bioRxiv Subject Collection: Neuroscience's Journal
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Monday, March 18th, 2024
| Time |
Event |
| 12:45a |
Causal evidence for increased theta and gamma phase consistency in a parieto-frontal network during the maintenance of visual attention
Endogenous visuo-spatial attention is under the control of a fronto-parietal network of brain regions. One key node in this network, the intra-parietal sulcus (IPS), plays a crucial role in maintaining endogenous attention, but little is known about its ongoing physiology and network dynamics during different attentional states. Here, we investigated the reactivity of the left IPS in response to brain stimulation under different states of selective attention. We recorded electroencephalography (EEG) in response to single pulses of transcranial magnetic stimulation (TMS) of the IPS, while participants (N=44) viewed bilateral random-dot motion displays. Individual MRI-guided TMS pulses targeted the left IPS, while the left primary somatosensory cortex (S1) served as an active control site. In separate blocks of trials, participants were cued to attend covertly to the motion display in one hemifield (left or right) and to report brief coherent motion targets. The perceptual load of the task was manipulated by varying the degree of motion coherence of the targets. Excitability, variability and information content of the neural responses to TMS were assessed by analysing TMS-evoked potential (TEP) amplitude and inter-trial phase clustering (ITPC), and by performing multivariate decoding of attentional state. Results revealed that a left posterior region displayed reduced variability in the phase of theta and gamma oscillations following TMS of the IPS, but not of S1, when attention was directed contralaterally, rather than ipsilaterally to the stimulation site. Under these same conditions, a right frontal cluster also displayed reduced theta variability and increased amplitude of TEPs after TMS of the IPS but not S1. Reliable decoding of attentional state was achieved after TMS pulses of both S1 and IPS. Taken together, our findings suggest that endogenous control of visuo-spatial attention leads to changes in the intrinsic oscillatory properties of the IPS and its associated fronto-parietal network. | | 3:32a |
ATF4 orchestrates IL-1α-induced senescence in adult neural stem cells
Adult neural stem cells (NSC) are a potential source for the regeneration of damaged tissue during neuropathological conditions, but much remains unexplored. In an attempt to study the influence of neuroinflammation on NSCs, we generated a transgenic reporter rat strain that expresses the Discosoma sp. red (DsRed) fluorophore in NSCs and subjected it to traumatic brain injury (TBI). Transcriptomic analysis of NSCs isolated from TBI revealed an enrichment of stress response genes that pertained to endoplasmic reticulum (ER) stress and integrated stress response (ISR). Downstream analysis on NSC cultures pinpointed IL-1 as a trigger of ISR in these cells. At concentration levels similar to the ones measured post-TBI in rats, IL-1 induced the translation of activating transcription factor 4 (ATF4), an ISR master regulator. Further, ATF4 was necessary for the IL-1 -dependent induction of a senescent profile in NSCs, which included a metabolic shift towards glycolysis, induction of senescence-associated secretory phenotype, SASP, and cell cycle arrest. In summary, the ISR/ATF4 pathway seems to play a major role in NSC function during neuroinflammation and provides a therapeutic tool for protecting the NSC pool during these conditions. | | 6:47a |
Representing the dynamics of natural marmoset vocal behaviors in frontal cortex
Here we tested the respective contributions of primate premotor and prefrontal cortex to support vocal behavior. We applied a model-based GLM analysis that better accounts for the inherent variance in natural, continuous behaviors to characterize the activity of neurons throughout frontal cortex as freely-moving marmosets engaged in conversational exchanges. While analyses revealed functional clusters of neural activity related to the different processes involved in the vocal behavior, these clusters did not map to subfields of prefrontal or premotor cortex, as has been observed in more conventional task-based paradigms. Our results suggest a distributed functional organization for the myriad neural mechanisms underlying natural social interactions and has implications for our concepts of the role that frontal cortex plays in governing ethological behaviors in primates. | | 6:47a |
Dissecting the binding mechanisms of synaptic membrane adhesion complexes using a micropattern based cellular model
The formation of adhesive cell-cell contacts is based on the intrinsic binding properties between specific transmembrane ligand-receptor pairs. In neurons, synaptic adhesion molecules provide a physical linkage between pre- and post-synaptic compartments, but the dynamics of these complexes in their actual membrane environments remain essentially unknown. To access such information, we developed a versatile assay to measure the affinity and binding kinetics of synaptic ligand-receptor interactions, based on the immobilization of Fc-tagged ligands on micropatterned substrates combined with live-cell imaging of fluorescently-tagged counter receptors in heterologous cells. We applied this strategy to study the heterophilic complex formed between neurexin-1{beta} (Nrx1{beta}) and neuroligin-1 (Nlg1), compared to the homophilic SynCAM1 complex. First, the control of ligand density combined to the measurement of steady-state