tracy Carlson, interviews author Kristen Hobbie to discuss the article, "Evaluation of Cystic Endometrial Hyperplasia and the Normal Estrous Cycle in Longitudinal Sections of Uterus from Female Harlan Sprague-Dawley Rats" which can currently be found in Vol. 48, Issue 5 of Toxicologic Pathology. Click here to read the article

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.22.215947v1?rss=1 Authors: Rouzer, S. K., Diaz, M. R. Abstract: Adolescents are phenotypically characterized with hyper-sensitivity to stress and inappropriate response to stress-inducing events. Despite behavioral distinctions from adults, investigations of developmental shifts in the function of stress peptide corticotrophin-releasing factor (CRF) are generally limited. Rodent models have determined that CRF receptor 1 (CRFR1) activation within the central amygdala is associated with a stress response and induces increased GABAergic synaptic neurotransmission within adult males. To investigate age-specific function of this system, we performed whole-cell patch clamp electrophysiology in brain slices from naive adolescent (postnatal days (P) 40-49) and adult (>P70) male and female Sprague Dawley rats to assess GABAergic activity in the medial central amygdala (CeM). Our results indicate a dynamic influence of age and sex on neuronal excitability within this region, as well as basal spontaneous and miniature (m) inhibitory post-synaptic currents (IPSCs) in the CeM. In addition to replicating prior findings of CRFR1-regulated increases in mIPSC frequency in adult males, we found that the selective CRFR1 agonist, Stressin-1, attenuated mIPSC frequency in adolescent males, at a concentration that did not affect adult males. Importantly, this age-specific distinction was absent in females, as Stressin-1 attenuated mIPSC frequency in both adolescent and adult females. Finally, only adult males exhibited an increase in mIPSC frequency in response to the CRF1R antagonist, NBI 35965, suggestive of tonic CRFR1 activation in the CeM of adult males. Together, these data emphasize the robust influence of age and sex on neurophysiological function of a brain region involved in the production of the stress response. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.08.193383v1?rss=1 Authors: Laura Luyten, Anna Elisabeth Schnell, Natalie Schroyens, Tom Beckers Abstract: When retrieved under specific circumstances, consolidated fear memories are thought to return to a labile state, thereby opening a window for modification (e.g., attenuation) of the memory. Several interventions during a critical time frame after this destabilization seem to be able to alter the retrieved memory, for example through pharmacological interference with the restabilization process, either by direct protein synthesis inhibition or indirectly, using drugs that can be safely administered in patients (e.g., propranolol).In a series of well-powered auditory fear conditioning experiments (four with propranolol, 10 mg/kg, two with rapamycin, 20-40 mg/kg, one with anisomycin, 150 mg/kg and cycloheximide, 1.5 mg/kg), we found no evidence for reduced cued fear memory expression during a drug-free test in adult male Sprague-Dawley rats that had previously received a systemic drug injection upon retrieval of the tone fear memory. All experiments used standard fear conditioning and reactivation procedures with freezing as the behavioral read-out (conceptual or exact replications of published reports) and common pharmacological agents. Additional tests confirmed that the applied drug doses and administration routes were effective in inducing their conventional effects on expression of fear (propranolol, acutely), body weight (rapamycin, anisomycin, cycloheximide) and consolidation of extinction memories (cycloheximide).Thus, in contrast with most published studies, we did not find evidence for drug-induced post-retrieval amnesia, underlining that this effect, as well as its clinical applicability, may be considerably more constrained and less readily reproduced than what the current literature would suggest.HighlightsWe aimed to replicate post-retrieval amnesia for auditory fear memories in ratsWe performed a series of well-powered pharmacological interference experimentsPropranolol, rapamycin, anisomycin or cycloheximide was injected upon retrievalBayesian stats found substantial evidence for the absence of post-retrieval amnesiaThe effect is less reproducible and generalizable than what the literature suggestsCompeting Interest StatementThe authors have declared no competing interest.View Full Text Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.07.191213v1?rss=1 Authors: jiang, c., Zeng, J., Zeng, S., Lindström, S. Abstract: Background : The aims of this study was determine if stimulation of tibial nerve afferents could induce a prolonged modulation of the micturition reflex in the rats. Methods: Fifteen female Sprague Dawley rats (250-350 g) were fully decorticated and paralysed for the study. Tibial nerve stimulation (TNS) was delivered by inserting two pairs of needle electrodes close to the nerves at the level of the medial malleolus. Constant flow cystometries (0.07 ml/min) at about 10 min interval were performed and the micturition threshold volume (MTV) was recorded and used as the dependent variable. After 4 - 5 stable control recordings, the tibial nerves of both sides were stimulated continuously for 5 min at 10 Hz, 3 times threshold for -motor axons. Six times of same stimulation were applied repeatedly with an interval of 5 min between the stimulations. The mean MTV was compiled from several cystometries in each half hour before the TNS and during, after 6 periods TNS. Results: During the experiment, all the animals survived in a good condition with reasonably stable micturition reflexes, a significant increase in MTV was revealed after TNS. The best effect (mean 178%) occurred during the first 30 min after 6 periods of stimulation. This clear threshold increase remained for at least 5 h. Conclusions: A prolonged increase in MTV was demonstrated by a short periods of TNS repeatedly. This post stimulation modulatory effects of micturition reflex would provide a theoretical explanation for the clinical beneficial effect of TNS in patients with overactive bladder (OAB). Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.29.178236v1?rss=1 Authors: Marti-Prats, L., Belin-Rauscent, A., Fouyssac, M., Puaud, M., Cocker, P. J., Everitt, B. J., Belin, D. Abstract: While most individuals with access to alcohol drink it recreationally, about 5% lose control over their intake and progressively develop an alcohol use disorder (AUD), characterised by compulsive alcohol drinking accompanied by decreased interest in alternative sources of reinforcement. The neural and molecular mechanisms underlying the vulnerability to switch from controlled to compulsive alcohol intake have not been fully characterized, so limiting the development of new treatments for AUD. It has recently been shown that rats having reduced levels of expression of the gamma-aminobutyric acid (GABA) transporter, GAT-3, in the amygdala tend to persist in seeking and drinking alcohol even when adulterated with quinine, suggesting that pharmacological interventions aimed at restoring GABA homeostasis in these individuals may provide a targeted treatment to limit compulsive alcohol drinking. Here, we tested the hypothesis that the GABAB receptor agonist baclofen, which decreases GABA release, specifically decreases compulsive alcohol drinking in vulnerable individuals. In a large cohort of Sprague-Dawley rats allowed to drink alcohol under an intermittent two-bottle choice procedure, a cluster of individuals was identified that persisted in drinking alcohol despite adulteration or the availability of an alternative ingestive reinforcer, saccharin. In these rats, that were characterised by decreased GAT-3 mRNA levels in the central amygdala, acute baclofen administration (1.5 mg/kg, intraperitoneal) resulted in a decrease in compulsive drinking. These results indicate that low GAT-3 mRNA levels in the central amygdala represent an endophenotype of AUD and that the associated compulsive alcohol drinking characteristic is sensitive to baclofen. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.22.165811v1?rss=1 Authors: Przybysz, K. R., Gamble, M. E., Diaz, M. R. Abstract: Adolescent alcohol exposure is associated with many negative outcomes that persist into adulthood, including altered affective and reward-related behaviors. However, the long-term neurological disruptions underlying these behavioral states are not fully understood. The basolateral amygdala (BLA) plays a critical role in many of these behaviors, and shifts in the excitatory/inhibitory balance in this area are capable of directly modulating their expression. While changes to BLA physiology have been demonstrated during the acute withdrawal phase following adolescent ethanol exposure, no studies to date have examined whether these persist long-term. The kappa opioid receptor (KOR) system is a neuromodulatory system that acts as a prominent mediator of negative affective behaviors, and alterations of this system have been implicated in the behavioral profile caused by chronic alcohol exposure in adulthood. Notably, in the BLA, the KOR system undergoes functional changes between adolescence and adulthood, but whether BLA KORs are functionally disrupted by adolescent ethanol exposure has not been examined. In this study, we exposed male and female Sprague-Dawley rats to a vapor inhalation model of moderate adolescent chronic intermittent ethanol (aCIE) and examined the long-term effects on GABAergic and glutamatergic neurotransmission within the adult BLA using whole-cell patch-clamp electrophysiology. We also assessed how KOR activation modulated these neurotransmitter systems in aCIE versus control rats using the selective KOR agonist, U69593. This investigation revealed that aCIE exposure disrupted basal glutamate transmission in females by increasing spontaneous excitatory postsynaptic current (sEPSC) frequency, while having no effects on glutamate transmission in males or GABA transmission in either sex. Interestingly, we also found that aCIE exposure unmasked a KOR-mediated suppression of spontaneous inhibitory postsynaptic current (sIPSC) frequency and sEPSC amplitude only in males, with no effects of aCIE exposure on KOR function in females. Together, these data suggest that moderate-level adolescent ethanol exposure produces long-term changes to BLA physiology and BLA KOR function, and that these changes are sex-dependent. This is the first study to examine persistent adaptations to both BLA physiology and KOR function following adolescent alcohol exposure, and opens a broad avenue for future investigation into other neurobiological and behavioral consequences of adolescent ethanol exposure-induced disruptions of these systems. