bioRxiv Subject Collection: Neuroscience's Journal

Neural signatures of human psychological resilience driven by acute stress
Neurophysiological mechanisms underlying psychological resilience, the ability to overcome adversity (1,2), have been extensively studied in animals. However, in comparison with animals, human resilience is unique in that it is underpinned by higher cognitive functions, such as self-confidence and a positive attitude to challenges (3,4). Given these discrepancies, the neurophysiological mechanisms underlying human resilience remain unclear. To address this issue, we recorded multimodal responses after acute stress exposure over 1.5 hours using functional brain imaging and peripheral physiological measurements. Here, we showed that the degree of individual resilience is indexed by multiple changes in neural dynamics 1 hour after acute stress. Both functional magnetic resonance imaging and electroencephalography show that activity in the cortical salience network and power in high-beta and gamma oscillations increase in less resilient individuals. Contrastingly, activity in the cortical default mode network and spontaneous activity in the posterior hippocampus increase in more resilient individuals. Machine learning analysis confirmed that, 1 hour after stress exposure, the functional connectivity in the salience network was the most influential, followed by that in the default mode network, gamma power, high-beta power, and hippocampal activity. The neurophysiological dynamics for resilience do not occur as previously thought, but rather in a time-lagged manner against stress exposure. Our findings Shed light on a new approach to recovery from stress-induced deficits such as delayed neuromodulation after a stressful event.

Ageing impacts basic auditory and timing processing
Deterioration in the peripheral and central auditory systems is common in older adults and often leads to hearing and speech comprehension difficulties. Even when hearing remains intact, electrophysiological data of older adults frequently exhibit altered neural responses across the auditory pathway, reflected in variability in the phase alignment of neural activity to speech sound onsets. However, it remains unclear whether speech processing challenges in older adults stem from more fundamental deficits in auditory and timing processing. Here, we investigated the efficiency of aging individuals in encoding temporal regularities in acoustic sequences and their ability to predict future events. We recorded EEG in older and young individuals listening to simple isochronous tone sequences. A comprehensive analysis pipeline evaluated the amplitude, latency, and variability of event-related responses (ERPs) to each tone onset along the auditory sequences. Spectral parametrization and Inter-Trial Phase Coherence (ITPC) analyses assessed how participants encoded the temporal regularity in the acoustic environment. Our findings indicate that aging individuals exhibit altered temporal processing and reduced capacity to generate and utilize temporal predictions to time-lock and adaptively suppress neural responses to predictable and repeated tones in auditory sequences. Given that deteriorations in these basic timing capacities may affect other higher-order cognitive processes (e.g., attention, perception, and action), our results underscore the need for future research examining the link between timing abilities and general cognition across the lifespan.

No Evidence of Altered Language Laterality in People Who Stutter across Different Brain Imaging Studies of Speech and Language
A long-standing neurobiological explanation of stuttering is the incomplete cerebral dominance theory, which refers to competition between two hemispheres for "dominance" over handedness and speech, causing altered language lateralisation. Renewed interest in these ideas came from brain imaging findings in people who stutter (PWS) of increased activity in the right hemisphere during speech production or of shifts in activity from right to left when fluency increased. Here, we revisited this theory using functional MRI data from children and adults who stutter, and typically fluent speakers (119 participants in total) during four different speech and language tasks: overt sentence reading, overt picture description, covert sentence reading and covert auditory naming. Laterality indices (LIs) were calculated for the frontal and temporal lobes using the LI toolbox running in Statistical Parametric Mapping. We also repeated the analyses with more specific language regions, namely the pars opercularis (Brodmann Area 44) and pars triangularis (Brodmann Area 45). Laterality indices in PWS and typically fluent speakers (TFS) did not differ and Bayesian analyses provided moderate to anecdotal levels of support for the null hypothesis (i.e., no differences in laterality in PWS compared with TFS). The proportions of the PWS and TFS who were left lateralised or had atypical rightwards or bilateral lateralisation did not differ. We found no support for the theory that language laterality is reduced or differs in PWS compared with TFS.

