Podcasts about abstract human

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.08.04.551937v1?rss=1 Authors: Luciani, M., Garsia, C., Beretta, S., Petiti, L., Peano, C., Merelli, I., Cifola, I., Miccio, A., Meneghini, V., Gritti, A. Abstract: Human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NSCs) are a promising source for cell therapy approaches to treat neurodegenerative and demyelinating disorders. Despite ongoing efforts to characterize hiPSC-derived cells in vitro and in vivo, we lack comprehensive genome- and transcriptome-wide studies addressing hiPSC-NSC identity and safety, which are critical for establishing accepted criteria for prospective clinical applications. Here, we evaluated the transcriptional and epigenetic signatures of hiPSCs and differentiated hiPSC-NSC progeny, finding that the hiPSC-to-NSC transition results in a complete loss of pluripotency and the acquisition of a radial glia-associated transcriptional signature. Importantly, hiPSC-NSCs share with somatic human fetal NSCs (hfNSCs) the main transcriptional and epigenetic patterns associated with NSC-specific biology. In vivo, long-term observation (up to 10 months) of mice intracerebrally transplanted as neonates with hiPSC-NSCs showed robust engraftment and widespread distribution of human cells in the host brain parenchyma. Engrafted hiPSC-NSCs displayed multilineage potential and preferentially generated glial cells. No hyperproliferation, tumor formation, or expression of pluripotency markers was observed. Finally, we identified a novel role of the Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1) in the regulation of astroglial commitment of hiPSC-NSCs. Overall, these comprehensive in vitro and in vivo analyses provide transcriptional and epigenetic reference datasets to define the maturation stage of NSCs derived from different hiPSC sources, and to clarify the safety profile of hiPSC-NSCs, supporting their continuing development as an alternative to somatic hfNSCs in treating neurodegenerative and demyelinating 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/2023.08.02.551645v1?rss=1 Authors: Shepard, N., Baez-Nieto, D., Iqbal, S., Campbell, A. J., Pan, J. Q., Sheng, M., Farsi, Z. Abstract: Human genetic studies have revealed rare missense and protein-truncating variants in GRIN2A, encoding for the GluN2A subunit of the NMDA receptors, that confer significant risk for schizophrenia (SCZ). Mutations in GRIN2A are also associated with epilepsy and developmental delay/intellectual disability (DD/ID). However, it remains enigmatic how alterations to the same protein can result in diverse clinical phenotypes. Here, we performed functional characterization of human NMDA receptors (GluN1/GluN2A heteromers) that contain SCZ-linked GluN2A variants, and compared them to NMDA receptors with GluN2A variants associated with epilepsy or DD/ID. All tested protein-truncating variants and a subset of missense variants associated with SCZ led to a loss-of-function (LoF) phenotype, whereas epilepsy and DD/ID-associated variants resulted in both gain- and loss-of-function phenotypes. We additionally show that M653I, a LoF GRIN2A variant associated with DD/ID, exerts a dominant-negative effect when co-expressed with a wild-type GluN2A, whereas Y698C, a LoF SCZ-linked variant, does not. These findings demonstrate that SCZ-associated GRIN2A variants are predominantly LoF and offer a potential mechanism by which SCZ and DD/ID-linked variants can cause different effects on receptor function and therefore result in divergent pathological outcomes. 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/2023.07.31.551212v1?rss=1 Authors: Gulbinaite, R., Nazari, M., Rule, M. E., Bermudez Contreras, E. J., Cohen, M. X., Heimel, J. A., Mohajerani, M. H. Abstract: Human primary visual cortex (V1) is entrained by the rhythmic light and responds more strongly, or resonates, to ~10, ~15-20, ~40-50 Hz flicker. Full-field flicker also elicits geometric hallucinations, the origin of which has only been explored in computational models and human EEG with limited spatial resolution. Here, we recorded cortical responses to flicker in awake mice using high spatial resolution widefield imaging in combination with high temporal resolution glutamate-sensing fluorescent reporter (iGluSnFR). Resonance frequencies in mouse V1 were similar to those in humans (8 Hz, 15 Hz, 33 Hz). Spatially, all flicker frequencies evoked responses in V1 corresponding to retinotopic stimulus location and some evoked additional spatial peaks. These flicker-induced cortical patterns displayed standing wave characteristics and matched linear wave equation solutions in an area restricted to the visual cortex. Taken together, the interaction of travelling waves with cortical area boundaries leads to spatiotemporal activity patterns, which may affect perception. 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/2023.07.27.550771v1?rss=1 Authors: Zhao, H., Wu, K., Chen, Z.-J., Zhang, Y., Zhao, R., Yang, C., Song, J., Liu, P., Li, Y., Liu, B., Li, T., Yin, C., Lu, M., Hou, Z., Zhang, C. Abstract: Human endometrial receptivity is a critical determinant of pregnancy success; however, in vivo studies of its features and regulation are particularly challenging due to ethical restriction. Recently,the development of human endometrial organoids has provided a powerful model to examine this intricate biological process. In this study, we established a specialized human window-of-implantation (WOI) endometrial organoid system that mimics the in vivo receptive endometrium.The endometrial organoid recapitulates not only the structural attributes of glands and stroma, but also the in vivo endometrium's cell types at the single-cell level. Furthermore, the WOI endometrial organoid exhibits the features of in vivo implantation endometrium such as hormone responsiveness, secretory functions, and distinctive implantation window hallmarks, including decidualization, extracellular matrix (ECM) remodeling, pinopode formation, cilia generation and metabolism. This in vitro model also effectively demonstrates the process of proliferation-secretory transformation, ciliary epithelium differentiation, and epithelial-mesenchymal transition (EMT). As such, WOI organoids hold great promise as a robust platform to unravel the intricate mechanisms governing endometrial receptivity regulation, maternal-fetal interactions, and associated diseases, ultimately driving impactful advancements in the field. 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/2023.07.20.549090v1?rss=1 Authors: Luo, A., Sydnor, V. J., Pines, A., Larsen, B., Alexander-Bloch, A. F., Cieslak, M., Covitz, S., Chen, A., Esper, N. B., Feczko, E., Franco, A. R., Gur, R. E., Gur, R. C., Houghton, A., Hu, F., Keller, A. S., Kiar, G., Mehta, K., Salum, G. A., Tapera, T., Xu, T., Zhao, C., Fair, D. A., Salo, T., Shinohara, R. T., Milham, M. P., Satterthwaite, T. D. Abstract: Human cortical maturation has been posited to be organized along the sensorimotor-association (S-A) axis, a hierarchical axis of brain organization that spans from unimodal sensorimotor cortices to transmodal association cortices. Here, we investigate the hypothesis that the development of functional connectivity during childhood through adolescence conforms to the cortical hierarchy defined by the S-A axis. We tested this pre-registered hypothesis in four large-scale, independent datasets (total n = 3,355; ages 5-23 years): the Philadelphia Neurodevelopmental Cohort (n = 1,207), Nathan Kline Institute-Rockland Sample (n = 397), Human Connectome Project: Development (n = 625), and Healthy Brain Network (n = 1,126). In each dataset, the development of functional connectivity systematically varied along the S-A axis. Connectivity in sensorimotor regions increased, whereas connectivity in association cortices declined, refining and reinforcing the cortical hierarchy. These robust and generalizable results establish that the sensorimotor-association axis of cortical organization encodes the dominant pattern of functional connectivity development. 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/2023.07.08.548227v1?rss=1 Authors: Salimpour, Y., Anderson, W. S., Dastgheyb, R., Liu, S., Ming, G.-L., Song, H., Maragakis, N. J., Habela, C. W. Abstract: Human induced pluripotent stem cell (hiPSC)- derived neurons offer the possibility of studying human-specific neuronal behaviors in physiologic and pathologic states in vitro. However, it is unclear whether these cultured neurons can achieve the fundamental network behaviors that are required to process information in the human brain. Investigating neuronal oscillations and their interactions, as occurs in cross-frequency coupling (CFC), is potentially a relevant approach. Microelectrode array culture plates provide a controlled framework to study populations of hiPSC-derived cortical neurons (hiPSC-CNs) and their electrical activity. Here, we examined whether networks of two-dimensional cultured hiPSC-CNs recapitulate the CFC that is present in networks in vivo. We analyzed the electrical activity recorded from hiPSC-CNs grown in culture with hiPSC-derived astrocytes. We employed the modulation index method for detecting phase-amplitude coupling (PAC) and used an offline spike sorting method to analyze the contribution of a single neurons spiking activities to network behavior. Our analysis demonstrates that the degree of PAC is specific to network structure and is modulated by external stimulation, such as bicuculine administration. Additionally, the shift in PAC is not driven by a single neurons properties but by network-level interactions. CFC analysis in the form of PAC explores communication and integration between groups of nearby neurons and dynamical changes across the entire network. In vitro, it has the potential to capture the effects of chemical agents and electrical or ultrasound stimulation on these interactions and may provide valuable information for the modulation of neural networks to treat nervous system disorders in vivo. 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/2023.07.04.547690v1?rss=1 Authors: Hensel, I. V., Elias, S., Steinhauer, M., Stoll, B., Benfatto, S., Merkt, W., Krienke, S., Lorenz, H.