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.11.146837v1?rss=1 Authors: Borrell, J. A., Krizsan-Agbas, D., Nudo, R. J., Frost, S. B. Abstract: Objective. The purpose of this study was to determine the effects of spinal cord injury (SCI) on spike activity evoked in the hindlimb spinal cord of the rat from cortical electrical stimulation. Approach. Adult, male, Sprague Dawley rats were randomly assigned to a Healthy or SCI group. SCI rats were given a 175 kDyn dorsal midline contusion injury at the level of the T8 vertebrae. At four weeks post-SCI, intracortical microstimulation (ICMS) was delivered at several sites in the hindlimb motor cortex of anesthetized rats, and evoked neural activity was recorded from corresponding sites throughout the dorsoventral depths of the spinal cord and EMG activity from hindlimb muscles. Main results. In healthy rats, post-ICMS spike histograms showed reliable, evoked spike activity during a short-latency epoch 10-12 ms after the initiation of the ICMS pulse train (short). Longer latency spikes occurred between ~20-60 ms, generally following a Gaussian distribution, rising above baseline at time LON, followed by a peak response (Lp), and then falling below baseline at time LOFF. EMG responses occurred between LON and Lp (25-27 ms). In SCI rats, short-latency responses were still present, long-latency responses were disrupted or eliminated, and EMG responses were never evoked. The retention of the short-latency responses indicates that spared descending spinal fibers, most likely via the cortico-reticulospinal pathway, can still depolarize spinal cord motor neurons after a dorsal midline contusion injury. Significance. This study provides novel insights into the role of alternate pathways for voluntary control of hindlimb movements after SCI that disrupts the corticospinal tract in the rat. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.11.146910v1?rss=1 Authors: Borrell, J. A., Krizsan-Agbas, D., Nudo, R. J., Frost, S. B. Abstract: Objective: The purpose of this study was to assess the ability of intraspinal microstimulation, triggered by action potentials (spikes) recorded in motor cortex, to alter synaptic efficacy in descending motor pathways in an anesthetized rat model of spinal cord injury. Approach. Experiments were carried out in adult, male, Sprague Dawley rats with a moderate contusion injury at T8. Four weeks after SCI, and under ketamine/xylazine anesthesia, fine wire electromyographic (EMG) electrodes were implanted into four muscles of the right hindlimb. After exposure of the left motor cortex hindlimb area and laminectomy of the T13-L1 vertebrae, intracortical microstimulation (ICMS) and intraspinal microstimulation (ISMS) were used to determine the location of evoked hip movements in cortex and spinal cord, respectively. For activity-dependent stimulation sessions, a single shank, 16-channel, recording microelectrode was used to detect neuronal spikes in motor cortex that triggered ISMS in the spinal cord grey matter. Spinal cord injured rats were randomly assigned to one of four experimental groups differing by: a) cortical spike-ISMS stimulus delay (10 or 25 ms) and b) number of ISMS pulses (1 or 3). Activity-dependent stimulation sessions were conducted in three consecutive 1-hour conditioning bouts for a total of 3 hours. At the end of each conditioning bout, changes in synaptic efficacy were assessed using ICMS to examine the number of spikes evoked in spinal cord neurons during five minute test bouts. Evoked spikes were recorded, sorted, and displayed in post-stimulus spike histograms in 1-ms bins. Post-stimulus spike histograms and EMG recordings were characterized using stimulus triggered averaging techniques. Main results: The results showed that activity-dependent stimulation resulted in an increase in cortically-evoked spikes in spinal cord neurons at specific combinations of spike-ISMS delays and numbers of pulses. Efficacy in descending motor pathways was increased throughout all dorsoventral depths of the hindlimb spinal cord, including the ventral horn, in the vicinity of motor neurons. Changes were evident in some conditions as early as 1 hour after conditioning. EMG responses were never evoked with ICMS pre-or post-conditioning. Significance: These results show that after a spinal cord contusion injury, activity-dependent stimulation, consisting of cortical spike-driven ISMS, can increase synaptic efficacy in spared pathways between motor cortex and spinal cord. This suggests that activity-dependent stimulation may serve as an effective therapeutic approach for enhancing descending motor control after spinal cord injury. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.21.108530v1?rss=1 Authors: Siemsen, B. M., Hooker, K. N., McFaddin, J. A., Carpenter, E. A., Prescott, M. E., Brock, A. G., Leath, M. N., McGinty, J. F., Scofield, M. D. Abstract: Both clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission underlie heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce linked molecular and cellular adaptations in both astrocytes and neurons in the nucleus accumbens (NA) core that are required for cued relapse. For example, decreased expression of the glutamate transporter GLT-1 and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate overflow from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Importantly, normalizing heroin-induced GLT-1 downregulation prevents glutamate overflow, medium spiny neuron plasticity, and relapse. Surprisingly, little is known about heroin-induced alterations in cortical astroglia and their interaction with neurons. Here we show that heroin SA followed by extinction leads to increased astrocyte complexity and association with synaptic markers in the PrL cortex in male Sprague-Dawley rats. Enhanced astroglial complexity and synaptic interaction were reversed during extinction by repeated treatment with N-acetylcysteine (NAC), an antioxidant drug previously shown to inhibit heroin seeking. We also show that dendritic spines of PrL cortical neurons projecting to the NAcore are enlarged, yet the density of spines is decreased, after extinction from heroin SA. Repeated NAC treatment prevented the decrease in spine density but not dendritic spine expansion. These results reveal circuit-level adaptations in cortical dendritic spine morphology that are related to heroin-induced alterations in astrocyte complexity and association at synapses and demonstrate that NAC reverses cortical heroin-induced adaptations in multiple cell types. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.11.088732v1?rss=1 Authors: Westbrook, S. R., Gulley, J. M. Abstract: Previous work suggests adolescent rats have deficient extinction consolidation relative to adults. Although the mechanisms underlying this age difference are currently unknown, studies in adult rats have implicated GluN2B-containing NMDA receptor function in extinction consolidation of drug-associated memory. Importantly, GluN2B neurotransmission emerges during adolescent development, and drugs of abuse during adolescence may delay the development of extinction consolidation by disrupting the ontogeny of GluN2B function. Here, we trained Sprague-Dawley rats of both sexes to self-administer methamphetamine (METH, 0.1 mg/kg/infusion i.v.) beginning during adolescence [postnatal (P) day 41] or adulthood (P91). Rats were given short access (2 h) to self-administer METH in seven daily sessions followed by fourteen sessions with long access (6 h). Subsequently, rats underwent four daily 30-min extinction sessions with immediate post-session injections of either a GluN2B antagonist (Ro25-6981; 6 mg/kg, i.p.) or a vehicle solution. After four daily 2-h extinction sessions, a priming injection (1 mg/kg METH, i.p.) was given prior to a final 2-h reinstatement session. During LgA, adolescent-onset rats earn more METH than adult-onset rats and display greater drug-loading behavior. Rats reduced their drug-seeking behavior across extinction sessions, with no significant group differences. Rats reinstated drug-seeking following the METH priming injection, with females displaying greater reinstatement than males. These results do not support our a priori hypothesis that adolescent-onset METH use disrupts the ontogeny of GluN2B transmission and contributes to age-of-onset differences in extinction of METH-seeking. However, our findings suggest that age-of-onset contributes to compulsive METH-taking, while sex confers vulnerability to relapse to METH-seeking. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.25.061176v1?rss=1 Authors: Bilchak, J. N., Yeakle, K., Caron, G., Malloy, D. C., Cote, M.-P. Abstract: After spinal cord injury (SCI), the majority of individuals develop spasticity, a debilitating condition involving involuntary movements, co-contraction of antagonistic muscles, and hyperreflexia. By acting on GABAergic and Ca2+-dependent signaling, current anti-spastic medications lead to serious side effects, including a drastic decrease in motoneuronal excitability which impairs motor function and rehabilitation efforts. Exercise, in contrast, decreases spastic symptoms without decreasing motoneuron excitability. These functional improvements coincide with an increase in expression of the chloride co-transporter KCC2 in lumbar motoneurons. Thus, we hypothesized that spastic symptoms can be alleviated directly through restoration of chloride homeostasis and endogenous inhibition by increasing KCC2 activity. Here, we used the recently developed KCC2 enhancer, CLP257, to evaluate the effects of acutely increasing KCC2 extrusion capability on spastic symptoms after chronic SCI. Sprague Dawley rats received a spinal cord transection at T12 and were either bike-trained or remained sedentary for 5 weeks. Increasing KCC2 activity in the lumbar enlargement improved the rate-dependent depression of the H-reflex and reduced both phasic and tonic EMG responses to muscle stretch in sedentary animals after chronic SCI. Furthermore, the improvements due to this pharmacological treatment mirror those of exercise. Together, our results suggest that pharmacologically increasing KCC2 activity is a promising approach to decrease spastic symptoms in individuals with SCI. By acting to directly to restore endogenous inhibition, this strategy has potential to avoid severe side effects and improve the quality of life of affected individuals. Copy rights belong to original authors. Visit the link for more info