Enteric glutamatergic interneurons regulate intestinal motility
The enteric nervous system (ENS) controls digestion autonomously via a complex neural network within the gut wall. Enteric neurons expressing glutamate have been identified by transcriptomic studies as a distinct subpopulation, and glutamate can affect intestinal motility by modulating enteric neuron activity. However, the nature of glutamatergic neurons, their position within the ENS circuit, and their function in regulating gut motility are unknown.

Here, we identify glutamatergic neurons as longitudinally projecting descending interneurons in the small intestine and colon, in addition to a novel class of circumferential neurons only in the colon. Both populations make synaptic contact with diverse neuronal subtypes, and signal with a variety of neurotransmitters and neuropeptides in addition to glutamate, including acetylcholine and enkephalin. Knocking out the glutamate transporter VGLUT2 from enkephalin neurons profoundly disrupts gastrointestinal transit, while ex vivo optogenetic stimulation of glutamatergic neurons initiates propulsive motility in the colon. This motility effect is reproduced when stimulating only the descending interneuron class, marked by Calb1 expression. Our results posit glutamatergic neurons as key interneurons that regulate intestinal motility.

Adult expression of the cell adhesion protein Fasciclin 3 is required for the maintenance of adult olfactory interneurons
The proper functioning of the nervous system is dependent on the establishment and maintenance of intricate networks of neurons that form functional neural circuits. Once neural circuits are assembled during development, a distinct set of molecular programs is likely required to maintain their connectivity throughout the lifetime of the organism. Here, we demonstrate that Fasciclin 3 (Fas3), an axon guidance cell adhesion protein, is necessary for the maintenance of the olfactory circuit in adult Drosophila. We utilized the TARGET system to spatiotemporally knockdown Fas3 in selected populations of adult neurons. Our findings show that Fas3 knockdown results in the death of olfactory circuit neurons and reduced survival of adults. We also demonstrated that Fas3 knockdown activates caspase-3 mediated cell death in olfactory local interneurons, which can be rescued by overexpressing p35, an anti-apoptotic protein. This work adds to the growing set of evidence indicating a critical role for axon guidance proteins in the maintenance of neuronal circuits in adults.

Adaptive chunking improves effective working memory capacity in a prefrontal cortex and basal ganglia circuit
How and why is working memory (WM) capacity limited? Traditional cognitive accounts focus either on limitations on the number or items that can be stored (slots models), or loss of precision with increasing load (resource models). Here we show that a neural network model of prefrontal cortex and basal ganglia can learn to reuse the same prefrontal populations to store multiple items, leading to resource-like constraints within a slot-like system, and inducing a tradeoff between quantity and precision of information. Such "chunking" strategies are adapted as a function of reinforcement learning and WM task demands, mimicking human performance and normative models. Moreover, adaptive performance requires a dynamic range of dopaminergic signals to adjust striatal gating policies, providing a new interpretation of WM difficulties in patient populations such as Parkinson's disease, ADHD and schizophrenia. These simulations also suggest a computational rather than anatomical limit to WM capacity.

Aging-associated weakening of the action potential in fast-spiking interneurons in the human neocortex
Aging is associated with the slowdown of neuronal processing and cognitive performance in the brain; however, the exact cellular mechanisms behind this deterioration in humans are poorly elucidated. Recordings in human acute brain slices prepared from tissue resected during brain surgery enable the investigation of neuronal changes with age. Although neocortical fast-spiking cells are widely implicated in neuronal network activities underlying cognitive processes, they are vulnerable to neurodegeneration. Herein, we analyzed the electrical properties of 147 fast-spiking interneurons in neocortex samples resected in brain surgery from 106 patients aged 11-84 years. By studying the electrophysiological features of action potentials and passive membrane properties, we report that action potential overshoot significantly decreases and spike half-width increases with age. Moreover, the action potential maximum-rise speed (but not the repolarization speed or the afterhyperpolarization amplitude) significantly changed with age, suggesting a particular weakening of the sodium channel current generated in the soma. Cell passive membrane properties measured as the input resistance, membrane time constant, and cell capacitance remained unaffected by senescence. Thus, we conclude that the action potential in fast-spiking interneurons shows a significant weakening in the human neocortex with age. This may contribute to the deterioration of cortical functions by aging.