-M., Haas, J., Wildeman, B., Resnik-Docampo, M. Abstract: Human intestinal epithelial cells are the interface between potentially harmful luminal content and basally residing immune cells. Their role is not only nutrient absorption but also the formation of a tight monolayer that constantly secrets mucus creating a multi-layered protective barrier. Alterations in this barrier can lead to increased gut permeability which is frequently seen in individuals with chronic extraintestinal autoimmune diseases, such as Systemic Lupus Erythematosus (SLE). Despite recent advances in identifying alterations in gut microbiota composition in SLE patients, not much attention has been given to the epithelial barrier itself. To date, it remains largely unexplored which role and function intestinal epithelial cells have in SLE pathology. Here, we present a unique near-physiologic in vitro model specifically designed to examine the effects of SLE on the epithelial cells. We utilize human colon organoids that are stimulated with serum obtained from SLE patients. Combining bulk and scRNA transcriptomic analysis with functional assays revealed that SLE serum stimulation induced a unique expression profile marked by a type I interferon gene signature. Additionally, organoids exhibited decreased mitochondrial fitness, alterations in mucus composition and imbalanced cellular composition. Similarly, transcriptomic analysis of SLE human colon biopsies revealed a downregulation of epithelial secretory markers. Our work uncovers a crucial connection between SLE and intestinal homeostasis that might be promoted in vivo through the blood, offering insights into the causal connection of barrier dysfunction and autoimmune 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/2023.07.03.547482v1?rss=1 Authors: Degano, G., Donhauser, P., Gwilliams, L., Merlo, P., Golestani, N. Abstract: Human language relies on hierarchically structured syntax to facilitate efficient and robust communication. The correct processing of syntactic information is essential for successful communication between speakers. As an abstract level of language, syntax has often been studied separately from the physical form of the speech signal, thus often masking the interactions that can promote better syntactic processing in the human brain. We analyzed a MEG dataset to investigate how acoustic cues, specifically prosody, interact with syntactic operations. We examined whether prosody enhances the cortical encoding of syntactic representations. We decoded left-sided dependencies directly from brain activity and evaluated possible modulations of the decoding by the presence of prosodic boundaries. Our findings demonstrate that prosodic boundary presence proves the representation of left-sided dependencies, indicating the facilitative role of prosodic cues in processing abstract linguistic features. This study gives neurobiological evidence for the boosting of syntactic processing via interaction with prosody. 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/2023.06.28.546754v1?rss=1 Authors: van Mastrigt, N. M., van der Kooij, K., Smeets, J. Abstract: Human movement is inevitably variable. This variability can be seen as a constraint to overcome, but it may also be a feature: being variable may result in the discovery of better movement solutions. Especially when feedback is limited to binary information on movement success or failure, variability is key for discovering which movements lead to success. Since moving faster increases variability, we aimed to answer the question whether movement speed can be harnessed to improve such reward-based motor learning. Subjects performed a stepping task in a slow and a fast session. They had to learn the gain between their step lengths and visual target distances on screen based on binary reward feedback. We successfully manipulated movement speed between sessions and participants could learn the gain in both. We found no difference in learning between speed sessions, despite the fact that variability in gain increased in the fast relative to the slow session. To distinguish between different sources of variability, we estimated inevitable motor noise from the variability following successful trials. We estimated exploration as the additional variability following non-successful trials relative to following successful trials. We found no relation between variability sources and learning. In conclusion, reward-based motor learning is possible in a gain-learning task. In this task, moving faster did not lead to higher learning. Since the role of variability may differ between experimental tasks, whether movement speed can be harnessed to improve motor learning needs to be tested in other experimental tasks. 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/2023.06.26.546513v1?rss=1 Authors: Spits, C., Lei, Y., Al Delbany, D., Krivec, N., Regin, M., Couvreu de Deckersberg, E., Janssens, C., Ghosh, M., Sermon, K. D. Abstract: Human pluripotent stem cell (hPSC) cultures are prone to genetic drift, as cells that have acquired specific genetic abnormalities experience a selective advantage in vitro. These abnormalities are highly recurrent in hPSC lines worldwide, but currently their functional consequences in differentiating cells are scarcely described. An accurate assessment of the risk associated with these genetic variants in both research and clinical settings is therefore lacking. In this work, we established that one of these recurrent abnormalities, the loss of chromosome 18q, impairs neuroectoderm commitment and affects the cardiac progenitor differentiation of hESCs. We show that downregulation of SALL3, a gene located in the common 18q loss region, is responsible for failed neuroectodermal differentiation. Knockdown of SALL3 in control lines impaired differentiation in a manner similar to the loss of 18q, while transgenic overexpression of SALL3 in hESCs with 18q loss rescued the differentiation capacity of the cells. Finally, we show by gene expression analysis that loss of 18q and downregulation of SALL3 leads to changes in the expression of genes involved in pathways regulating pluripotency and differentiation, including the WNT, NOTCH, JAK-STAT, TGF-beta and NF-kB pathways, suggesting that these cells are in an altered state of pluripotency. 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/2023.05.05.539537v1?rss=1 Authors: Lotter, L. D., Saberi, A., Hansen, J. Y., Misic, B., Barker, G. J., Bokde, A. L. W., Desrivieres, S., Flor, H., Grigis, A., Garavan, H., Gowland, P., Heinz, A., Bruehl, R., Martinot, J.-L., Paillere, M.-L., Artiges, E., Papadopoulos Orfanos, D., Paus, T., Poustka, L., Hohmann, S., Froehner, J. H., Smolka, M. N., Vaidya, N., Walter, H., Whelan, R., Schumann, G., IMAGEN Consortium,, Nees, F., Banaschewski, T., Eickhoff, S. B., Dukart, J. Abstract: Human brain morphology undergoes complex developmental changes with diverse regional trajectories. Various biological factors influence cortical thickness development, but human data are scarce. Building on methodological advances in neuroimaging of large cohorts, we show that population-based developmental trajectories of cortical thickness unfold along patterns of molecular and cellular brain organization. During childhood and adolescence, distributions of dopaminergic receptors, inhibitory neurons, glial cell populations as well as features of brain metabolism explain up to 50% of variance associated with regional cortical thickness trajectories. Cortical maturation patterns in later life are best explained by distributions of cholinergic and glutamatergic systems. These observations are validated in longitudinal data from over 8,000 adolescents, explaining up to 59% of developmental change at population- and 18% at single-subject level. Integrating multilevel brain atlases with normative modeling and population neuroimaging provides a biologically and clinically meaningful path to understand typical and atypical brain development in living humans. 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/2023.04.22.537784v1?rss=1 Authors: Majumder, A., Joshi, R., Mukherjee, S., Suryawanshi, T., Shukla, S. Abstract: Human mesenchymal stem cells (hMSCs) are multipotent cells that can differentiate into adipocytes, chondrocytes and osteoblasts. Due to their differentiation potential, hMSCs are among the most frequently used cells for therapeutic applications in tissue engineering and regenerative medicine. However, the number of cells obtained through isolation alone is insufficient for hMSC-based therapies and basic research, necessitating their in-vitro expansion. Conventionally, this is often carried out on rigid surfaces such as tissue culture petriplates (TCPs). However, during in-vitro expansion, hMSCs lose their proliferative ability and multilineage differentiation potential, making them unsuitable for clinical use. Although multiple approaches have been tried to maintain hMSC stemness over prolonged expansion, finding a suitable culture system to achieve this remains an unmet need. Recently, few research groups including ours have shown that hMSCs maintain their stemness over long passages when cultured on soft substrate. In addition, it has been shown that hMSCs cultured on soft substrates have more condensed chromatin and lower levels of histone acetylation compared to those cultured on stiff substrates. It has also been shown that condensing/decondensing chromatin by deacetylation/acetylation can delay/hasten replicative senescence in hMSCs during long-term expansion on TCPs. However, how chromatin condensation/decondensation influences nuclear morphology and DNA damage - which are strongly related to the onset of senescence and cancer - is still not known. To answer this question, here we cultured hMSCs for long duration (P4-P11) in presence of epigenetic modifiers histone acetyltransferase inhibitor (HATi) which promotes chromatin condensation by preventing histone acetylation and histone deacetylase inhibitor (HDACi) which promotes chromatin decondensation and investigated their effect on various nuclear markers related to senescence and cancer. We have found that consistent acetylation causes severe nuclear abnormalities whereas chromatin condensation by deacetylation helps in safeguarding nucleus from damages caused by in-vitro expansion. 