In this podcast, Editorial Board member Elizabeth McInnes invites authors Evan Janovitz and Magnus Söderberg to discuss their article "Evaluation of Uracil, Sodium Ascorbate, and Rosiglitazone as Promoters of Urinary Bladder Transitional Cell Carcinomas in Male Sprague-Dawley Rats" featured in the February 2018 issue of Toxicologic Pathology.   Click here to read the article.

In this podcast, Associate Editor Kevin Keane and author James "Rick" Hailey discuss his article "A Diagnostic Approach for Rodent Progressive Cardiomyopathy and Like Lesions in Toxicology Studies up to 28 Days in the Sprague Dawley Rat (Part 1 of 2)" currently featured in Toxicologic Pathology's Online First queue.    Click here to read the article. 

In Episode 143 of The Real Food Reel we are joined by Chiropractor, health advocate and self-confessed biohacker, Dr Anthony Gustin. In today's episode we discuss the paleo diet, the ketogenic diet, fasting, biohacking, exogenous ketones and so much more. This is a must listen episode for anyone interested in optimizing their health. Show Notes Follow Dr Gustin online: http://www.dranthonygustin.com Learn more about Perfect Keto & try our Perfect Keto Bulletproof here: https://www.thenaturalnutritionist.com.au/perfect-keto-bulletproof-coffee/ Research into exogenous ketones: Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743170/ Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer: https://www.ncbi.nlm.nih.gov/pubmed/24615175  Metabolic effects of exogenous ketone supplementation – an alternative or adjuvant to the ketogenic diet as a cancer therapy?: http://www.fasebj.org/content/30/1_Supplement/1167.2 The post RFR 143: Biohacking, Fasting & Exogenous Ketones with Dr Anthony Gustin appeared first on The Wellness Couch.