Topographical polarity reveals continuous EEG microstate transitions and electric field direction in healthy aging
EEG microstate sequences, representing whole-brain spatial potential distribution patterns of the EEG, offer valuable insights for capturing spatiotemporally continuous and fluctuating neural dynamics with high temporal resolution through appropriate discretization. Recent studies suggest that EEG microstate transitions are gradual and continuous phenomena, contrary to the classical view of binary transitions. This study aimed to update conventional microstate analysis to reflect continuous EEG dynamics and examine differences in age-related electrophysiological state transitions. We considered the relative positions of EEG microstates on the neural manifold and their topographical polarity. Transition probability results showed fewer transitions on the microstate D-C-E axis in older adults. In contrast, transitions among microstates A, D, and B increased in the older group and were mainly observed within polarity. Furthermore, the 100 microstate transitions, which are variations of the shortest transitions between 10 microstates, could be reduced to 8 principal components based on the co-occurrence of each transition, including hubs C and E, planar transitions through msA/B and D, and unidirectional transition components. Several transition components were potentially significant predictors of age group. These features were nearly replicated in independent data, indicating their robustness in characterizing age-related electrophysiological spatiotemporal dynamics.

Perception - action dissociations depend on factors that affect multisensory processing
Behavioral perception-action dissociations are widely used to test models of high-level vision, but debates concerning their interpretation have underestimated the role of multisensory mechanisms in such tests. Sensorimotor tasks engage multisensory processing in fundamentally different ways in comparison to perceptual tasks, and these differences can modulate the effects of illusion in specific ways in accord with the features of the experimental task. To test this idea, we compared perception and action using a well-understood size-contrast effect, the Uznadze illusion, and manipulated both unimodal and crossmodal stimulation as well as conditions that are known to favor or hinder multisensory integration. Results demonstrate that varying such conditions can cause a visual task to be affected by the illusion, or remain fully unaffected, whereas a visuomotor task can be affected by the illusion, remain immune from the illusion, or, unexpectedly, even show a robust reverse effect. Thus, similar or dissociable effects on perception and action can be observed depending on factors that are known to affect multisensory processing. These findings provide a novel perspective on a long standing debate in behavioral cognitive neuroscience.

Intercellular Signaling Pathways as Therapeutic Targets for Vascular Dementia Repair
Vascular dementia (VaD) is a white matter ischemic disease and the second-leading cause of dementia, with no direct therapy. Within the lesion site, cell-cell interactions dictate the trajectory towards disease progression or repair. To elucidate the underlying intercellular signaling pathways, a VaD mouse model was developed for transcriptomic and functional studies. The mouse VaD transcriptome was integrated with a human VaD snRNA-Seq dataset. A custom-made database encompassing 4053 human and 2032 mouse ligand-receptor (L-R) interactions identified significantly altered pathways shared between human and mouse VaD. Two intercellular L-R systems, Serpine2-Lrp1 and CD39-A3AR, were selected for mechanistic study as both the ligand and receptor were dysregulated in VaD. Decreased Seprine2 expression enhances OPC differentiation in VaD repair. A clinically relevant drug that reverses the loss of CD39-A3AR function promotes tissue and behavioral recovery in the VaD model. This study presents novel intercellular signaling targets and may open new avenues for VaD therapies.