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/2023.04.16.537082v1?rss=1 Authors: Ding, R., ten Oever, S., Martin, A. E. Abstract: Human language offers a variety of ways to create meaning, one of which is referring to entities, objects, or events in the world. One such meaning maker is understanding to whom or to what a pronoun in a discourse refers to. To understand a pronoun, the brain must access matching entities or concepts that have been encoded in memory from previous linguistic context. Models of language processing propose that internally stored linguistic concepts, accessed via exogenous cues such as phonological input of a word, are represented as (a)synchronous activities across a population of neurons active at specific frequency bands. Converging evidence suggests that delta band activity (1-3Hz) is involved in temporal and representational integration during sentence processing. Moreover, recent advances in the neurobiology of memory suggest that recollection engages reinstatement of neural dynamics that occurred during memory encoding. Integrating from these two research lines, we here predicted that neural dynamic patterns, especially in delta frequency range, underlying referential meaning representation would be reinstated during pronoun resolution. By leveraging neural decoding techniques (i.e., representation similarity analysis) on a magnetoencephalogram (MEG) dataset acquired during a naturalistic story-listening task, we provide evidence that delta-band activity underlies referential meaning representation. Our findings suggest that, during spoken language comprehension, endogenous linguistic representations such as referential concepts may be retrieved and represented via reinstatement of dynamic neural patterns. 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/2023.04.13.536491v1?rss=1 Authors: Stanton, M. M., Hariani, H. N., Sorokin, J., Taylor, P. M., Modan, S., Rash, B. G., Rao, S. B., Enriquez, L., Quang, D., Hsu, P.-K., Paek, J., Owango, D., Castrillo, C., Nicola, J., Ramkumar, P., Lash, A., Flanzer, D., Shah, K., Kato, S., Skibinski, G. Abstract: Human-derived cortical organoids (hCOs) recapitulate cell diversity and 3D structure found in the human brain and offer a promising model for discovery of new gene therapies targeting neurological disorders. Adeno-associated viruses (AAVs) are the most promising vehicles for non-invasive gene delivery to the central nervous system (CNS), but reliable and reproducible in vitro models to assess their clinical potential are lacking. hCOs can take on these issues as they are a physiologically relevant model to assess AAV transduction efficiency, cellular tropism, and biodistribution within the tissue parenchyma, all of which could significantly modulate therapeutic efficacy. Here, we examine a variety of naturally occurring AAV serotypes and measure their ability to transduce neurons and glia in hCOs from multiple donors. We demonstrate cell tropism driven by AAV serotype and hCO donor and quantify fractions of neurons and astrocytes transduced with GFP as well as overall hCO health. 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/2023.03.23.533971v1?rss=1 Authors: Clarke, A., Tyler, L. K., Randall, B., Marslen-Wilson, W. D. Abstract: Human speech comprehension is remarkable for the immediacy with which the listener hears what is being said. Here, we focus on the neural underpinnings of this process in isolated spoken words, to define the intrinsic properties of these core mechanisms independent of contextual constraints or predictions. We analysed source-localised MEG data for a set of 218 spoken nouns heard in isolation, using Representational Similarity Analysis to probe the spatiotemporal coordinates of processes sensitive to speech phonology, lexical form, and the semantics of emerging word candidates. Phonological model fit was detectable within 40-50 ms from onset, rapidly engaging a bilateral network including superior and middle temporal cortex and extending into anterior temporal and inferior parietal regions. Model fit to lexical form emerged within 60-70 ms, and model fit to cohort semantics from 100-110 ms, both overlapping strongly with the spatial pattern of phonological model fit in bilateral temporo-parietal cortices. Strikingly, the majority of vertices in a central core of brain regions showed significant model fit to all three dimensions tested, consistent with a fully distributed neural substrate for early speech analysis. The early interpretation of speech seems to be conducted in a unified integrative representational space, in conflict with the conventional view that speech analysis is underpinned by a linguistically stratified representational hierarchy. 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/2023.03.16.533037v1?rss=1 Authors: Tangtartharakul, G. T., Morgan, C. A., Rushton, S. K., Schwarzkopf, D. S. Abstract: Human visual cortex contains topographic visual field maps whose organization can be revealed with retinotopic mapping. Unfortunately, constraints posed by standard mapping hinders its use in patients, atypical subject groups, and individuals at either end of the lifespan. This severely limits the conclusions we can draw about visual processing in such individuals. Here we present a novel data-driven method to estimate connective fields, fine-grained maps of the functional connectivity between brain areas. We find that inhibitory connectivity fields accompany, and often surround, facilitatory fields. The visual field extent of these inhibitory subfields falls off with cortical magnification. We further show that our method is robust to large eye movements and myopic defocus. Importantly, freed from the controlled stimulus conditions in standard mapping experiments, using entertaining stimuli and unconstrained eye movements our approach can generate retinotopic maps, including the periphery visual field hitherto only possible to map with special stimulus displays. Generally, our results show that the connective field method can gain knowledge about retinotopic architecture of visual cortex in patients and participants where this is at best difficult and confounded, if not impossible, with current methods. 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/2023.03.17.533197v1?rss=1 Authors: Dietrich, A., Pinzuti, E., Cabral-Calderin, Y., Mueller-Dahlhaus, F., Wibral, M., Tuescher, O. Abstract: Human behaviour is inextricably linked to the interaction of emotion and cognition. For decades, emotion and cognition were perceived as separable processes, yet with mutual interactions. Recently, this differentiation has been challenged by more integrative approaches, but without addressing the exact neurophysiological basis of their interaction. Here, we aimed to uncover neurophysiological mechanisms of emotion-cognition interaction. We used an emotional Flanker task paired with EEG/FEM beamforming in a large cohort (N=121) of healthy human participants, obtaining high temporal and fMRI-equivalent spatial resolution. Spatially, emotion and cognition processing overlapped in the right inferior frontal gyrus (rIFG), specifically in pars triangularis. Temporally, emotion and cognition processing overlapped during the transition from emotional to cognitive processing, with a stronger interaction in beta-band power leading to worse behavioral performance. Despite functionally segregated subdivisions in rIFG, frequency-specific information flowed extensively within IFG and top-down to visual areas (V2, Precuneus) -- explaining the behavioral interference effect. Thus, for the first time we here show the neural mechanisms of emotion-cognition interaction in space, time, frequency and information transfer with high temporal and spatial resolution, revealing a central role for $beta$-band activity in rIFG. Our results support the idea that rIFG plays a broad role in both inhibitory control and emotional interference inhibition as it is a site of convergence in both processes. Furthermore, our results have potential clinical implications for understanding dysfunctional emotion-cognition interaction and emotional interference inhibition in psychiatric disorders, e.g. major depression and substance use disorder, in which patients have difficulties in regulating emotions and executing inhibitory control 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/2023.03.17.533103v1?rss=1 Authors: Gallardo, G., Eichner, C., Sherwood, C. C., Hopkins, W. D., Anwander, A., Friederici, A. D. Abstract: Human language is supported by a cortical network involving Broca's area which comprises Brodmann Areas 44 and 45 (BA44, BA45). While cytoarchitectonic homolog areas have been identified in nonhuman primates, it remains unknown how these regions evolved to support human language. Here, we use histological data and advanced cortical registration methods to precisely compare the morphology of BA44 and 45 between humans and chimpanzees. We found a general expansion of Broca's areas in humans, with the left BA44 enlarging the most, growing anteriorly into a region known to process syntax. Together with recent functional studies, our findings show that BA44 evolved from a purely action-related region to a more expanded region in humans, with a posterior portion supporting action and an anterior portion supporting syntactic processes. Furthermore, our findings provide a solution for the long- standing debate concerning the structural and functional evolution of Broca's area and its role in action and language. 