bioRxiv Subject Collection: Neuroscience's Journal

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency
Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.

Arm movements increase acoustic markers of expiratory flow
The gesture-speech physics theory suggests that there are biomechanical interactions of the voice with the whole body, driving speech to align fluctuations in loudness and F0 with upper-limb movement. This exploratory study offers a possible falsification of the gesture-speech physics theory, which would predict effects of upper-limb movement on voice as well as respiration. We therefore investigate co-movement expiration. Seventeen participants were asked to produce a continuous exhalation for several seconds. After 3s, they execute one of five within-subject movement conditions with their arm with and without a wrist weight (no movement, elbow flexion, elbow extension, internal arm rotation, external arm rotation). We analyzed the smoothed amplitude envelope of the acoustic signal in relation to arm movement. Compared to no movement, all four movements lead to higher positive peaks in the amplitude peaks, while weight did not influence the amplitude. We also found that across movement conditions, positive amplitude peaks are structurally timed relative to peaks in kine-matics (speed, acceleration). We conclude that the reason why upper-limb movements affect voice loudness is still best understood through gesture-speech physics theory, where upper-limb movements affect the voice directly by modulating sub-glottal pressures. Multimodal prosody is therefore partly literally embodied.

A choroid plexus apocrine secretion mechanism shapes CSF proteome and embryonic brain development
We discovered that apocrine secretion by embryonic choroid plexus (ChP) epithelial cells contributes to the cerebrospinal fluid (CSF) proteome and influences brain development in mice. The apocrine response relies on sustained intracellular calcium signaling and calpain-mediated cytoskeletal remodeling. It rapidly alters the embryonic CSF proteome, activating neural progenitors lining the brains ventricles. Supraphysiological apocrine secretion induced during mouse development by maternal administration of a serotonergic 5HT2C receptor agonist dysregulates offspring cerebral cortical development, alters the fate of CSF-contacting neural progenitors, and ultimately changes adult social behaviors. Critically, exposure to maternal illness or to the psychedelic drug LSD during pregnancy also overactivates the ChP, inducing excessive secretion. Collectively, our findings demonstrate a new mechanism by which maternal exposure to diverse stressors disrupts in utero brain development.

Effects of Alzheimer's disease plasma marker levels on multilayer centrality in healthy individuals
Finding early and non-invasive biomarkers that help identify individuals in the earliest stages of the Alzheimers disease continuum is paramount. Electrophysiology and plasma biomarkers are great candidates in this pursuit. Furthermore, the combination of functional connectivity metrics with graph-theory analyses allows for a deeper understanding of network alterations. Despite this, this is the first MEG study to assess multilayer centrality considering inter-band connectivity in an unimpaired population at high risk of Alzheimers disease. Our objective is twofold. First, to address the relationship between a compound centrality score designed to overcome previous inconsistencies stemming from the use of various individual metrics, and plasma pathology markers of Alzheimers disease in unimpaired individuals with elevated levels of the latter. Lastly, to evaluate whether hubs centrality is more affected by the pathology.

33 individuals with available MEG recordings and elevated plasma pathology markers were included. A compound centrality score for each brain source of every subject was calculated combining widely used centrality metrics, considering intra- and inter-band connections.

Spearman correlations were carried out to address the association between each nodes centrality score and biomarkers levels. Next, to test whether greater associations were found in hubs, a correlation between the obtained rho and the grand-average of the centrality score was carried out.

Increasing concentrations of p-tau231 were associated with greater centrality within the network of posterior areas, which increased their connectedness in the theta range with the remaining areas, regardless of the latters frequency range. The opposite relationship was found for left areas, that decreased their connectedness in the gamma frequency range. Hubs centrality was significantly more affected by p-tau231 levels.

Our results expand previous literature demonstrating early network reorganizations associated with elevated plasma p-tau231 in cognitively unimpaired individuals. Multilayer centrality increases in the theta band in posterior regions are congruent with previous results and theoretical models, that predict a longitudinal evolution towards a loss of centrality. On the other hand, the changes in multilayer centrality found in the gamma band could be associated with inhibitory neuron dysfunction, classical in AD pathology. Lastly, hubs were more likely to increase their centrality in association to p-tau231, thus corroborating hubs vulnerability.