Development and Organization of the Retinal Orientation Selectivity Map
Orientation or axial selectivity, the property of neurons in the visual system to respond preferentially to certain angles of a visual stimuli, plays a pivotal role in our understanding of visual perception and information processing. This computation is performed as early as the retina, and although much work has established the cellular mechanisms of retinal orientation selectivity, how this computation is organized across the retina is unknown. Using a large dataset collected across the mouse retina, we demonstrate functional organization rules of retinal orientation selectivity. First, we identify three major functional classes of retinal cells that are orientation selective and match previous descriptions. Second, we show that one orientation is predominantly represented in the retina and that this predominant orientation changes as a function of retinal location. Third, we demonstrate that neural activity plays little role on the organization of retinal orientation selectivity. Lastly, we use in silico modeling followed by validation experiments to demonstrate that the overrepresented orientation aligns along concentric axes. These results demonstrate that, similar to direction selectivity, orientation selectivity is organized in a functional map as early as the retina.

Probe-dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho-Tau-Associated Proteomes Between Tauopathies
Tauopathies represent a diverse group of neurodegenerative disorders characterized by the abnormal aggregation of the microtubule-associated protein tau. Despite extensive research, the precise mechanisms underlying the complexity of different types of tau pathology remain incompletely understood. Here we describe an approach for proteomic profiling of aggregate-associated proteomes on slides with formalin-fixed, paraffin-embedded (FFPE) tissue that utilizes proximity labelling upon high preservation of aggregate morphology, which permits the profiling of pathological aggregates regardless of their size. To comprehensively investigate the common and unique protein interactors associated with the variety of tau lesions present across different human tauopathies, Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's disease (PiD), and progressive supranuclear palsy (PSP), were selected to represent the major tauopathy diseases. Implementation of our widely applicable Probe-dependent Proximity Profiling (ProPPr) strategy, using the AT8 antibody, permitted identification and quantification of proteins associated with phospho-tau lesions in well-characterized human post-mortem tissue. The analysis revealed both common and disease-specific proteins associated with phospho-tau aggregates, highlighting potential targets for therapeutic intervention and biomarker development. Candidate validation through high-resolution co-immunofluorescence of distinct aggregates across disease and control cases, confirmed the association of retromer complex protein VPS35 with phospho-tau lesions across the studied tauopathies. Furthermore, we discovered disease-specific associations of proteins including ferritin light chain (FTL) and the neuropeptide precursor VGF within distinct pathological lesions. Notably, examination of FTL-positive microglia in CBD astrocytic plaques indicate a potential role for microglial involvement in the pathogenesis of these tau lesions. Our findings provide valuable insights into the proteomic landscape of tauopathies, shedding light on the molecular mechanisms underlying tau pathology. This first comprehensive characterization of tau-associated proteomes across different tauopathies enhances our understanding of disease heterogeneity and provides a resource for future functional investigation, as well as development of targeted therapies and diagnostic biomarkers.

Loss of the Familial Dysautonomia gene Elp1 in cerebellar granule cell progenitors leads to ataxia in mice
Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have been described. ELP1 is highly expressed in the normal developing and adult cerebellum, but its role in cerebellum development is unknown. To investigate the cerebellar function of Elp1, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent 7 days after birth, when Elp1cKO animals also exhibited fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 within the developing cerebellum, and suggests that Elp1 loss in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.

Base editing of Ptbp1 in neurons alleviates symptoms in a mouse model for Parkinson's disease
Parkinson's disease (PD) is a multifactorial disease caused by irreversible progressive loss of dopaminergic neurons. Recent studies reported successful conversion of astrocytes into dopaminergic neurons by repressing polypyrimidine tract binding protein 1 (PTBP1), which led to a rescue of motor symptoms in a mouse model for PD. However, the mechanisms underlying this cell type conversion remain underexplored and controversial. Here, we devised a strategy using adenine base editing to effectively knockdown PTBP1 in astrocytes and neurons in a PD mouse model. Using AAV delivery vectors at a dose of 2x10-8 vg per animal, we found that Ptbp1 editing in neurons, but not astrocytes, of the substantia nigra pars compacta and striatum resulted in the formation of tyrosine hydroxylase (TH)+ cells and the rescue of forelimb akinesia and spontaneous rotations. Phenotypic analysis of TH+ cells indicates that they originated from non-dividing neurons and acquired dopaminergic neuronal markers upon PTBP1 downregulation. While further research is required to fully understand the origin, identity, and function of these newly generated TH+ cells, our study reveals that the downregulation of PTBP1 can reprogram neurons to mitigate symptoms in PD mice.