receptor enrichment at micropatterns demonstrates the high specificity of the matching molecular interactions and allows for the to quantification ofy the two-bidimensional affinity of the interaction in a membrane environment. Second, long-term FRAP experiments performed on the two molecular complexes and fitted with analytical models, demonstrate a diffusion-limited regime for SynCAM1 and a reaction-limited regime for Nlg1. This analysis provides a very long bond lifetime of the Nrx1{beta}-Nlg1 complex, which by comparison with a monomeric mutant of Nlg1, can be attributed to the constitutive dimerization of Nlg1. Finally, we used the stable Nrx1{beta}-Nlg1 complex as a pseudo-synaptic platform to analyze the rapid binding kinetics between the scaffolding protein PSD-95 and the intracellular domain of Nlg1, dissecting the contribution of the different PDZ domains through the use of specific PSD-95 point mutants. | | 7:16a |
The Diversified Astrocyte Developmental Programs are Modulated by Primary Ciliary Signaling
Astrocyte diversity is greatly influenced by local environmental modulation. Here, we report that the vast majority of brain astrocytes across the entire brain possess a singular primary cilium, a specialized signaling antenna localized to cell soma. Comparative single-cell transcriptomics reveals that primary cilia mediate canonical Shh signaling to modulate astrocyte subtype-specific core features in synaptic regulation, intracellular transport, energy and metabolism. Independent of canonical Shh signaling, primary cilia are important regulators for astrocyte morphology and intracellular signaling balance. Dendritic spine analysis and transcriptomics reveal that perturbation of astrocytic cilia leads to disruption of neuronal development and global intercellular connectomes in the brain. Ultimately, mice with primary ciliary deficient astrocytes show behavioral deficits in sensorimotor function, sociability, learning and memory. Our results uncover a critical role for primary cilia in transmitting local cues that drive the region-specific diversification of astrocytes within the developing brain. | | 2:37p |
Cytokine expression patterns predict suppression of vulnerable neural circuits in a mouse model of Alzheimer's disease
Alzheimer's disease is a neurodegenerative disorder characterized by progressive amyloid plaque accumulation, tau tangle formation, neuroimmune dysregulation, synapse an neuron loss, and changes in neural circuit activation that lead to cognitive decline and dementia. Early molecular and cellular disease-instigating events occur 20 or more years prior to presentation of symptoms, making them difficult to study, and for many years amyloid-{beta}, the aggregating peptide seeding amyloid plaques, was thought to be the toxic factor responsible for cognitive deficit. However, strategies targeting amyloid-{beta} aggregation and deposition have largely failed to produce safe and effective therapies, and amyloid plaque levels poorly correlate with cognitive outcomes. However, a role still exists for amyloid-{beta} in the variation in an individual's immune response to early, soluble forms of aggregates, and the downstream consequences of this immune response for aberrant cellular behaviors and creation of a detrimental tissue environment that harms neuron health and causes changes in neural circuit activation. Here, we perform functional magnetic resonance imaging of awake, unanesthetized Alzheimer's disease mice to map changes in functional connectivity over the course of disease progression, in comparison to wild-type littermates. In these same individual animals, we spatiotemporally profile the immune milieu by measuring cytokines, chemokines, and growth factors across various brain regions and over the course of disease progression from pre-pathology through established cognitive deficit. We identify specific signatures of immune activation predicting hyperactivity followed by suppression of intra- and then inter-regional functional connectivity in multiple disease-relevant brain regions, following the pattern of spread of amyloid pathology. | | 2:37p |
Validation of Enhancer Regions in Primary Human Neural Progenitor Cells using Capture STARR-seq
Genome-wide association studies (GWAS) and expression analyses implicate noncoding regulatory regions as harboring risk factors for psychiatric disease, but functional characterization of these regions remains limited. We performed capture STARR-sequencing of over 78,000 candidate regions to identify active enhancers in primary human neural progenitor cells (phNPCs). We selected candidate regions by integrating data from NPCs, prefrontal cortex, developmental timepoints, and GWAS. Over 8,000 regions demonstrated enhancer activity in the phNPCs, and we linked these regions to over 2,200 predicted target genes. These genes are involved in neuronal and psychiatric disease-associated pathways, including dopaminergic synapse, axon guidance, and schizophrenia. We functionally validated a subset of these enhancers using mutation STARR-sequencing and CRISPR deletions, demonstrating the effects of genetic variation on enhancer activity and enhancer deletion on gene expression. Overall, we identified thousands of highly active enhancers and functionally validated a subset of these enhancers, improving our understanding of regulatory networks underlying brain function and disease. | | 2:37p |
Neural dynamics of semantic control underlying generative storytelling