There are very few people who I consider to be personal mentors, extremely trustworthy individuals in my life who I can look to for fitness, health and longevity advice, or people who I think put out truly "cutting-edge" health information. is one of those people. Dr. Mercola is a board certified family physician who had seen tens of thousands of patients before transitioning to a full time internet journalist, as he felt he could help far more people than he could in private practice. It turns out he was right...because every month he has ten million unique visitors and 80 million unique visitors each year.  has been the most visited natural health site for the last 12 years and is now translated into six different languages. Dr. Mercola's passion is optimizing mitochondrial health, and during today's discussion, you'll discover: -How Dr. Mercola built Mercola.com into one of the most popular health websites in the world...[14:00] -Dr. Mercola's unique system that allows him to digest dozens of books each month while taking a quarter billion+ steps over his lifetime...[19:15] -Why you should wear blue light blocking glasses during the day, not just at night...[24:30] -How to ground your computer and keep your laptop and monitor from destroying your health...[26:35 & 35:20] -Why Dr. Mercola eats both seafood and one surprising compound found in seafood every day of the week...[29:20] -The little-known biohacks Dr. Mercola uses to maximize his mitochondrial density...[36:50] -Why scrambled eggs are very bad for you, and what you can do about it...[41:30] -The myth about iron levels and a crucial test you must take to keep iron from "rusting out" your body...[53:55] -The best book Dr. Mercola has ever read on strength training, and how he combines it with a special hack called "EWOT"...[20:20 & 79:10] -Dr. Mercola's take on whether or not quantification devices like rings and wristbands are good or bad for you, and what he personally uses...[60:45] -Why Dr. Mercola limits protein intake, and how he strikes a balance between anti-aging effects of muscle and aging effects of too much protein...[67:30] -How to make your own "anti-aging" cocktail...[72:30] -A unique one-two combo you can use prior to saunas to maximize your detoxification, fat burn and fat cell death...[75:10] -Two ingredients Dr. Mercola sprinkles on his garden soil to get 10x+ production of cherries, organic produce and more...[87:40] -The liquid dropper that Dr. Mercola takes on every airplane ride...[94:10] -And much more! Resources from this episode: - - - - -The book "" by Kelly Starrett - - - - - - - - - - - - - - - - - - - - - - - -This one-two combination of and pre-sauna -. - - - - - Do you have questions, comments or feedback for Dr. Mercola or me? Leave your thoughts at  and one of us will reply! ------------------------- Addendum: Ben's notes on the DeltaSleeper/PEMF discussion: The info below regarding the does not take a genius to figure out. The Ramazzini team followed what is commonly known as an initiation-promotion protocol. Male and female Sprague-Dawley rats were exposed in their mothers’ wombs and then for the rest of their lives to 50 Hz magnetic fields at an intensity of either 20μT or 1,000μT (200 mG or 10 G). At the age of six weeks, they each received a single 0.1Gy dose of gamma radiation, a known cancer agent. So let's take a look at what we have here. 1. The six week old rats were given a single 0.1 Gy dose of Gamma radiation. A KNOWN cancer agent. Gamma rays are classified as ionizing. This means they have the power to cause permanent cellular damage. See Below: Primer on Electromagnetic Fields. 2. They were exposed continuously for the rest of their lives to 50Hz magnetic fields at either 200 milliGauss or 10 Gauss fields. This is completely unnatural. The Earth's magnetic field is 3-6 milliGaus (0.3-0.6 Gauss). The SR1 creates a field exactly within this natural range. I don't believe the 50Hz magnetic pulse itself would cause any damage however the SR1 device provides a much lower frequency pattern. So basically, these rats did not stand a chance of not developing cancer. Further into the report we find the following from Fiorella Belpoggi, the Scientific Director of the Institute who notes that: "No Cancer Seen with EMFs Alone" In an interview, Belpoggi said that they are planning to publish the results of a concurrent experiment in which rats were exposed to power-frequency EMFs, without any other treatment. “In our preliminary data, ELF EMFs alone didn’t appear to show an increase of cancer in experimental animals so far,” she disclosed. "The main result of our experiment,” she said, is that “ELF EMFs have a synergistic effect: They are able to enhance the effects of a well-known carcinogen at low doses that was negative at those doses in the same experimental model." It's important to understand the difference between EMF's in something like a DeltaSleeper and EMF's from higher power devices, so keep reading... ...EMFs are classified as ionizing or non-ionizing according to their frequency. Ionizing fields have very short wavelengths and frequencies between 1016 Hz. and 1023 Hz. These fields are above visible light on the electromagnetic spectrum (1015 Hz.) and include cosmic rays, gamma rays and X-rays which have the power to knock electrons off their nuclear orbits and cause permanent cellular damage. Non-ionizing fields have longer wavelengths and frequencies below 1014 Hz. Although they have less power than ionizing fields they are still capable of having biologic effects. Important EMF modalities in medicine today are non-thermal applications of non-ionizing radiation. Medical applications of non-thermal, non-ionizing EM fields include non-union fracture bone repair, neuronal stimulation, nerve stimulation, tissue regeneration, immune system stimulation, osteoarthritis therapy, wound healing etc. Non-ionizing fields are classified as thermal, which means in biological terms, causes gross tissue heating, or non-thermal, indicating no gross tissue heating is involved. And the SR1 Device is a non-ionizing, non-thermal device. Furthermore, is switched on for just 22 minutes per use. The Earth's magnetic field ranges from 0.3 Gauss - 0.6 Gauss. The SR1 Device field strength falls within this range. They are in effect "Copying Nature" with that technology.  