Neural substrates and behavioral relevance of speech envelope tracking: evidence from post-stroke aphasia
Neural tracking of the low-frequency temporal envelope of speech has emerged as a prominent tool to investigate the neural mechanisms of natural speech processing in the brain. However, there is ongoing debate regarding the functional role of neural envelope tracking. In this context, our study aims to offer a novel perspective by investigating the critical brain areas and behavioral skills required for neural envelope tracking in aphasia, a language disorder characterized by impaired neural envelope tracking. We analyzed an EEG dataset of 39 individuals with post-stroke aphasia suffering a left-hemispheric stroke who listened to natural speech. Our analysis involved lesion mapping, where left lesioned brain voxels served as binary features to predict neural envelope tracking measures. We also examined the behavioral correlates of receptive language, naming, and auditory processing (via rise time discrimination task) skills. The lesion mapping analysis revealed that lesions in language areas, such as the middle temporal gyrus, supramarginal gyrus and angular gyrus, were associated with poorer neural envelope tracking. Additionally, neural tracking was related to auditory processing skills and language (receptive and naming) skills. However, the effects on language skills were less robust, possibly due to ceiling effects in the language scores. Our findings highlight the importance of central brain areas implicated in language understanding, extending beyond the primary auditory cortex, and emphasize the role of intact auditory processing and language abilities in effectively processing the temporal envelope of speech. Collectively, these findings underscore the significance of neural envelope tracking beyond mere audibility and acoustic processes.

The respiratory cycle modulates distinct dynamics of affective and perceptual decision-making
Respiratory rhythms play a critical role not only in homeostatic survival, but also in modulating other non-interoceptive perceptual and affective processes. Recent evidence from both human and rodent models indicates that neural and behavioural oscillations are influenced by respiratory state as breathing cycles from inspiration to expiration. To explore the mechanisms behind these effects, we carried out a psychophysical experiment where 41 participants categorised dot motion and facial emotion stimuli in a standardised discrimination task. When comparing behaviour across respiratory states, we found that inspiration accelerated responses in both domains. We applied a hierarchical evidence accumulation model to determine which aspects of the latent decision process best explained this acceleration. Computational modelling showed that inspiration reduced evidential decision boundaries, such that participants prioritised speed over accuracy in the motion task. In contrast, inspiration shifted the starting point of affective evidence accumulation, inducing a bias towards categorising facial expressions as more positive. These findings provide a novel computational account of how respiratory rhythms modulate distinct aspects of perceptual and affective decision-dynamics.

Repetitive head impacts induce neuronal loss and neuroinflammation in young athletes
Repetitive head impacts (RHI) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE). Currently, CTE can only be diagnosed after death and the multicellular cascade of events that trigger initial hyperphosphorylated tau (p-tau) deposition remain unclear. Further, the symptoms endorsed by young individuals with early disease are not fully explained by the extent of p-tau deposition, severely hampering development of therapeutic interventions. Here, we show that RHI exposure associates with a multicellular response in young individuals (<51 years old) prior to the onset of CTE p-tau pathology that correlates with number of years of RHI exposure. Leveraging single nucleus RNA sequencing of tissue from 8 control, 9 RHI-exposed, and 11 low stage CTE individuals, we identify SPP1+ inflammatory microglia, angiogenic and inflamed endothelial cell profiles, reactive astrocytes, and altered synaptic gene expression in excitatory and inhibitory neurons in all individuals with exposure to RHI. Surprisingly, we also observe a significant loss of cortical sulcus layer 2/3 neurons in contact sport athletes compared to controls independent of p-tau pathology. These results provide robust evidence that multiple years of RHI exposure is sufficient to induce lasting cellular alterations that may underlie p-tau deposition and help explain the early clinical symptoms observed in young former contact sport athletes. Furthermore, these data identify specific cellular responses to repetitive head impacts that may direct future identification of diagnostic and therapeutic strategies for CTE.