bioRxiv Subject Collection: Neuroscience's Journal
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Friday, December 29th, 2023
| Time |
Event |
| 2:46a |
A multiscale model of striatum microcircuit dynamics
Building large-scale simulations of neuronal activity is currently a main challenge in neuroscience research. An efficient approach has been recently adopted which is based on the use of mean-field models to build whole-brain simulations, where large neuronal populations are represented by single mean-field models. However, these methods are normally based on generic mean-field models that do not capture the cellular and structural specificity of each brain region, which imposes a strong limitation to its applicability. Thus, the development of region specific mean-field models is currently of great relevance, which can provide a big advance to these methods. In this paper we present spiking network and mean-field models of the striatum microcircuit, the largest structure in the basal ganglia, an area known for its key role in functions such as learning and motor control. To this end we adopt a recent formalism based on a bottom-up approach that starts from single-cell models and spiking networks to build a mean-field model of populations of neurons with different cell types. We start with a brief introduction to the microcircuit of the striatum and we describe step by step the construction of a spiking network model, and its mean-field, for this area. Then we test the mean-field model by analyzing the response of the system to the main brain rhythms observed in the striatum and comparing our results to the corresponding spiking networks. Next, we study the effects of dopamine in striatal cells, a very important feature of the area, and we show its dynamical consequences at the network level, and how it can be captured by the mean-field model. Finally we introduce a basic implementation of reinforcement learning (one of the main known functions of the basal-ganglia) using the mean-field model of the striatum microcircuit. | | 2:46a |
EEG and computational aspects of how aging affects sleep slow waves
Sleep slow-waves have been reported to vary with age in human subjects, as well as in mouse, but the underlying mechanisms remain unclear. Here, we perform a precise quantification of the effect of aging on the shape and dynamics of sleep slow waves, in a large cohort of human subjects recorded with the electro-encephalogram (EEG) during sleep. The fine-structure analysis of slow waves reveals that they slow-down, increase of variability and decrease in amplitude with age. We next investigate a computational model of the genesis of slow-wave activity and model the aging by a global decrease of the strength of the external excitatory drive to the network. This simple model reproduces some of the main features observed in the EEG, suggesting that changes of long-range excitatory connection strength may explain the evolution of slow-waves with age. | | 4:31p |
A neural network for religious fundamentalism derived from patients with brain lesions
Religious fundamentalism, characterized by rigid adherence to a set of beliefs putatively revealing inerrant truths, is ubiquitous across cultures and has a global impact on society. Understanding the psychological and neurobiological processes producing religious fundamentalism may inform a variety of scientific, sociological, and cultural questions. Research indicates that brain damage can alter religious fundamentalism. However, the precise brain regions involved with these changes remain unknown. Here, we analyzed brain lesions associated with varying levels of religious fundamentalism in two large datasets from independent laboratories. Lesions associated with greater fundamentalism were connected to a specific brain network with nodes in the right orbitofrontal, dorsolateral prefrontal, and inferior parietal lobes. This fundamentalism network was strongly right hemisphere lateralized and highly reproducible across the independent datasets (r = 0.82) with cross-validations between datasets. To explore the relationship of this network to lesions previously studied by our group, we tested for similarities to twenty-one lesion-induced conditions. Lesions associated with confabulation and criminal behavior showed a similar connectivity pattern as lesions associated with greater fundamentalism. Moreover, lesions associated with poststroke pain showed a similar connectivity pattern as lesions associated with lower fundamentalism. These findings are consistent with hemispheric specializations in reasoning and lend insight into previously observed epidemiological associations with fundamentalism, such as cognitive rigidity and outgroup hostility. | | 5:46p |
A targeted CRISPR-Cas9 mediated F0 screen identifies genes involved in establishment of the enteric nervous system
The vertebrate enteric nervous system (ENS) is a crucial network of enteric neurons and glia resident within the entire gastrointestinal tract (GI). Overseeing essential GI functions such as gut motility and water balance, the ENS serves as a pivotal bidirectional link in the gut-brain axis. During early development, the ENS is primarily derived from enteric neural crest cells (ENCCs). Disruptions to ENCC development, as seen in conditions like Hirschsprung disease (HSCR), lead to absence of ENS in the GI, particularly in the colon. In this study, using zebrafish, we devised an in vivo F0 CRISPR-based screen employing a robust, rapid pipeline integrating single-cell RNA sequencing, CRISPR reverse genetics, and high-content imaging. Our findings unveil various genes, including those encoding for opioid receptors, as possible regulators of ENS establishment. In addition, we present evidence that suggests opioid receptor involvement in neurochemical coding of the larval ENS. In summary, our work presents a novel, efficient CRISPR screen targeting ENS development, facilitating the discovery of previously unknown genes, and increasing knowledge of nervous system construction. | | 5:46p |
Psychometric validation and clinical correlates of an experiential foraging task