The predictive outfielder: a critical test across gravities
Intercepting moving targets, like fly balls, is a common challenge faced by several species. Historically, models attempting to explain this behavior in humans have relied on optical variables alone. Such models, while insightful, fall short in several respects, particularly in their lack of predictive capabilities. This absence of prediction limits the ability to plan movements or compensate for inherent sensorimotor delays. Moreover, these traditional models often imply that an outfielder must maintain a constant gaze on the target throughout to achieve successful interception. In this study, we present a new model that continuously updates its predictions, not just on the immediate trajectory of the ball, but also on its eventual landing position in the 3D scene and remaining flight time based on the outfielders real time movements. A distinct feature is the models adaptability to different gravitational scenarios, making its predictions inherently tailored to specific environmental conditions. By actively integrating gravity, our model produces trajectory predictions that can be validated against actual paths, providing a significant departure from previous models. To compare our model to the traditional ones, we conducted experiments within a virtual reality setting, strategically varying simulated gravity among other parameters. This gravity variation yielded qualitatively distinct predictions between error-nulling optical-based heuristics and our model. The trajectories, kinematic patterns and timing responses produced by participants were in good agreement with the predictions of our proposed model, suggesting a paradigm shift in our understanding of interceptive actions.

Significance statementCatching a moving target, a challenge consistently faced across various species, exemplifies the complex interplay between perception, prediction, and motor action in dynamic environments. Prevailing models have been largely rooted in optical cues, often overlooking the predictive capacities essential for understanding real-world human behaviors and sidestepping crucial physical variables such as gravity. Our research introduces a novel model that emphasizes both the predictive component and the broader gravitational dynamics allowing for a more holistic understanding of interception tasks. This innovative approach not only holds implications for refining existing models of interception but also carries broader significance for training platforms, ensuring relevance across diverse settings, from Earth to altered gravity environments.

Vestibular prepulse inhibition of the human blink reflex
ObjectiveAuditory and somatosensory prepulses are commonly used to assess prepulse inhibition (PPI). The effect of a vestibular prepulse upon blink reflex (BR) excitability has not been hitherto assessed.

MethodsTwenty-two healthy subjects and two patients with bilateral peripheral vestibular failure took part in the study. Whole body yaw rotation in the dark provided a vestibular inertial prepulse. BR was electrically evoked after the end of the rotation. The area-under-the-curve (area) of the BR responses (R1, R2, and R2c) was recorded and analysed.

ResultsA vestibular prepulse inhibited the R2 (p < 0.001) and R2c area (p < 0.05). Increasing the angular acceleration did not increase the R2/R2c inhibition (p>0.05). Voluntary suppression of the vestibular-ocular reflex did not affect the magnitude of inhibition (p>0.05). Patients with peripheral vestibular failure did not show any inhibition.

ConclusionsOur data support a vestibular-gating mechanism in humans.

SignificanceThe main brainstem nucleus mediating PPI - the pedunculopontine nucleus (PPN) - is heavily vestibular responsive, which is consistent with our findings of a vestibular-mediated PPI. Our technique may be used to interrogate the fidelity of brain circuits mediating vestibular-related PPN functions. Given the PPNs importance in human postural control, our technique may also provide a neurophysiological biomarker of balance.

HighlightsO_LIThis is the first report of a vestibular prepulse inhibition of the blink reflex.
C_LIO_LIA vestibular prepulse inhibits the R2/R2c area in healthy subjects but not in patients with bilateral peripheral vestibular failure.
C_LIO_LIVestibular PPI is a potential neurophysiological marker of vestibular-motor integration at the brainstem level.
C_LI

HUB-DT: A tool for unsupervised behavioural discovery and analysis
There has been an expansion in the diversity of tools used to measure various aspects of brain function in behaving animals. While these tools have great potential to transform our understanding of brain function, they are of little value if the behavior of interest is poorly defined or quantified. Traditional methods of behavioural labelling focus on easily quantified gross measure, such as velocity, gate crossing, nosepokes, etc. While these measures are specific and reproducible, they are crude descriptions of behaviour at best. Manually defined behaviours, while providing increased granularity and descriptive power over specific gross measures, suffer from being inexact and somewhat arbitrary. Consistent labelling between human observers is often difficult, and even if manually defined behaviours are subsequently labelled in an automated fashion (via a supervised learning algorithm) these behaviours need to be defined ahead of time, possibly biasing the range of behaviours of interest for a given task.