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/2023.03.03.531045v1?rss=1 Authors: Adelman, J. W., Rosas, S., Schumacher, M., Mokry, R., Terhune, S. S., Ebert, A. Abstract: Human cytomegalovirus (HCMV) is a highly prevalent viral pathogen that typically presents asymptomatically in healthy individuals despite lifelong latency. However, in 10-15% of congenital cases, this beta-herpesvirus demonstrates direct effects on the central nervous system, including microcephaly, cognitive/learning delays, and hearing deficits. HCMV has been widely shown to infect neural progenitor cells, but the permissiveness of fully differentiated neurons to HCMV is controversial and chronically understudied, despite potential associations between HCMV infection with neurodegenerative conditions. Using a model system representative of the human forebrain, we demonstrate that induced pluripotent stem cell (iPSC)-derived, excitatory glutamatergic and inhibitory GABAergic neurons are fully permissive to HCMV, demonstrating complete viral replication, competent virion production, and spread within the culture. Interestingly, while cell proliferation was not induced in these post-mitotic neurons, HCMV did increase expression of proliferative markers Ki67 and PCNA suggesting alterations in cell cycle machinery. These finding are consistent with previous HCMV-mediated changes in various cell types and implicate the ability of the virus to alter proliferative pathways to promote virion production. HCMV also induces significant structural changes in forebrain neurons, such as the formation of syncytia and retraction of neurites. Finally, we demonstrate that HCMV disrupts calcium signaling and decreases neurotransmission, with action potential generation effectively silenced after 15 days post infection. Taken together, our data highlight the potential for forebrain neurons to be permissive to HCMV infection in the CNS, which could have significant implications on overall brain health and function. 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/2023.02.28.530401v1?rss=1 Authors: Ujma, P. P., Bodizs, R., Dresler, M., Simor, P., Purcell, S., Stone, K., Yaffe, K., Redline, S. Abstract: Human cognitive performance is a key function whose biological foundations have been partially revealed by genetic and brain imaging studies. The sleep electroencephalogram (EEG) is tightly linked to structural and functional features of the central nervous system and serves as another promising biomarker. We used data from MrOS, a large cohort of older men and cross-validated regularized regression to link sleep EEG features to cognitive performance in cross-sectional analyses. In independent validation samples 2.5-10% of variance in cognitive performance can be accounted for by sleep EEG features, depending on the covariates used. Demographic characteristics accounted for more covariance between sleep EEG and cognition than health variables, and consequently reduced this association by a greater degree, but even with the strictest covariate sets a statistically significant association was present. Sigma power in NREM and beta power in REM sleep were associated with better cognitive performance, while theta power in REM sleep was associated with worse performance, with no substantial effect of coherence and other sleep EEG metrics. Our findings show that cognitive performance is associated with the sleep EEG (r=0.283), with the strongest effect ascribed to spindle-frequency activity. This association becomes weaker after adjusting for demographic (r=0.186) and health variables (r=0.155), but its resilience to covariate inclusion suggest that it also partially reflects trait-like differences in cognitive ability. 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/2023.03.02.530870v1?rss=1 Authors: O'Brien, B. S., Mokry, R., Schumacher, M., Rosas, S., Terhune, S. S., Ebert, A. Abstract: Human cytomegalovirus (HCMV) is a beta herpesvirus that causes severe congenital birth defects including microcephaly, vision loss, and hearing loss. Infection of cerebral organoids with HCMV causes significant downregulation of genes involved in critical neurodevelopmental pathways. The precise features of the infection causing this dysregulation remain unknown. Entry of HCMV into human cells is determined by the composition of glycoproteins in viral particles, which is influenced by the source of the virus. This includes a trimer complex and a pentamer complex with the latter enriched from replication in epithelial cells. To begin dissecting which features contribute to neuronal pathogenesis, we evaluated infection using virus from different sources along with the distribution of cellular entry receptors on cells in cerebral organoids. We observed significant increases in the number of viral genomes, viral spread and penetrance, and multinucleated syncytia in neural tissues infected with HCMV propagated in epithelial cells compared to fibroblasts. To determine if this was related to entry receptor distribution, we measured expressions of cellular entry receptors and observed similar distributions of all receptors on cells obtained from organoids indicating that source of virus is likely the key determinant. Next, we asked whether we could limit pathogenesis using neutralization antibodies. We found that pre-treatment with antibodies against viral glycoprotein B (gB) and gH successfully decreased viral genome levels, viral gene expression, and virus-induced syncytia. In contrast, targeting specific cellular entry receptors failed to limit infection. Using an antibody against gB, we also observed partial protection of developmental gene expression that was further improved by the addition of brain derived neurotropic factor (BDNF). These studies indicate that source of HCMV is a key determinant of neuronal pathogenesis that can be limited by neutralization antibodies and neurotropic factors. 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/2023.03.01.530630v1?rss=1 Authors: Libe-Philippot, B., Iwata, R., Recupero, A. J., Wierda, K., Ditkowska, M., Gaspariunaite, V., Vermaercke, B., Peze-Heidsieck, E., Remans, D., Charrier, C., Polleux, F., Vanderhaeghen, P. Abstract: Human-specific (HS) genes are potential drivers of brain evolution, but their impact on human neuron development and disease remains unclear. Here we studied HS genes SRGAP2B/C in human cortical projection neurons (CPNs) in vivo, using xenotransplantation in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs greatly accelerated synaptic development, indicating their requirement for human-specific synaptic neoteny. SRGAP2B/C acted by downregulating their ancestral paralog SRGAP2A, thereby upregulating postsynaptic levels of SYNGAP1, a major intellectual deficiency/autism spectrum disorder (ID/ASD) gene. Combinatorial genetic invalidation revealed that the tempo of synaptogenesis is set by a balance between SRGAP2A and SYNGAP1, which in human CPNs is tipped towards neoteny by SRGAP2B/C. Our results demonstrate that HS genes can modify the phenotypic expression of ID/ASD mutations through regulation of synaptic neoteny. 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/2023.02.28.530322v1?rss=1 Authors: Carli, J. M., Monks, J., McManaman, J. L. Abstract: Human milk delivers critical nutritional and immunological support to the infant. The milk fat globule and its membrane contain many bioactive components, yet the mechanism of milk fat secretion and how milk fat globule (MFG) components are regulated are poorly defined. In this study, we perform quantitative proteomic profiling of milk fat globules from human and mouse milk, as well as from isolated membranes physically disrupted from human milk fat globules. Using paired analyses of the human samples we report membrane enrichment of the proteins involved in docking/tethering the lipid droplet to the membrane as well as minor components involved in the signaling pathway for secretion. Comparing abundance between human and mouse milk fat globules we find that 8 of 12 major milk fat globule proteins are shared between the two species. Comparative pathway enrichment analyses between human and mouse samples reveal similarities in shared membrane trafficking and signaling pathways involved in milk fat secretion. Our results advance knowledge of the composition and relative quantities of proteins in human and mouse milk fat globules in greater detail, provide a quantitative profile of specifically enriched human milk fat globule membrane proteins, and identify core cellular systems involved in milk lipid secretion. 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/2023.02.15.528685v1?rss=1 Authors: Polino, A. J., Sviben, S., Melena, I., Piston, D. W., HUGHES, J. Abstract: Human islet primary cilia are vital glucose-regulating organelles whose structure remains uncharacterized. Scanning electron microscopy (SEM) is a useful technique for studying the surface morphology of membrane projections like primary cilia, but conventional sample preparation does not reveal the sub-membrane axonemal structure which holds key implications for cilia function. To overcome this challenge, we combined SEM with membrane-extraction techniques to examine cilia in native human islets. Our data show well-preserved cilia subdomains which demonstrate both expected and unexpected ultrastructural motifs. Morphometric features were quantified when possible, including axonemal length and diameter, microtubule conformations and chirality. We further describe a novel ciliary ring, a structure that may be a specialization in human islets. Key findings are correlated with fluorescence microscopy and interpreted in the context of cilia function as a cellular sensor and communications locus in pancreatic islets. 