Two brilliant scientists are racing to be the first to commercialise exogenous ketones. The applications include athletic performance and metabolic therapies for CNS oxygen toxicity, epilepsy, and neurodegenerative diseases. In the red corner, Dr. Richard Veech, one of the greatest living minds in basic biochemistry. In the blue corner, the also brilliant renegade chemist Patrick Arnold. Stuck somewhere in the middle is superhuman researcher Dominic D’Agostino, associate professor in the department of molecular pharmacology and physiology at the University of South Florida, and a visiting research scientist at the IHMC. Patrick clearly has the head start, and I’ve been supplementing with his KetoForce and KetoCaNa products for over two years for bike races. Imagine my horror then when Dr. Veech appeared on the Bulletproof and Ben Greenfield podcasts to claim that Patrick’s racemic ketone salts were “harmful and inhibitory” and “a dumb for convenience of manufacturing”. Caution is warranted. A racemic mixture is one that includes both the D and L enantiomers. The source of the D and L labels was the Latin words dexter (on the right) and laevus (on the left). You may also have seen the labels R and S. R comes from rectus (right-handed) and S from sinister (left-handed). The physiological form of beta-hydroxybutyrate (BHB) is the D form. This is the same reason why Tommy would never recommend synthetic vitamins (vitamin E is a good example), because you get a racemic mixture and the inactive form tends to inhibit the more active form. L-BHB is also metabolised. BHB is not like the synthetic vitamins. Through some elegant radiotracer studies, Dr. Veech’s colleague  Dr. Henri Brunengraber showed that the L-form is neither harmful nor inhibitory, and is also metabolised and converts to acetoacetate and back to D-BHB. The conversion is less efficient from the L-form, and relatively more of it is used for lipid synthesis and direct oxidation. 100% D-BHB might be better than a racemic mixture, but it’s not harmful or inhibitory. As Dominic points out, racemic compounds have anti-seizure, anti-cancer and anti-inflammatory effects. If this all sounds a bit cloak and dagger. It’s because it probably is. After an in depth conversation and then interview for the Keto Summit, Professor Kieran Clarke of Oxford University made a compelling case for the D-BHB ester that has yet to be commercialised. My feeling is that her and Dr. Veech have a superior product, but that Dr. Veech’s recent comments about racemic mixtures are anticompetitive opinion not backed up by evidence. Is Dominic completely neutral in all this? Probably not. See US patent US20140350105 and US20140073693 (Savind, Inc is Patrick Arnold’s company). Are we neutral? Nope. We sell an MCT oil powder! Do you have questions for Dominic or Patrick? Please leave them in the comments section below then sign up for the Keto Summit and I’ll do my best to ask the experts when I interview them next month. Also see the two new excellent podcast interviews with Dominic on STEM-Talk and The Quantified Body. Here’s the outline of this interview with Dr. Tommy Wood: 0:00:20    Podcast: Bulletproof Radio. 0:00:26    Podcast: Ben Greenfield. 0:01:10    Dr. Richard Veech. 0:02:28    1995 paper: Insulin, ketone bodies, and mitochondrial energy transduction. 0:03:08    Prototype Nutrition. 0:07:37    Atrial natriuretic peptide. 0:08:10    KetoCaNa. 0:10:04    Dominic and Patrick’s study Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. 0:13:19    Khan Academy: Stereochemistry. 0:15:03    D-L-alpha tocopherol. 0:22:32    NAD+/NADH ratios. See The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling Pathways. 0:22:35    Ubiquinone. 0:23:25    Khan Academy: ATP hydrolysis: Gibbs free energy. 0:25:13    28% increase in cardiac efficiency 0:33:12    Dr. Mary Newport. 0:33:25    Steve Newport case study. 0:35:07    Sirtuins. 0:35:41    Lactate and pyruvate. 0:41:52    Kraft dried blood spot oral glucose tolerance test with insulin. 0:44:35    PHAT FIBRE hypoallergenic MCT oil powder. 0:44:56    Concierge Clinical Coaching private membership group.

„Investigations on effects of Xenon application time on cerebral outcome following cardiopulmonary bypass with cerebral air embolism in the rat” Cerebral air embolism (CAE) is thought to be one of the risk factors for adverse cerebral outcome following cardiac surgery with cardiopulmonary bypass (CPB). Neurologic and neurocognitive deficits after cardiac surgery remain a common and severe complication, alleviating patients´ quality of life for years. Providing neuroprotective properties and cardiovascular stability Xenon may also improve cerebral outcome after cardiac surgery with CPB. However, Xenon`s disposition to expand air bubbles could possibly be a disadvantage for its use in combination with CPB, as such air bubbles can be detected during CPB. In this study Xenon was administered before (group XEv), during (group XEw) or after CPB (group XEn) to investigate differential effects of application time on cerebral outcome after CPB with cerebral air embolism in a rat model. 50 male Sprague-Dawley rats (BW: 330-390 g) were assigned to five groups of ten animals each. Control group (Ko) animals were neither exposed to CPB nor received Xenon. The CPB-groups such as Xenon before CPB, Xenon during CPB, Xenon after CPB and no Xenon (kXE) were anesthetized with isofluran, intubated and ventilated with 2.0-2.5 Vol % isoflurane in 50 % oxygen. The right superficial epigastric artery and vein, the right external jugular vein and the sacral artery were cannulated for blood sampling, application of drugs, invasive blood pressure monitoring as well as inflow and return connection to the CPB circuit. A catheter was inserted into the right internal carotid artery and ten repetitively administered air emboli of 0.3 µl each were applicated. After completion of surgery all animals received an additional basic intravenous anesthesia (continuous infusion of midazolam, fentanyl and atracurium) which was maintained until the end of operation (60 min after CPB). Rats subjected to Xenon before CPB were ventilated with Xenon (56 % Xenon, 5 % N2, 34 % O2 and 5 % CO2) applied for 60 minutes before connection to CPB. The Xenon during CPB group received the above mentioned Xenon gas mixture through the oxygenator for 90 minutes during CPB. Xenon after CPB animals were treated in the same fashion but inhaled Xenon for 60 minutes after CPB and no Xenon animals continously received an oxygen-air-mixture (61 % N2, 34 % O2 und 5 % CO2). Emerging from anesthesia the rats recovered by being placed in an oxygen-enriched environment. Animals underwent standardized functional neurologic testing on the 1st-4th, 8th, 12th, 16th and 21st postoperative days. Beginning with the 4th postoperative day cognitive performance as well as behaviour was ascertained up to the 21st postoperative day using the modified hole-board test. All neurologic, cognitive and behavioural testing was performed by a investigator blinded to treatment. After testing on the 21st postoperative day the rats were killed by exsanguination in deep isofluran anesthesia and subjected to in situ brain fixation with formaline. Brains were removed in total, were serially cut and stained with hematoxylin and eosin for further histological evaluation determining maximal infarction size and infarction volume. This is the first investigative study on the effects of different Xenon application times, that is before, during and after CPB in combination with CAE. The occurrence of CAE is more likely during CPB in contrast to before and after CPB where CAE are rarer. In this setting rats showed short-time sensomotoric and long-term cognitive and behavioural changes which was confirmed by histopathological results. The significant worse outcome of animals treated with Xenon after CPB is of profound relevance discussing the safety of Xenon`s use associated with CPB. Interestingly rats subjected to CPB without Xenon achieved no better results neither at cognitive and behavioural testing nor at histopathological evaluation. Knowledge about the pathophysiology of CAE remains sparse and further investigation in this direction would be of high importance in trying to explain the results of this study.