Storytelling has been pivotal for the transmission of knowledge and cultural norms across human history. A crucial process underlying the generation of narratives is the exertion of cognitive control on the semantic representations stored in memory, a phenomenon referred as semantic control. Despite the extensive literature investigating the neural mechanisms of semantic control in generative language tasks, little effort has been done towards storytelling under naturalistic conditions. Here, we probed human participants to generate stories in response to a set of instructions which triggered a narrative that was either appropriate (ordinary), novel (random), or balanced (creative), while recording functional magnetic resonance imaging (fMRI) signal. By leveraging deep language models, we demonstrated how participants ideally balanced the level of semantic control during story generation. At the neural level, creative stories were differentiated by a multivariate pattern of neural activity in frontal cortices compared to ordinary ones and in fronto- temporo-parietal cortices with respect to randomly generated stories. Crucially, similar brain regions were also encoding the features that distinguished the stories behaviourally. Moreover, we decomposed the neural dynamics into connectome harmonic modes and found specific spatial frequency patterns underlying the modulation of semantic control during story generation. Finally, we found different functional coupling within and between the default mode, salience and control networks when contrasting creative stories with their controls. Together, our findings highlight the neural mechanisms underlying the regulation of semantic exploration during narrative ideation and contribute to a deeper understanding of the neural dynamics underpinning the role of semantic control in generative storytelling. | | 2:37p |
Translation of monosynaptic circuits underlying amygdala fMRI neurofeedback training
Background: fMRI neurofeedback targeting the amygdala is a promising therapeutical tool in psychiatry. It induces resting-state functional connectivity (rsFC) changes between the amygdala and regions of the salience and default mode networks (SN and DMN, respectively). We hypothesize these rsFC changes happen on the amygdala's underlying anatomical circuits. Methods: We used the coordinates from regions of interest (ROIs) from studies showing pre-to-post-neurofeedback changes in rsFC with the left amygdala. Using a cross-species brain parcellation, we identified the homologous locations in non-human primates. We injected bidirectional tracers in the amygdala of adult macaques and used bright- and dark-field microscopy to identify cells and axon terminals in each ROI. We also performed additional injections in specific ROIs to validate the results following amygdala injections and delineate potential disynaptic pathways. Finally, we used high-resolution diffusion MRI data from four post-mortem macaque brains and one in vivo human brain to translate our findings to the neuroimaging domain. Results: The amygdala had significant monosynaptic connections with all the SN and DMN ipsilateral ROIs. Amygdala connections with the DMN contralateral ROIs are disynaptic through the hippocampus and parahippocampal gyrus. Diffusion MRI in both species benefitted from using the ground-truth tracer data to validate its findings, as we identified false-negative ipsilateral and false-positive contralateral connectivity results. Conclusions: Amygdala neurofeedback modulates the SN and DMN through monosynaptic connections and disynaptic pathways - including hippocampal structures involved in the neurofeedback task. Neurofeedback may be a tool for rapid modulation and reinforcement of these anatomical connections, leading to clinical improvement. | | 8:18p |
Genome-Wide Association Study in Outbred Heterogeneous Stock Rats Identifies Multiple Loci for the Incentive Salience of Reward Cues.
Addiction vulnerability is associated with the tendency to attribute incentive salience to reward predictive cues; both addiction and the attribution of incentive salience are influenced by environmental and genetic factors. To characterize the genetic contributions to incentive salience attribution, we performed a genome-wide association study (GWAS) in a cohort of 1,645 genetically diverse heterogeneous stock (HS) rats. We tested HS rats in a Pavlovian conditioned approach task, in which we characterized the individual responses to food-associated stimuli (cues). Rats exhibited either cue-directed sign-tracking behavior or food-cup directed goal-tracking behavior. We then used the conditioned reinforcement procedure to determine whether rats would perform a novel operant response for unrewarded presentations of the cue. We found that these measures were moderately heritable (SNP heritability, h2 = .189-.215). GWAS identified 14 quantitative trait loci (QTLs) for 11 of the 12 traits we examined. Interval sizes of these QTLs varied widely. 7 traits shared a QTL on chromosome 1 that contained a few genes (e.g. Tenm4, Mir708) that have been associated with substance use disorders and other mental health traits in humans. Other candidate genes (e.g. Wnt11, Pak1) in this region had coding variants and expression-QTLs in mesocorticolimbic regions of the brain. We also conducted a Phenome-Wide Association Study (PheWAS) on other behavioral measures in HS rats and found that regions containing QTLs on chromosome 1 were also associated with nicotine self-administration in a separate cohort of HS rats. These results provide a starting point for the molecular genetic dissection of incentive salience and provide further support for a relationship between attribution of incentive salience and drug abuse-related traits. |
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