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/2023.02.07.527559v1?rss=1 Authors: VIELLE, C., MAURICE, N., PELLETIER, F., PECCHI, E., BAUNEZ, C. Abstract: Human social behavior is a complex construct requiring a wide range of cognitive abilities and is critically impaired in numerous neuropsychiatric diseases. Living in complex social groups, rodents offer suitable models to elucidate neural processing of social cognition. Recently, a potential involvement of the subthalamic nucleus (STN) in rats social behavior has been pointed out. For example, we showed that STN lesions abolish the modulatory effect of the familiarity on the rewarding value of social stimuli, questioning the involvement of STN in peer recognition. In this study, we thus assess the effects of STN lesions and optogenetic manipulations on peer and object recognition. STN optogenetic inhibition, like lesions, impair social recognition memory, while STN optogenetic high-frequency (HF) stimulation leads to a specific alteration of social encoding memory. None of these manipulations seem to interfere with social investigation, objects recognition memory, nor social novelty preference. Finally, STN optogenetic inhibition, but neither HF-stimulation, nor lesions, leads to an alteration of the cage-mate recognition memory. Overall, these results show that physiological activity of STN is necessary for rats to show a proper social recognition memory performance and question the possible detrimental effects of STN deep brain stimulation on these processes in human patients 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/2023.01.31.525662v1?rss=1 Authors: Smits, M. A. J., Schomakers, B. V., van Weeghel, M., Wever, E. J. M., Wust, R. C. I., Dijk, F., Janssens, G. E., Goddijn, M., Mastenbroek, S., Houtkooper, R., Hamer, G. Abstract: Human ovarian ageing encompasses the age-related decline in female fertility. Oxidative stress and mitochondrial dysfunction in oocytes are suggested as causal, but corroborating evidence is limited. Using immunofluorescence imaging on human ovarian tissue, we found oxidative damage by protein and lipid (per)oxidation at the primordial follicle stage. Additionally, using comprehensive metabolomics and lipidomics, a cohort of 150 human germinal vesicles and metaphase I oocytes and 15 corresponding cumulus cell samples displayed a shift in glutathione to oxiglutathione ratio and depletion of phospholipids. Age-related changes in polar metabolites suggested a decrease in mitochondrial function, as demonstrated by NAD+, purine and pyrimidine depletion, while glycolysis substrates and glutamine accumulated with age. Oocytes of advanced maternal age likely used alternative energy sources like glycolysis and the adenosine salvage pathway, and possibly increased ATP production in cumulus cells. These findings indicate that oocytes of advanced maternal age suffer from oxidative damage and mitochondrial dysfunction. 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/2023.01.23.525254v1?rss=1 Authors: Kahn, A. E., Szymula, K., Bassett, D. S., Nyema, N., Haggerty, E. B., Aguirre, G. K. Abstract: Human experience is built upon sequences of discrete events. From those sequences, humans build impressively accurate models of their world. This process has been referred to as graph learning, a form of structure learning in which the mental model encodes the graph of event-to-event transition probabilities, typically in medial temporal cortex. Recent evidence suggests that some network structures are easier to learn than others, but the neural properties of this effect remain unknown. Here we use fMRI to show that the network structure of a temporal sequence of stimuli influences the fidelity with which those stimuli are represented in the brain. Healthy adult human participants learned a set of stimulus-motor associations following one of two graph structures. The design of our experiment allowed us to separate regional sensitivity to the structural, stimulus, and motor response components of the task. As expected, whereas the motor response could be decoded from neural representations in postcentral gyrus, the shape of the stimulus could be decoded from lateral occipital cortex. The structure of the graph impacted the nature of neural representations: when the graph was modular as opposed to lattice-like, BOLD representations in visual areas better predicted trial identity in a held-out run and displayed higher intrinsic dimensionality. Our results demonstrate that even over relatively short timescales, graph structure determines the fidelity of event representations as well as the dimensionality of the space in which those representations are encoded. More broadly, our study shows that network context influences the strength of learned neural representations, motivating future work in the design, optimization, and adaptation of network contexts for distinct types of learning over different timescales. 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/2023.01.11.523683v1?rss=1 Authors: Huang, W., Dong, X., Ma, G., Zhang, Z., Su, L., Shu, N. Abstract: Human brain shows higher individual variability in functional connectivity in heteromodal association cortex but lower in unimodal cortex. Structural connectivity is the anatomical substrate of the functional connectivity. However, the spatial pattern of individual variability in structural connectivity still remains unclear. In the present study, we depicted the temporal-spatial pattern of individual variability in structural connectivity, which increases with aging and is lowest in unimodal sensorimotor regions, intermediate in association regions and highest in para-limbic regions. Our results demonstrated that this specific spatial distribution relates to the plasticity of synapse and white matter. Considering the brain systems and pathways involved in a cognition maybe different among individuals, we proposed a modified ridge regression model that is able to predict individual cognition and generate idiographic brain mapping. The individual variability in structural connectivity and idiographic brain mapping is significantly correlated. Overall, our study has potential implications for understanding biological and genetic mechanisms of individual differences in structural connectivity, guiding interventions to promote successful cognitive and interpreting statistical maps in human connectome. 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/2023.01.12.523752v1?rss=1 Authors: Yang, L., Liang, P., Yang, H., Coyne, C. Abstract: Human trophoblast organoids (TOs) are a three-dimensional ex vivo culture model that can be used to study various aspects of placental development, physiology, and pathology. Previously, we showed that TOs could be derived and cultured from full-term human placental tissue and used as models of trophoblast innate immune signaling and teratogenic virus infections (Yang et al., 2022). However, a remaining challenge of TOs cultured in domes of Matrigel or other extracellular matrix is their inverted polarity, with proliferative cytotrophoblasts (CTBs) on the outer surface of organoids and the multi-nucleated syncytiotrophoblast (STB) primarily localized within the inner surface, which is in direct contrast to the orientation that occurs in vivo. Here, we developed a method to culture TOs under conditions that recapitulate the cellular orientation of chorionic villi in vivo. We show that standard TOs containing the STB layer inside the organoid (STBin) develop into organoids containing the STB on the outer surface (STBout) when cultured in suspension with gentle agitation. STBout organoids secrete higher levels of hormones and cytokines from the STB, including human chorionic gonadotropin (hCG) and interferon (IFN)-lambda2. Using membrane capacitance measurements, we also show that the outermost surface of STBout organoids contain large syncytia comprised of greater than 60 nuclei compared to STBin organoids that contain small syncytia ( less than 6 nuclei) and mononuclear cells. The growth of TOs under conditions that mimic the cellular orientation of chorionic villi in vivo thus allows for the study of a variety of aspects of placental biology under physiological conditions. 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/2023.01.10.523345v1?rss=1 Authors: Vinci-Booher, S., McDonald, D., Berquist, E., Pestilli, F. Abstract: Human learning is a complex phenomenon that varies greatly among individuals and is related to the microstructure of major white matter tracts in several learning domains, yet the impact of the existing myelination of major white matter tracts on future learning outcomes remains unclear. We employed a machine-learning model selection framework to evaluate whether existing microstructure might predict individual differences in the potential for learning a sensorimotor task, and further, if the mapping between the microstructure of major white matter tracts and learning was selective for learning outcomes. We used diffusion tractography to measure the mean fractional anisotropy (FA) of major white matter tracts in 60 adult participants who then underwent training and subsequent testing to evaluate learning. During training, participants practiced drawing a set of 40 novel symbols repeatedly using a digital writing tablet. For testing, we measured drawing learning as the slope of draw duration over the practice session; we measured visual recognition learning as the performance accuracy in an old/new 2-AFC recognition task. We performed two separate analyses, one that assessed the relationship between pre-training FA and learning to draw novel symbols and a second that assessed the relationship between pre-training FA and learning to visually recognize symbols after training. Both analyses focused on the microstructure of white matter tracts that connect dorsal and ventral cortices, the posterior vertical pathway (PVP), as well as tracts within the dorsal motor system and within the ventral perceptual system. Results demonstrated that the microstructure of major white matter tracts selectively predicted learning outcomes, with left hemisphere pArc and SLF 3 tracts predicting drawing learning and the left hemisphere MDLFspl predicting visual recognition learning. These results were replicated in a repeat, held-out data set and supported with complementary analyses. Overall, results suggest that individual differences in the microstructure of human white matter tracts may be selectively related to future learning outcomes that arise from a single experience and open avenues of inquiry concerning the impact of existing tract myelination and individual differences in the potential for learning. 