„Investigation of neurologic outcome and cerebral inflammation after deep hypothermic circulatory arrest in the rat: The impact of the rewarming rate” Despite considerable progress in medicine, and the adapt use of CPB with DHCA, congenital heart defects are still considered a challenge for surgery. Today`s scientific research focuses on CPB with DHCA and the possible cerebral inflammatory reaction, contributing to the often adverse neurologic and neurocognitive outcome following CPB with DHCA. Aim o f this study is to investigate the impact of the rate and duration of rewarming have on postoperative neurologic function, histologic outcome and cerebral inflammatory reaction in a clinically relevant animal model of CPB with 45 min of DHCA in the rat. 20 male Sprague Dawley rats (330 – 390 g) were anaesthetized, endotracheally intubated and ventilated with 2 to 2.5 Vol % Isoflurane in 40 Vol % O2. For pain management all animals received repititive 5µg boli of Fentanyl. Animals were surgically cannulated as follows: the A. sacralis mediana for arterial inflow during CPB, the taking of blood samples and drug administration. The A. epigastrica superficialis for blood pressure monitoring and the V. jugularis externa and V. cava cranialis for venous drainage during CPB. During the cooling phase anaesthesia was maintained with 0.8 to 1Vol % Isoflurane and Cisartracurium was given additionally for muscle relaxation (1,6mg/h). To cool rats down to a rectal temperature of 15 – 18 °C within 30 min, cooling blankets, ice bags and a heat exchanger in the oxygenator were used. At 15 – 18 °C, CPB and anaesthesia were terminated for 45 minutes and the venous drainage was opened every ten minutes to allow the animals to exsanguinate to prevent a right heart dilatation. Rats were then randomly assigned to one of two rewarming groups (n = 10): with reinstitution of CPB and anaesthesia, one group was rewarmed slowly over 40 minutes and a second group fast over 20 minutes back to a rectal temperature of 35.5 °C. When reaching 35.5 °C, animals were weaned from CPB, and anaesthesia was maintained for one hour folllowing CPB. During that time the blood left in the circuit was collected, centrifuged, adjusted with HES and calcium to a hematocrit below 50% and returned to raise the animal`s hematocrit above 30%. Anaesthesia was terminated one hor following CPB. Animals were extubated when showing sufficient spontaneous breathing and allowed to recover under observation in an oxygen enriched environment. Rats were neurologically tested one day prior to CPB with DHCA as well as on the postoperative day. 24 hours following the end of CPB, animals were sacrificed, their brains removed and deep frozen (-70 °C) for further analysis. H&E staining was performed using slices taken at bregma –0.3 and –3.3 to investigate the histological damage in the Gyrus cinguli, Striatum, motor cortex, Hippocampus and Vermis. NF-kB- positive neurons were labelled with an immunhistochemical double staining and counted using light microscopy. Inflammatory parameters TNF-α, COX-2 and I-kB were evalueted using Wetsern Blotting. For the first time this study compares the neurologic outcome following two different rewarming protocols after DHCa in a clinically relevant animal model of CPB with DHCA. Unexpectedly, a better neurologic outcome is seen after fast rewarming. Although results for histology and immunehistochemistry show higher amounts of eosinohilic and NF-kB- positive neurons in this group. Western Blot also shows increased levels of inflammatory parameters COX-2 and I-kB in the fast rewarming group. These findings suggest that the rewarming rate alone is not the chief cause for an adverse neurological out-come after CPB with DHCA. Further studies concerning the mechanisms leading to adverse neurologic outcome and cerebral inflammatory reaction following CPB with DHCA are required.

Long-term effects of Dexmedetomidin on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia in rats This study investigates the effect of the α2-adrenozeptor agonist Dexmedetomidine on the expression of the apoptosis-regulating proteins Bax, p53, Bcl-2 and Mdm-2 following incomplete cerebral ischemia in rats within a period of 28 days from the insult. 72 fasted male Sprague-Dawley rats (400 g) were randomly assigned to one of the following groups: Group 1: (n = 32, controls): fentanyl and N2O/O2 (FiO2 = 0.33) Group 2: (n = 32, dexmedetomidine) : fentanyl and N2O/O2 (FiO2 = 0.33), administration of dexmedetomidine intraperitoneal 30 min before ischemia, the animals of these groups were randomly assigned in groups (n = 8) with a postischemic observation period of 1, 3, 7 or 28 days. Group 3: (n = 8, naive): without treatment, show reference value The apoptosis-regulating proteins Bax, p53, Bcl-2 and Mdm-2 in the hippocampal regions were analysed qualitatively and quantitatively by using the Immunfluorescence-technique and the Western-Blot-technique. The concentration of the pro-apoptotic protein Bax is decreased in the hippocampus for at least 28 days after cerebral ischemia. The anti-apototic Bcl-2 protein was increased during the first three days after cerebral ischemia in group 2 compared to group 1. The Mdm-2 protein of group 2 was significantly increased during the whole period of investigation in the Western-Blot-analysis.

The Effect of Hyperventilation on Cognitive Performance, Motor Functions and Lesion Volume after Controlled Cortical Impact in the Rat Introduction: We investigated the effects of short-term moderate hyperventilation on neurocognitive and motor functions as well as lesion volume in rats subjected to focal traumatic brain injury. Thereby the model of controlled cortical impact (CCI) was established associated with the evaluation of a battery of behavioral tests. Methode: 21 male Sprague-Dawley rats (369±15 g) were trained to achieve the modified Hole-Board Test (mHB-Test) for a period of 14 days and some more behavioral tests (Beam Walking, Beam Balance, neurologic score) for 3 days. After completion of specific baseline parameters of the mHB-Test rats were anesthetized with 1.0-1.5 Vol% halothane in O2/N2O (FiO2=0,33), intubated and mechanically ventilated for surgical preparation. After cranio-tomy CCI was induced using a pneumatic pistol (Ø 5 mm, 1,75 mm depth, 200 ms, 4 m/s). Animals were then randomly assigned to one of two groups for four hours post-traumatic ventilation with Halothan (0,8-1,0 Vol%): group 1=normoventilation (n=10; PaCO2=38-42 mmHg); group 2=hyperventilation (n=11; PaCO2=28-32 mmHg). During the entire study, brain temperature and mean arterial blood pressure were kept at normal physiological levels. Additionally breathing and heart rate, PaO2, pH, glucose and heamoglobin were messured. Upon recovery all behavioral tests were continued to euthanasia on the 20th day. During deep anesthesia rats were decapitated and their brains were sampled, frozen and then cut in 10 µm thick sections to evaluate lesion volume after cresyl violet staining. Results are tabu-lar shown Mean+/-SD and graphical Mean+/-SEM (statistic: ANOVA and post hoc t-test). Results: Hyperventilated rats developed a significant deficit in declarative memory (mHB-Test), with variances especially on days 1-2 after trauma associated with a decreased neuro-logical score on days 1-3 compared to normoventilated animals which had a decrease only on day 1. For motor impairments after CCI the Beam Walking and Beam Balance were most sensitive with deficits in both groups and a significant disability of hyperventilated rats. All impairments were just transient after the traumatic brain injury and adjusted to baseline pa-rameters on day 6. Bodyweight measurements, time of food intake or inactivity (mHB-Test) and all several motoric parameters show a marginal reduction of constitution in the rats after CCI. Exploration parameters of mHB-Test demonstrate that normoventilated rats are more active and explorativ following the CCI in comparison to hyperventilated rats. On day 20 after injury, lesion volume was significant larger in the hyperventilated group (69,7±13,0 mm3) versus the normoventilated group (48,3±15,6 mm3). Discussion: We evaluated a model of CCI, that is inducing a standardized and reproduce-able traumatic brain injury. Four hours of post-traumatic hyperventilation transiently impairs hippocampus-dependent declarative memory as well as neurocognitive and motor functions. Hyperventilation also enhances long-term histological damage. These data suggest, that hyperventilation without controlling intracranial pressure is able to deteriorate primary lesion and should be used with caution after acute head trauma.