Here we present HUB-DT, a behavioural discovery pipeline built on the frameworks of several existing tools and methods in the space of behavioural categorisation, the specifics of which will be highlighted in this report, and designed to address the requirements of behavioral discovery.

Single cell transcriptomics of vomeronasal neuroepithelium reveals a differential endoplasmic reticulum environment amongst neuronal subtypes
Specialized chemosensory signals elicit innate social behaviors in individuals of several vertebrate species, a process that is thought to be mediated via the accessory olfactory system (AOS). The AOS comprising the peripheral sensory vomeronasal organ (VNO) has evolved elaborate molecular and cellular mechanisms to detect chemo signals. To gain insight into the cell types, developmental gene expression patterns and functional differences amongst neurons, we performed single cell transcriptomics of the mouse vomeronasal sensory epithelium. Our analysis reveals diverse cell types with gene expression patterns specific to each, which we made available as a searchable web resource accessed from www.scvnoexplorer.com. Pseudo-time developmental analysis indicates that neurons originating from common progenitors diverge in their gene expression during maturation with transient and persistent transcription factor expression at critical branch points. Comparative analysis across two of the major neuronal subtypes that express divergent GPCR families and the G-protein subunits Gnai2 or Gnao1, reveals significantly higher expression of endoplasmic reticulum (ER) associated genes within Gnao1 neurons. These gene expression patterns, along with differential localization of ER chaperones and structural proteins indicate fundamental differences in ER function associated with neuronal differentiation.

Two-photon all-optical electrophysiology for the dissection of larval zebrafish brain functional connectivity
One of the most audacious goals of modern neuroscience is unraveling the complex web of causal relations underlying the activity of neuronal populations on a whole-brain scale. This endeavor, prohibitive just a couple of decades ago, has recently become within reach owing to the advancements in optical methods and the advent of genetically encoded indicators/actuators. These techniques, applied to the translucent larval zebrafish have enabled recording and manipulation of the activity of extensive neuronal populations spanning the entire vertebrate brain. Here, we present the conception of a custom two-photon optical system, coupling light-sheet imaging and 3D excitation with acousto-optic deflectors for simultaneous high-speed volumetric recording and optogenetic stimulation. By employing a zebrafish line with pan-neuronal expression of both the calcium reporter GCaMP6s and the red-shifted opsin ReaChR, we implemented a crosstalk-free, noninvasive all-optical approach and applied it to the reconstruction of the functional connectivity of the left habenula.

Continuous structural neuroplasticity during motor learning - a diffusion MRI study
Learning is a complex, continuously evolving process which induces widespread structural and functional brain alterations. In recent years, diffusion magnetic resonance imaging (dMRI) has been used to detect microstructural modifications after short learning periods. While previous studies primarily explored changes following learning (i.e., by comparing images acquired before and after learning), the continuous temporal dynamics of microstructural alterations during the encoding phase of learning itself are yet to be examined. Here, we introduce a novel approach for continuous acquisition of dMRI images which allow tracking microstructural changes throughout learning and demonstrate the utility of this approach on a motor sequence learning (finger tapping) task (n=58). Voxel-wise analysis revealed a decrease in mean diffusivity (MD) in task-related brain regions, including the parahippocampal gyrus, hippocampus, inferior temporal gyrus, and cerebellum. Further analysis of the temporal patterns of decrease revealed a rapid MD reduction in the right temporal gyrus after 11 minutes of learning, with additional decrease in the right parahippocampal gyrus and left cerebellum after 22 minutes. We computed "neuroplasticity networks" of brain areas showing similar change patterns and detected similarities between these networks and canonical functional connectivity networks. Our findings offer novel insights on the spatio-temporal dynamics of neuroplasticity and advance our understanding of motor learning by demonstrating continuous microstructural modifications from the very first minutes of training.