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/2023.01.09.523096v1?rss=1 Authors: Wang, Y., Lee, H., Kuhl, B. A. Abstract: Human neuroimaging studies have shown that the contents of episodic memories are represented in distributed patterns of neural activity. However, these studies have mostly been limited to decoding simple, unidimensional properties of stimuli. Semantic encoding models, in contrast, offer a means for characterizing the rich, multidimensional information that comprises episodic memories. Here, we extensively sampled four human fMRI subjects to build semantic encoding models and then applied these models to reconstruct content from natural scene images as they were viewed and recalled from memory. First, we found that multidimensional semantic information was successfully reconstructed from activity patterns across visual and lateral parietal cortices, both when viewing scenes and when recalling them from memory. Second, whereas visual cortical reconstructions were much more accurate when images were viewed versus recalled from memory, lateral parietal reconstructions were comparably accurate across visual perception and memory. Third, by applying natural language processing methods to verbal recall data, we showed that fMRI-based reconstructions reliably matched subjects' verbal descriptions of their memories. In fact, reconstructions from ventral temporal cortex more closely matched subjects' own verbal recall than other subjects' verbal recall of the same images. Fourth, encoding models reliably transferred across subjects: memories were successfully reconstructed using encoding models trained on data from entirely independent subjects. Together, these findings provide evidence for successful reconstructions of multidimensional and idiosyncratic memory representations and highlight the differential sensitivity of visual cortical and lateral parietal regions to information derived from the external visual environment versus internally-generated memories. 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/2023.01.03.522057v1?rss=1 Authors: Nakajima, I., Tsukimura, T., Ono, T., Shiga, T., Shitara, H., Togawa, T., Sakuraba, H., Miyaoka, Y. Abstract: Human induced pluripotent stem cells (iPSCs) have already been used in transplantation therapies. Currently, cells from healthy people are transplanted into patients with diseases. With the rapid evolution of genome editing technology, genetic modification could be applied to enhance the therapeutic effects of iPSCs, such as the introduction of secreted molecules to make the cells a drug delivery system. Here, we addressed this possibility by utilizing a Fabry disease mouse model, as a proof of concept. Fabry disease is caused by the lack of -Galactosidase A (GLA). We previously developed an immunotolerant therapeutic molecule, modified -N-acetylgalactosaminidase (mNAGA). We confirmed that secreted mNAGA from genome-edited iPSCs compensated for the GLA activity in GLA-deficient cells using an in vitro co-culture system. Moreover, iPSCs transplanted into Fabry model mice secreted mNAGA and supplied GLA activity to the liver. This study demonstrates the great potential of genome-edited iPSCs secreting therapeutic molecules. 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/2022.12.23.521743v1?rss=1 Authors: Wehrheim, M. H., Faskowitz, J., Sporns, O., Fiebach, C., Kaschube, M., Hilger, K. Abstract: Human functional brain connectivity can be temporally decomposed into states of high and low cofluctuation, defined as coactivation of brain regions over time. Despite their low frequency of occurrence, states of particularly high cofluctuation have been shown to reflect fundamentals of intrinsic functional network architecture (derived from resting-state fMRI) and to be highly subject-specific. However, it is currently unclear whether such network-defining states of high cofluctuation also contribute to individual variations in cognitive abilities, which strongly rely on the interactions among distributed brain regions. By introducing CMEP, an eigenvector-based prediction framework, we show that functional connectivity estimates from as few as 20 temporally separated time frames ( less than 3% of a 10 min resting-state fMRI scan) are significantly predictive of individual differences in intelligence (N = 281, p less than .001). In contrast and against previous expectations, individual's network-defining time frames of particularly high cofluctuation do not achieve significant prediction of intelligence. Multiple functional brain networks contribute to the prediction, and all results replicate in an independent sample (N = 831). Our results suggest that although fundamentals of person-specific functional connectomes can be derived from few time frames of highest brain connectivity, temporally distributed information is necessary to extract information about cognitive abilities from functional connectivity time series. This information, however, is not restricted to specific connectivity states, like network-defining high-cofluctuation states, but rather reflected across the entire length of the brain connectivity time series. 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/2022.12.23.521819v1?rss=1 Authors: Meliss, S., Murayama, K. Abstract: Human memory is selective and not all experiences are remembered. Both monetary rewards/incentives and curiosity have been found to motivate and facilitate learning by dopaminergic midbrain projections to the hippocampus during encoding. In this study, we examined potential brain mechanisms during early consolidation period that jointly or independently contribute to these facilitating effects. Participants (N = 50) watched 36 videos of magic tricks and rated their "subjective feelings of curiosity" while the availability of extrinsic incentives was manipulated between groups. Functional magnetic resonance imaging (fMRI) data were acquired before, during, and after learning, and memory for magic tricks was assessed one week after. Our analysis focused on the change in resting-state functional connectivity (RSFC) between the dopaminergic midbrain and the anterior hippocampus, a dopaminergic consolidation mechanism previously reported in the context of extrinsically motivated learning. Changes in RSFC were correlated with behavioural measures of learning, i.e., the total number of items encoded and the curiosity-driven memory benefit. We found that brain-behaviour correlations differed depending on the availability of extrinsic incentives. More specifically, the correlation between the total number of items encoded and RSFC change was significantly different in the incentivised compared to the control group. The curiosity-driven memory benefit, however, did not correlate with changes in RSFC in either of the groups. In sum, this suggests that curiosity-motivated learning might be supported by different consolidation mechanisms compared to extrinsically motivated learning and that extrinsic incentives influence consolidation mechanisms supporting learning. 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/2022.12.21.521442v1?rss=1 Authors: Raschick, M., Richter, A., Fischer, L., Knopf, L., Schult, A., Yakupov, R., Behnisch, G., Guttek, K., Düzel, E., Dunay, I. R., Seidenbecher, C. I., Schraven, B., Reinhold, D., Schott, B. H. Abstract: Human cognitive abilities, and particularly hippocampus-dependent memory performance typically decline with increasing age. Immunosenescence, the age-related disintegration of the immune system are increasingly coming into the focus of research as a considerable factor contributing to cognitive decline. In the present study, we investigated potential associations between plasma levels of pro- and anti-inflammatory cytokines and learning and memory performance as well as hippocampal anatomy in young and older adults. Plasma concentrations of the inflammation marker CRP as well as the pro-inflammatory cytokines IL-6 and TNF- and the anti-inflammatory cytokine TGF-{beta}1 were measured in 142 healthy adults (57 young, 24.47 +/- 4.48 years; 85 older, 63.66 +/- 7.32 years) who performed tests of explicit memory (Verbal Learning and Memory Test, VLMT; Wechsler Memory Scale, Logical Memory, WMS) with an additional delayed recall test after 24 hours. Hippocampal volumetry and hippocampal subfield segmentation were performed using FreeSurfer, based on T1-weighted and high-resolution T2-weighted MR images. When investigating the relationship between memory performance, hippocampal structure, and plasma cytokine levels, we found that TGF-{beta}1 concentrations were positively correlated with the volumes of the hippocampal CA4-dentate gyrus region in older adults. These volumes were in turn positively associated with better performance in the WMS, particularly in the delayed memory test. Our results support the notion that endogenous anti-inflammatory mechanisms may act as protective factor in neurocognitive aging. 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/2022.12.08.519616v1?rss=1 Authors: Zhang, Y., Gregorich, Z. R., Wang, Y., Braz, C. U., Zhang, J., Liu, Y., Liu, P., Aori, N., Hacker, T. A., Granzier, H., Guo, W. Abstract: Human patients carrying genetic mutations in RNA binding motif 20 (RBM20) develop a clinically aggressive dilated cardiomyopathy (DCM). RBM20 is a splicing factor with two canonical domains, an RNA recognition motif (RRM) and an arginine-serine rich (RS) domain. RRM loss-of-function disrupts the splicing of RBM20 target transcripts and leads to systolic dysfunction without overt DCM, while mutations in the RS domain precipitate DCM. We show that mice lacking the RS domain (Rbm20deltaRS) manifest DCM with mis-splicing of RBM20 target transcripts. We found that RBM20 is mis-localized in Rbm20{Delta}RS mice but not in mice lacking the RRM, which are also deficient in RBM20 splicing. We determine that the RS domain, not other domains including the RRM, is critical for RBM20 nuclear import and define the core nuclear localization signal (NLS) within this domain. Mutation analysis of phosphorylation sites within the RS domain indicate that phosphorylation is dispensable for RBM20 nuclear import. Collectively, our findings establish disruption of the NLS in RBM20 as a causative mechanism in DCM through nucleocytoplasmic transport. 