The long-term effect of sevoflurane and propofol on necrotic and apoptotic cell death after incomplete cerebral ischemia and reperfusion in the rat The present study investigates the effect of the anesthetic agents propofol and sevoflurane on irreversible cell damage (necrosis) and programmed cell death (apoptosis) for a time period of 28 days after incomplete transient cerebral ischemia and reperfusion in the rat. Ninety-six fasted male Sprague-Dawley rats (415±40g) were anesthetized, intubated and ventilated with 2 Vol% isoflurane and N2O/O2 (FiO2=0.33). Catheters were inserted into the right femoral artery and vein as well as in the right jugular vein for drug administration and blood withdrawal. At the end of surgery animals were randomly assigned to one of the following groups: control (n=32): 25 µg/kg/h fentanyl i.v. and N2O/O2 (FiO2=0.33); propofol (n=32): 25 µg/kg/h propofol i.v. and O2/air (FiO2=0.33); sevoflurane (n=32) 2 Vol% sevoflurane in O2/air (FiO2=0.33). Ischemia (45min) was produced by unilateral common carotid artery occlusion plus hemorrhagic hypotension (MAP=40 mmHg). Pericranial temperature (37.5°C), arterial blood gases and pH were maintained constant. Animals were then randomly assigned to a postischemic reperfusion time of 01, 03, 07, or 28 days. At the end of the observation period the animals were deeply anesthetized and killed, the brains were removed, frozen at –70 °C, and sectioned for further evaluation. Hematoxylin-Eosin staining was used to evaluate eosinophilic cell damage and tissue damage in 7 μm sections in the hippocampus, dentate gyrus and surrounding tissues. Immunohistochemistry was used to detect activated caspase-3 as a marker of apoptotic cell death. To distinguish activated caspase-3-positive neurons from other cells, a double staining, using the specific neuronal marker NeuN was used additionally. The results showed that with the exception of one animal in the sevoflurane group there is no tissue damage or eosinophilic cell damage in either the propofol or the sevoflurane treated animals up to 28 days after ischemia. The only eosinophilic tissue damage was present in the control group. About one percent of the hippocampal neurons of all three groups were activated caspase-3-positive, independently of the observation period. Though there was a tendency in both treatment groups to a lower number of activated caspase-3-positive cells. Results of the double staining showed that activated caspase-3, though mainly expressed in neurons, is also expressed in other cells. The present study showed that propofol and sevoflurane both produce a sustained inhibition of eosinophilic cell damage up to 28 days after incomplete cerebral ischemia in rats. Although the amount of activated caspase-3-positive neurons was similar in the three groups there was a tendency towards a lower number in the treatment groups compared to control. This suggests that neuroprotection seen with both, propofol and sevoflurane, involves anti-necrotic mechanisms rather than anti-apoptotic mechanisms. Further investigations will be required in the future to investigate the detailed mechanisms of propofol and sevoflurane to develop a successful treatment of ischemic insults and their consequences.

Cultured cardiac myocytes from adult Sprague-Dawley rats express both insulin-like growth factor-I (IGF-I) receptors and insulin-like growth factor-II/mannose 6-phosphate (IGF-II/Man6P) receptors and respond to IGF-I with a dose-dependent accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and inositol 1,4-bisphosphate [Ins(1,4)P2]. Specific binding of [125I]IGF-I to isolated membranes from cultured cardiac myocytes amounted to 1-1.2%. Binding of [125I]IGF-I was inhibited by unlabeled IGF-I at nanomolar concentrations and insulin at much higher concentrations. These data suggest that IGF-I binds to its own receptor on rat cardiac myocytes. Competitive binding studies using isolated membranes from cardiac myocytes and [125I]IGF-II showed 2-4% specific binding. Binding of [125I]IGF-II was inhibited by IGF-II and much less potently by IGF-I and insulin. Immunoglobulin G (IgG) 3637 (an IgG directed against the IGF-II/Man6P receptor) partially inhibited binding of [125I]IGF-II whereas nonimmune IgG did not. Affinity cross-linking studies with [125I]IGF-II and cardiac myocyte membranes and subsequent analysis of the ligand-receptor complex using SDS-PAGE and autoradiography showed a radiolabeled band of approximately 250 kilodalton (kDa). The formation of the [125I]IGF-II-receptor complex was inhibited by incubation with IGF-II and IgG 3637 but not by insulin or nonimmune IgG. Western blotting of protein extracts from cultured cardiac myocytes was performed using IgG 3637 and an immunoperoxidase technique for the visualization of the IGF-II/Man6P receptor protein. A specific band at 220 kDa under nonreducing conditions was detected on the blots, providing further evidence for the expression of the IGF-II/Man6P receptor by cardiac myocytes. The effect of IGFs on the accumulation of inositol phosphates was measured by HPLC analysis of perchloric acid extracts from myo-[3H]inositol-labeled cultured cardiac myocytes. IGF-I (50 ng/ml) stimulated the accumulation both of Ins(1,4,5)P3 and Ins(1,4)P2 after 30 sec by 43% and 63%. IGF-II (up to 500 ng/ml) had no significant effect on inositol phosphate accumulation under the same conditions. However, in the presence of millimolar concentrations of Man6P, IGF-II (500 ng/ml) also increased Ins(1,4,5)P3 accumulation by 59%. We conclude that cardiac myocytes from adult rats express IGF receptors and respond to IGFs with the accumulation of Ins(1,4,5)P3 and Ins(1,4)P2. This effect seems to be mediated by an IGF-I receptor-specific pathway.