Measuring the function of decision-making systems is a central goal of computational psychiatry. Individual measures of decisional function could be used to describe neurocognitive profiles that underpin psychopathology and offer insights into deficits that are shared across traditional diagnostic classes. However, there are few demonstrably reliable and mechanistically relevant metrics of decision making that can accurately capture the complex overlapping domains of cognition whilst also quantifying the heterogeneity of function between individuals. The WebSurf task is a reverse-translational human experiential foraging paradigm which indexes naturalistic and clinically relevant decision-making. To determine its potential clinical utility, we examined the psychometric properties and clinical correlates of behavioural parameters extracted from WebSurf in an initial exploratory experiment and a pre-registered validation experiment. Behaviour was stable over repeated administrations of the task, as were individual differences. The ability to measure decision making consistently supports the potential utility of the task in predicting an individual's propensity for response to psychiatric treatment, in evaluating clinical change during treatment, and in defining neurocognitive profiles that relate to psychopathology. Specific aspects of WebSurf behaviour also correlate with anhedonic and externalising symptoms. Importantly, these behavioural parameters may measure dimensions of psychological variance that are not captured by traditional rating scales. WebSurf and related paradigms might therefore be useful platforms for computational approaches to precision psychiatry. | | 6:17p |
Molecular identification of wide-field amacrine cells in mouse retina that encode stimulus orientation
Visual information processing is sculpted by a diverse group of inhibitory interneurons in the retina called amacrine cells. Yet, for most of the >60 amacrine cell types, molecular identities and specialized functional attributes remain elusive. Here, we developed an intersectional genetic strategy to target a group of wide-field amacrine cells (WACs) in mouse retina that co-express the transcription factor Bhlhe22 and the Kappa Opioid Receptor (KOR; B/K WACs). B/K WACs feature straight, unbranched dendrites spanning over 0.5 mm (~15{o} visual angle) and produce non-spiking responses to either light increments or decrements. Two-photon dendritic population imaging reveals Ca2+ signals tuned to the physical orientations of B/K WAC dendrites, signifying a robust structure-function alignment. B/K WACs establish divergent connections with multiple retinal neurons, including unexpected connections with non-orientation-tuned ganglion cells and bipolar cells. Our work sets the stage for future comprehensive investigations of the most enigmatic group of retinal neurons: WACs. | | 8:16p |
Recruitment of Homodimeric Proneural Factors by Conserved CAT-CAT E-Boxes Drives Major Epigenetic Reconfiguration in Cortical Neurogenesis
The proneural factors of the basic-helix-loop-helix (bHLH) family of transcription factors coordinate early processes of neurogenesis and neurodifferentiation. Among them, Neurog2 and Neurod2 subsequently act specifying neurons of the glutamatergic lineage. The disruption of proneural factors, their target genes, and the DNA motifs they bind, have been linked to various neuropsychiatric disorders. Proneural factors operate on the DNA forming homodimers or heterodimers with other bHLH factors and binding to specific motifs called E-boxes, which are hexanucleotides of the form CANNTG, composed of two CAN half sites on opposed strands. These E-box motifs are highly enriched in regulatory elements that become active during corticogenesis. Although neurogenesis and neurodifferentiation appear to rely heavily on the activity of E-boxes, our understanding of the specific dynamics of DNA binding and partner usage throughout neurogenesis and neurodifferentiation remains largely unknown. To shed light on this critical facet of neural development, we conducted a comprehensive analysis leveraging ChIP-seq data of NEUROG2 and NEUROD2, paired with time-matched single-cell RNA-seq and ATAC-seq assays and DNA methylation data, collected from the developing mouse brain. Our analyses revealed that distinct trajectories of chromatin accessibility are selectively linked to specific subsets of NEUROG2 and NEUROD2 binding sites and E-boxes. Notably, while E-boxes composed of CAT-CAG half sites or two CAG half sites are more commonly found within their binding sites, E-boxes consisting of two CAT half sites exhibit a striking enrichment in developmentally dynamic enhancers. These CAT-CAT E-boxes also manifest substantial DNA demethylation effects throughout the process of neurodifferentiation and display the highest levels of evolutionary constraint. Aided by a combination of a detailed DNA-footprinting and structural modeling approach, we propose a compelling model to explain the combinatorial action of bHLH factors across the various stages of neurogenesis. Finally, we hypothesize that NEUROD2 acts as a chromatin remodeler in cortical neurodifferentiation by binding CAT-CAT E-boxes as a homodimer, a mechanism that could be extended to other members of this bHLH class of transcription factors. | | 9:31p |
Bidirectional Modulation Of Synaptic Transmission By Insulin-Like Growth Factor I
Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity and is an essential factor in learning and memory processes. Indeed, we have demonstrated that IGF-IR activation induces long-term potentiation (LTP) of synaptic transmission (LTPIGF-I) both in the barrel cortex, improving object recognition (Noriega-Prieto et al., 2021), and in the prefrontal cortex, facilitating the extinction of conditioned fear (Maglio et al., 2021). However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of NMDAR-dependent LTP at layer 2/3 PNs of the mouse barrel cortex is favored or prevented by IGF-I (10nM) or IGF-I (7nM), respectively, when IGF-I is applied 1 hour before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10nM IGF-I generates LTP (LTPIGF-I) of the post-synaptic potentials (PSPs) by inducing LTD of the inhibitory post-synaptic currents (IPSCs), 7nM IGF-I generates LTD of the PSPs (LTDIGF-I) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain. |
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