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/2022.11.29.518317v1?rss=1 Authors: Wilbers, R., Metodieva, V. D., Duverdin, S., Heyer, D. B., Galakhova, A. A., Mertens, E. J., Versluis, T. D., Baayen, J. C., Idema, S., Noske, D. P., Verburg, N., Willemse, R. B., de Witt Hamer, P. C., Kole, M. H. P., de Kock, C. P. J., Mansvelder, H. D., Goriounova, N. A. Abstract: Human cortical pyramidal neurons are large, have extensive dendritic trees, and yet have surprisingly fast input-output properties: rapid subthreshold synaptic membrane potential changes are reliably encoded in timing of action potentials (APs). Here, we tested whether biophysical properties of voltage-gated sodium (Na+) and potassium (K+) currents in human pyramidal neurons can explain their fast input-output properties. Human Na+ and K+ currents had depolarized voltage-dependence, slower inactivation and exhibited a faster recovery from inactivation than their mouse counterparts. Computational modeling showed that despite lower Na+ channel densities in human neurons, the biophysical properties of Na+ channels resulted in higher channel availability and contributed to fast AP kinetics stability. Finally, human Na+ channel properties also resulted in a larger dynamic range for encoding of subthreshold membrane potential changes. Thus, biophysical adaptations of voltage-gated Na+ and K+ channels enable fast input-output properties of large human pyramidal neurons. 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/2022.12.02.514196v1?rss=1 Authors: Walhovd, K. B., Krogsrud, S. K., Amlien, I. K., Sorensen, O., Wang, Y., Brathen, A. C. S., Overbye, K., Kransberg, J., Mowinckel, A. M., Magnussen, F., Herud, M., Haberg, A. K., Fjell, A. M., Vidal-Pineiro, D. Abstract: Human fetal development has been associated with brain health at later stages. It is unknown whether and how consistently growth in utero, as indexed by birth weight (BW), relates to lifespan brain characteristics and changes, and to what extent these influences are of a genetic and/or environmental nature. We hypothesized that associations of BW and structural brain characteristics persist through the lifespan, with topographically consistent effects across samples of varying age and origin, that BW is not protective against atrophy in aging, and that effects are partly environmental. The associations of BW and cortical area, thickness, volume and their change were investigated vertex-wise in developmental (ABCD), older adult and aging (UKB) and lifespan (LCBC) longitudinal samples. In total, 5794 persons (4-82 years, w/ 386 monozygotic twins), were followed for up to 8.3 years, yielding 12,088 brain MRIs. Positive associations between BW and cortical surface area and volume were remarkably stable through the lifespan, within and across samples of different origin, with spatial correlations in the range r = .51- .79. In contrast, there was modest and no consistent effect of BW on brain changes. Effects of BW discordance in the monozygotic twin subsample indicated the effects were partly environmental. In conclusion, the influence of prenatal growth on cortical topography is stable through the lifespan, and is reliably seen in development, adulthood, and aging. These findings support early life influence on the brain through the lifespan according to a threshold model of brain reserve, rather than a maintenance model. 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/2022.11.25.517972v1?rss=1 Authors: Maurizi, E., Merra, A., Macaluso, C., Schiroli, D., Pellegrini, G. Abstract: Human corneal endothelial cells are organized in a tight mosaic of hexagonal cells and serve a critical function in maintaining corneal hydration and clear vision. Regeneration of the corneal endothelial tissue is hampered by its poor proliferative capacity, which is partially retrieved in vitro, albeit only for a limited number of passages before the cells undergo mesenchymal transition (EnMT). Although different culture conditions have been proposed in order to delay this process and prolong the number of cell passages, EnMT has still not been fully understood and successfully counteracted. In this perspective, we identified herein a single GSK3 inhibitor, CHIR99021, able to revert and avoid EnMT in primary human corneal endothelial cells (HCEnCs) from old donors until late passages in vitro (P8), as shown from cell morphology analysis (circularity). In accordance, CHIR99021 reduced expression of alpha-SMA, an EnMT marker, while restored endothelial markers such as ZO-1, Na+/K+ ATPase and N-cadherin, without increasing cell proliferation. A further analysis on RNA expression confirmed CHIR99021 induced downregulation of EnMT markers (alpha-SMA and CD44), upregulation of the proliferation repressor p21 and revealed novel insights into the beta-catenin and TGFbeta; pathways intersections in HCEnCs. The use of CHIR99021 sheds light on the mechanisms involved in EnMT and brings a substantial advantage in maintaining primary HCEnCs in culture until late passages, while preserving the correct morphology and phenotype. Altogether, these results bring crucial advancements towards the improvement of the corneal endothelial cells based therapy. 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/2022.11.23.517672v1?rss=1 Authors: Luna, R., Vadillo, M. A., Luque, D. Abstract: Human behaviour is driven by two types of processes running in parallel: goal-directed and habitual, each supported by different computational-learning mechanisms, model-free and model-based respectively. In model-free strategies, stimulus-response associations are strengthened when actions are followed by a reward and weakened otherwise. In model-based learning, previous to selecting an action, the current values of the different possible actions are computed based on a detailed model of the environment. Previous research with the two-stage task suggests that participants' behavior usually shows a mixture of both strategies. But, interestingly, a recent study by da Silva and Hare (2020) found that participants deploy a purely model-based behavior when they are given detailed instructions about the structure of the task. In the present study, we reproduce this essential experiment using a larger sample size (N=59). However, our results do not suggest a sole model-based behaviour, but rather a hybrid one. Furthermore, an additional experiment shows that slight changes in the task, like a consistent stimulus-response mapping, can encourage reliance on model-free strategies, even if participants are presented with improved instructions. This suggests that the model-free marker, as measured by the two-stage task, is related to S-R learning. 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/2022.11.23.517478v1?rss=1 Authors: Dobs, K., Yuan, J., Martinez, J., Kanwisher, N. Abstract: Human face recognition is highly accurate, and exhibits a number of distinctive and well documented behavioral "signatures" such as the use of a characteristic representational space, the disproportionate performance cost when stimuli are presented upside down, and the drop in accuracy for faces from races the participant is less familiar with. These and other phenomena have long been taken as evidence that face recognition is "special". But why does human face perception exhibit these properties in the first place? Here we use convolutional neural networks (CNNs) to test the hypothesis that all of these signatures of human face perception result from optimization for the task of face recognition. Indeed, as predicted by this hypothesis, these phenomena are all found in CNNs trained on face recognition, but not in CNNs trained on object recognition, even when the amount of face experience is matched. To test whether these signatures are in principle specific to faces, we optimized a CNN on car discrimination and tested it on upright and inverted car images. As for face perception, the car-trained network showed a drop in performance for inverted versus upright cars. Similarly, CNNs trained only on inverted faces produce an inverted inversion effect. These findings show that the behavioral signatures of human face perception reflect and are well explained as the result of optimization for the task of face recognition, and that the nature of the computations underlying this task may not be so "special" after all. 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/2022.11.16.516719v1?rss=1 Authors: Weber, J., Iwama, G., Solbakk, A.-K., Blenkmann, A. O., Larsson, P. G., Ivanovic, J., Knight, R. T., Endestad, T., Helfrich, R. Abstract: Human prefrontal cortex (PFC) constitutes the structural basis underlying flexible cognitive control, where mixed-selective neural populations encode multiple task-features to guide subsequent behavior. The mechanisms by which the brain simultaneously encodes multiple task-relevant variables while minimizing interference from task-irrelevant features remain unknown. Leveraging intracranial recordings from the human PFC, we first demonstrate that competition between co-existing representations of past and present task variables incurs a behavioral switch cost. Our results reveal that this interference between past and present states in the PFC is resolved through coding partitioning into distinct low-dimensional neural states; thereby strongly attenuating behavioral switch costs. In sum, these findings uncover a fundamental coding mechanism that constitutes a central building block of flexible cognitive control. 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/2022.11.03.514996v1?rss=1 Authors: Seidlitz, J., Mallard, T. T., Vogel, J. W., Lee, Y. H., Warrier, V., Ball, G., Hansson, O., Hernandez, L. M., Mandal, A. S., Wagstyl, K., Lombardo, M. V., Courchesne, E., Glessner, J. T., Satterthwaite, T. D., Bethlehem, R. A. I., Lifespan Brain Chart Consortium,, Tasaki, S., Ng, B., Gaiteri, C., Smoller, J. W., Ge, T., Gandal, M. J., Alexander-Bloch, A. F. Abstract: Human brain size increases dynamically through early development, peaks in adolescence, and varies up to two-fold among adults. Although previous studies have elucidated changes in brain size across evolution, development, traits, and diseases, the molecular underpinnings of interindividual variation in brain size remain unknown. Here, we leverage postmortem brain RNA sequencing and estimates of brain weight (BW) in 2,531 individuals across three independent datasets, to identify 928 genes that show genome-wide significant associations with either higher or lower BW (BW+, BW-, respectively). These BW gene sets showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto developmental, functional and cellular axes of brain organization. Expression differences among evolutionarily conserved BW genes were predictive of interspecies differences in brain size, and functional annotation of BW genes revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses of in vivo neuroimaging phenotypes confirmed that the genetic regulation of BW- transcripts influences cortical surface area and volume, as well as behavioral traits related to brain function and disease. Cumulatively, our study represents a major step towards the goal of delineating the causal mechanisms of human brain size variation in health and disease. 