Mesenteric, hepatic and splanchnic extraction of C-terminal and N-terminal atrial natriuretic factor was investigated in male Sprague-Dawley rats. Plasma concentrations (mean ± S.E.M.) of C-terminal atrial natriuretic factor were 55.0 ± 6.1 fmol/ml, 31.2 ± 4.0 fmol/ml and 23.5 ± 3.3 fmol/ml (n = 12) in the abdominal aorta, the portal vein and the hepatic vein, respectively. N-terminal atrial natriuretic factor plasma levels in these vessels were 3031 ± 756 fmol/ml, 2264 ± 661 fmol/ml and 1618 ± 496 fmol/ml (n = 6), respectively. Although the mesenteric extraction ratio was higher (p < 0.05) for C-terminal atrial natriuretic factor (42% ± 6%) than for N-terminal atrial natriuretic factor (28% ± 4%), there were no significant differences in the hepatic extraction ratio (41% ± 5% vs. 39% ± 6%) and the splanchnic extraction ratio (56% ± 5% vs. 50% ± 7%). These data suggest a major role of the liver in the splanchnic extraction of C-terminal and of N-terminal atrial natriuretic factor in the rat. (HEPATOLOGY 1992;16:790-793.

Sun, 1 Jan 1989 12:00:00 +0100 https://epub.ub.uni-muenchen.de/6117/1/6117.pdf Kellerer, Albrecht M.; Masse, R.; Morin, M.; Chameaud, J.; Chmelevsky, D.; Lafuma, J.

Sun, 1 Jan 1984 12:00:00 +0100 https://epub.ub.uni-muenchen.de/8752/1/8752.pdf Masse, R.; Morin, M.; Lafuma, J.; Kellerer, Albrecht M.; Chmelevsky, D.

Tue, 1 Jan 1980 12:00:00 +0100 https://epub.ub.uni-muenchen.de/8485/1/8485.pdf Kellerer, Albrecht M.; Chmelevsky, D.; Shellabarger, C. J.

Female 61 to 63 - day - old Sprague-Dawley rats were exposed once to a single dose of either 0.43 - MeV neutrons or 250 - kVX - rays . For neutrons 23 rats were exposed in plastic tubes rotated around and 31 c m from a water-cooled tritium impregnated target bombarded with 2.45 - MeV protons from a V a n de Graaff generator. The mean kerma was measured at the rat location by integrating the response of a rat - sized homogeneous tissue equivalent ionization chamber of minimum mass. The ratio between absorbed dose and kerma is under investigation and is anticipated to be approximately 0.7. A compensated GM gamma-ray dosimeter indicated that the gamma - ray doses were 3.5% of the total dose. All rats were examined weekly for the presence of breast tumours and these were removed, fixed, stained and verified histologically as mammary neoplasms. At 10 months after exposure 98

An analysis of experimental findings indicates that the induction of a manmmary neoplasm in the Sprague-Dawley rat is dependent on the action of radiation on more than one cell. Although a linear relation between incidence and x-ray dose might be consistent with available data, such a relation would be fortuitous and linear extrapolation to lower doses is unjustified.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.15.041491v1?rss=1 Authors: Ramakrishna, Y., Manca, M., Sadeghi, S. G. Abstract: Vestibular nerve afferents are divided into regular and irregular groups based on the variability of interspike intervals in their resting discharge. Most afferents receive inputs from bouton terminals that contact type II hair cells as well as from calyx terminals that cover the basolateral walls of type I hair cells. Calyces have an abundance of different subtypes of KCNQ (Kv7) potassium channels and muscarinic acetylcholine receptors (mAChRs) and receive cholinergic efferent inputs from neurons in the brainstem. We investigated whether mAChRs affected membrane properties and firing patterns of calyx terminals through modulation of KCNQ channel activity. Patch clamp recordings were performed from calyx terminals in central regions of the cristae of the horizontal and anterior canals in 13 - 18 day old Sprague-Dawley rats. KCNQ mediated currents were observed as voltage sensitive currents with slow kinetics (activation and deactivation), resulting in spike frequency adaptation so that calyces at best fired a single action potential at the beginning of a depolarizing step. Activation of mAChRs by application of oxotremorine methiodide or inhibition of KCNQ channels by linopirdine dihydrochloride decreased voltage activated currents by ~30%, decreased first spike latencies by ~40%, decreased spike thresholds by ~50%, and resulted in continuous firing during depolarizing steps. Interestingly, some of the calyces showed spontaneous discharge in the presence of these drugs. Together, these findings suggest that cholinergic efferents can modulate the response properties and encoding of head movements by afferents. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.15.042812v1?rss=1 Authors: Wahlstrom, K. L., Alvarez-Dieppa, A., McIntyre, C. K., LaLumiere, R. T. Abstract: Previous work from our laboratory suggests that projections from the basolateral amygdala (BLA) to the medial entorhinal cortex (mEC) are a critical pathway by which the BLA modulates the consolidation of spatial learning. Posttraining optogenetic stimulation of this pathway enhances retention of spatial memories. Evidence also indicates that intra-BLA administration of memory-enhancing drugs increases protein levels of activity-regulated cytoskeletal-associated protein (ARC) in the dorsal hippocampus (DH) and that blocking ARC in the DH impairs spatial memory consolidation. Yet, whether optical manipulations of the BLA-mEC pathway after spatial training also alter ARC in the DH is unknown. To address this question, male and female Sprague-Dawley rats received optogenetic stimulation of the BLA-mEC pathway immediately after spatial training using a Barnes maze and, 45 min later, were sacrificed for ARC analysis. Initial experiments found that spatial training increased ARC levels in the DH of rats above those observed in control rats and rats that underwent a cued-response version of the task. Optogenetic stimulation of the BLA-mEC pathway following spatial training, using parameters effective at enhancing spatial memory consolidation, enhanced ARC protein levels in the DH of male rats without affecting ARC levels in the dorsolateral striatum (DLS) or somatosensory cortex. In contrast, similar optical stimulation decreased ARC protein levels in the DLS of female rats without altering ARC in the DH or somatosensory cortex. Together, the present findings suggest a mechanism by which BLA-mEC stimulation enhances spatial memory consolidation in rats and reveals a possible sex-difference in this mechanism. Copy rights belong to original authors. Visit the link for more info