Stimulus-induced gamma sources weaken but not shrink with healthy aging in human EEG
Aging alters brain structure and function, and studying such changes may help understand the neural basis underlying aging and devise interventions to detect deviations from healthy progression. Electroencephalogram (EEG) offers an effective way to study healthy aging owing to its high temporal resolution and affordability. Recent studies have shown that narrow-band stimulus-induced gamma oscillations (20-70 Hz) in EEG weaken with healthy aging and onset of Alzheimers Disease while remaining highly reproducible for a given subject, thus hold promise as potential biomarkers. However, functional connectivity (FC) sometimes changes in a different way compared to sensor power with aging. This difference could be potentially addressed by studying how underlying gamma sources change with aging, since either a reduction in source power or a shrinkage of the sources (or both) could reduce the power in the sensors but may have different effects on other measures such as FC. We therefore reconstructed EEG gamma sources through a linear inverse method called eLORETA on a large (N=217) cohort of healthy elderly subjects (>50 years). We further characterized gamma distribution in cortical space as an exponential fall off from a seed voxel with maximal gamma source power, which could help delineate a reduction in magnitude versus shrinkage. We found significant reduction in magnitude but not shrinkage with healthy aging. Overall, our results shed light on changes in EEG gamma source distribution with healthy aging which could provide clues about underlying neural mechanisms.

The INO80 chromatin remodeling complex regulates histone H2A.Z mobility and the G1-S transition in oligodendrocyte precursors
Chromatin remodelling complexes (CRCs) participate in oligodendrocyte (OL) differentiation, survival and maintenance. We asked whether CRCs also control proliferation of OL precursors (OPs) - focusing on the INO80 complex, which is known to regulate proliferation of a variety of other cell types during development and disease. CRISPR/Cas9-mediated inactivation of Ino80 in vitro, or Cre-mediated deletion in vivo, slowed the OP cell cycle substantially by prolonging G1, without inducing OL differentiation. RNAseq analysis revealed that E2F target genes were dysregulated in OPs from INO80-deficient mice, but correlated RNAseq and ATAC-seq uncovered no general correlation beween gene expression and altered nucleosome positioning at transcription start sites. Fluorescence photobleaching experiments in cultured OPs demonstrated that histone H2A.Z mobility increased following loss of INO80, suggesting that INO80 regulates the cell cycle machinery in OPs through H2A.Z/ H2A exchange. We also present evidence that INO80 associates with OLIG2, a master regulator of OL development.

Hippocampal trauma memory processing conveying susceptibility to traumatic stress
While the majority of the population is ever exposed to a traumatic event during their lifetime, only a fraction develops posttraumatic stress disorder (PTSD). Disrupted trauma memory processing has been proposed as a core factor underlying PTSD symptomatology. We used transgenic Targeted- Recombination-in-Active-Populations (TRAP) mice to investigate potential alterations in trauma- related hippocampal memory engrams associated with the development of PTSD-like symptomatology. Mice were exposed to a stress-enhanced fear learning paradigm, in which prior exposure to a stressor affects the learning of a subsequent fearful event (contextual fear conditioning using foot shocks), during which neuronal activity was labeled. One week later, mice were behaviorally phenotyped to identify mice resilient and susceptible to developing PTSD-like symptomatology. Three weeks post-learning, mice were re-exposed to the conditioning context to induce remote fear memory recall, and associated hippocampal neuronal activity was assessed. While no differences in the size of the hippocampal neuronal ensemble activated during fear learning were observed between groups, susceptible mice displayed a smaller ensemble activated upon remote fear memory recall in the ventral CA1, higher regional hippocampal PV+ neuronal density and a relatively lower activity of PV+ interneurons upon recall. Investigation of potential epigenetic regulators of the engram revealed rather generic (rather than engram-specific) differences between groups, with susceptible mice displaying lower hippocampal histone deacetylase 2 expression, and higher methylation and hydroxymethylation levels. These finding implicate variation in epigenetic regulation within the hippocampus, as well as reduced regional hippocampal activity during remote fear memory recall in interindividual differences in susceptibility to traumatic stress.