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/2022.10.28.514329v1?rss=1 Authors: Miyoshi, K., Nishida, S. Abstract: Human decision behavior entails a graded awareness of its certainty, known as a feeling of confidence. Until now, considerable interest has been paid to behavioral and computational dissociations of decision and confidence, which has raised an urgent need for measurement frameworks that can quantify the efficiency of confidence rating relative to decision accuracy (metacognitive efficiency). As a unique addition to such frameworks, we have developed a new signal detection theory paradigm utilizing the generalized gaussian distribution (GGSDT). This framework evaluates the observer's internal standard deviation ratio and metacognitive efficiency through the scale and shape parameters respectively. The shape parameter quantifies the kurtosis of internal distributions and can practically be understood in reference to the proportion of the gaussian ideal observer's confidence being disrupted with random guessing (metacognitive lapse rate). This interpretation holds largely irrespective of the contaminating effects of decision accuracy or operating characteristic asymmetry. Thus, the GGSDT enables hitherto unexplored research protocols (e.g., direct comparison of yes/no versus forced-choice metacognitive efficiency), expected to find applications in various fields of behavioral science. This paper provides a detailed walkthrough of the GGSDT analysis with an accompanying R package (ggsdt). 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/2022.10.27.514100v1?rss=1 Authors: Eisenkolb, V. M., Held, L. M., Utzschmid, A., Lin, X., Krieg, S. M., Meyer, B., Gempt, J., Jacob, S. N. Abstract: Human single-unit studies currently rely on neurosurgical procedures that provide only limited brain coverage and on recording devices that do not integrate easily into established surgical routines. Here, we report reliable and robust acute multi-channel recordings with broad cortical access using planar microelectrode arrays (MEA) implanted intracortically in awake brain surgery. We provide a comprehensive characterization of extracellular neuronal activity acquired intraoperatively in tumor patients with large open craniotomies. MEA implantation was fast, safe and yielded high-quality signals at the microcircuit, local field potential level, and at the cellular, single-unit level. Recording from parietal association cortex, a region previously unexplored in human single-unit studies, we demonstrate applications on these complementary spatial scales and describe travelling waves of oscillatory activity as well as single-neuron and neuronal population responses during numerical cognition including operations with uniquely human number symbols. Intraoperative MEA recordings are practicable and can be scaled up to explore cellular and microcircuit mechanisms of a wide range of human brain functions. 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/2022.10.27.514074v1?rss=1 Authors: Suleiman, A., Solomonow-Avnon, D., Mawase, F. Abstract: Human motor behavior involves planning and execution, but we often perform some actions more frequently. Experimentally manipulating the probability distribution of a movement through intensive repetition toward a certain direction causes physiological bias toward that direction, which can be cortically-evoked by transcranial magnetic stimulation (TMS). However, because movement execution and plan histories were indistinguishable to date, to what extent TMS-evoked biases are due to more frequently executed movement, or recent planning of movement, is unclear. Here, we use novel experimentation to separately manipulate recent history of movement plans and execution, and probe the effects of this on physiological biases using TMS, and on default plan for goal-directed actions using a behavioral timed-response task. At baseline, physiological biases shared similar low-level kinematic properties (direction) to default plan for upcoming movement. However, when recent movement execution history was manipulated via thumb movement repetitions toward a specific direction, we found a significant effect on physiological biases, but not plan-based goal-directed movement. To further determine if physiological biases reflect ongoing motor planning, we biased movement plan history by increasing the likelihood of a specific target location, and found a significant effect on the default plan for goal-directed movements. However, TMS-evoked movement during the preparation period did not become biased toward the most frequent plan. This suggests that physiological biases provide a readout of the default state of M1 population activity in the movement-related space, but not ongoing neural activation in the planning-related space, potentially ruling out relevance of cortically-evoked physiological biases to voluntary movements. 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/2022.10.25.513688v1?rss=1 Authors: Jia, X., Bian, X., Zhu, J., Liu, S., Liang, W., Yu, S., Jiang, L., Mao, R., Rao, Y. Abstract: Human mutations in the gene encoding the solute carrier (SLC) 6A17 caused intellectual disability (ID). The physiological role of SLC6A17 and pathogenesis of Slc6a17-based-ID were both unclear. Here we report learning deficits in SLC6A17 knockout and point mutants. Biochemistry, proteomics and electron microscopy (EM) support SLC6A17 protein localization in synaptic vesicles (SVs). Chemical analysis of SVs by liquid chromatography coupled to mass spectrometry (LC-MS) revealed glutamine (Gln) in SVs containing SLC6A17. Virally mediated overexpression of SLC6A17 increased Gln in SVs. Either genetic or virally mediated targeting of SLC6A17 reduced Gln in SVs. One ID mutation caused SLC6A17 mislocalization while the other caused defective Gln transport. Multidisciplinary approaches with 7 types of genetically modified mice have uncovered Gln as a new molecule in SVs, established the necessary and sufficient roles of SLC6A17 in Gln transport into SVs, and suggested SV Gln decrease as the key pathogenetic mechanism in human ID. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

By Carl Shulman and Nick Bostrom. Abstract:Human capital is an important determinant of individual and aggregate economic outcomes, and a major input to scientific progress. It has been suggested that advances in genomics may open up new avenues to enhance human intellectual abilities genetically, complementing environmental interventions such as education and nutrition. One way to do this would be via embryo selection in the context of in vitro fertilization (IVF). In this article, we analyze the feasibility, timescale, and possible societal impacts of embryo selection for cognitive enhancement. We find that embryo selection, on its own, may have significant (but likely not drastic) impacts over the next 50 years, though large effects could accumulate over multiple generations. However, there is a complementary technology – stem cell-derived gametes – which has been making rapid progress and which could amplify the impact of embryo selection, enabling very large changes if successfully applied to humans. Read the full paper:https://nickbostrom.com/papers/embryo.pdfMore episodes at:https://radiobostrom.com/

By Nick Bostrom, Anders Sandberg, and Matthew van der Merwe.This is an updated version of The Wisdom of Nature, first published in the book Human Enhancement (Oxford University Press, 2009).Abstract:Human beings are a marvel of evolved complexity. When we try to enhance poorly-understood complex evolved systems, our interventions often fail or backfire. It can appear as if there is a “wisdom of nature” which we ignore at our peril. A recognition of this reality can manifest as a vaguely normative intuition, to the effect that it is “hubristic” to try to improve on nature, or that biomedical therapy is ok while enhancement is morally suspect. We suggest that one root of these moral intuitions may be fundamentally prudential rather than ethical. More importantly, we develop a practical heuristic, the “evolutionary optimality challenge”, for evaluating the plausibility that specific candidate biomedical interventions would be safe and effective. This heuristic recognizes the grain of truth contained in “nature knows best” attitudes while providing criteria for identifying the special cases where it may be feasible, with present or near-future technology, to enhance human nature.Read the full paper:https://www.nickbostrom.com/evolutionary-optimality.pdfMore episodes at:https://radiobostrom.com/

By Nick Bostrom, Anders Sandberg, and Matthew van der Merwe.This is an updated version of The Wisdom of Nature, first published in the book Human Enhancement (Oxford University Press, 2009).Abstract:Human beings are a marvel of evolved complexity. When we try to enhance poorly-understood complex evolved systems, our interventions often fail or backfire. It can appear as if there is a “wisdom of nature” which we ignore at our peril. A recognition of this reality can manifest as a vaguely normative intuition, to the effect that it is “hubristic” to try to improve on nature, or that biomedical therapy is ok while enhancement is morally suspect. We suggest that one root of these moral intuitions may be fundamentally prudential rather than ethical. More importantly, we develop a practical heuristic, the “evolutionary optimality challenge”, for evaluating the plausibility that specific candidate biomedical interventions would be safe and effective. This heuristic recognizes the grain of truth contained in “nature knows best” attitudes while providing criteria for identifying the special cases where it may be feasible, with present or near-future technology, to enhance human nature.Read the full paper:https://www.nickbostrom.com/evolutionary-optimality.pdfMore episodes at:https://radiobostrom.com/