The landscape of glial pathology and T-call response in Parkinson's substantia nigra
Parkinsons Disease (PD) is a progressive neurodegenerative disease that leads to debilitating movement disorders and often dementia. Recent evidence, including identification of specific peripheral T-cell receptor sequences, indicates the adaptive immune response is associated with disease pathogenesis. However, the properties of T-cells in the brain regions where neurons degenerate are uncharacterized. We have analyzed the identities and interactions of T-cells in PD in post-mortem brain tissue using single nucleus RNA sequencing, spatial transcriptomics and T-cell receptor sequencing. We found that T-cells in the substantia nigra of PD brain donors exhibit a CD8+ resident memory phenotype, increased clonal expansion, and altered spatial relationships with astrocytes, myeloid cells, and endothelial cells. We also describe regional differences in astrocytic responses to neurodegeneration. Our findings nominate potential molecular and cellular candidates that allow a deeper understanding of the pathophysiology of neurodegeneration in PD. Together, our work represents a major single nucleus and spatial transcriptional resource for the fields of neurodegeneration and PD.

Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer's Disease
The emergence of A{beta} pathology is one of the hallmarks of Alzheimers disease (AD), but the mechanisms and impact of A{beta} in progression of the disease is unclear. The nuclear pore complex (NPC) is a multi-protein assembly in mammalian cells that regulates movement of macromolecules across the nuclear envelope and its function is shown to undergo age-dependent decline during normal aging and is also impaired in multiple neurodegenerative disorders. Yet not much is known about the impact of A{beta} on NPC function in neurons. Here, we examined NPC and nucleoporin (NUP) distribution and nucleocytoplasmic transport using a mouse model of AD (AppNL-G-F/NL-G-F) that expresses A{beta} in young animals. Our studies revealed that a time-dependent accumulation of intracellular A{beta} corresponded with a reduction of NPCs and NUPs in the nuclear envelope which resulted in the degradation of the permeability barrier and inefficient segregation of nucleocytoplasmic proteins, and active transport. As a result of the NPC dysfunction AD neurons become more vulnerable to inflammation-induced necroptosis - a programmed cell death pathway where the core components are activated via phosphorylation through nucleocytoplasmic shutting. Collectively, our data implicates A{beta} in progressive impairment of nuclear pore function and further confirms that the protein complex is vulnerable to disruption in various neurodegenerative diseases and is a potential therapeutic target.

The ventral hippocampus and nucleus accumbens underlie long-term social memory about female conspecifics in male mice
For many social animals, including humans, the ability to remember and recognize conspecifics (i.e., having social memory), especially a mating partner, is essential for adaptive reproductive strategies. Our previous studies have shown that social memory about same-sex conspecifics, namely male-to-male social memory, is stored in hippocampal ventral CA1 (vCA1) neurons and that neural projections from the vCA1 to the nucleus accumbens (NAc) are crucial for social discriminatory behavior. However, how the memory of an opposite-sex conspecific, specifically male-to-female social memory, and how the social memory modulates sexual behavior in males remain unknown. Herein, we investigated the ultrasonic vocalizations (USVs) and socially approaching behavior of males toward a female before and after social memory formation. We found that the total duration of USVs was reduced when the male mice interacted with a familiar female. This reduction in USV emission was blocked by optogenetic inhibition of vCA1 neurons, as well as D1- and D2-dopamine receptor (D1R and D2R) expressing neurons in the NAc. Furthermore, fiber photometry recordings in the NAc revealed that the activities of both D1R and D2R neuronal populations were altered during social interaction with familiar or novel females after the process of familiarization. The response of D1R-neurons was reduced only when interacting with familiar females. In contrast, although responses of D2R-neurons were reduced toward both familiar and novel females after social memory formation, the reduction towards novel females was significantly more pronounced compared to that towards familiar females. Our findings suggested that the activities of both vCA1 neurons and D1R- and D2R-expressing NAc neurons in males were differentially modulated by the presence of social memory about females during adaptive reproductive strategies.

Significance StatementLong-term social memory about females modulates male sexual behavior, specifically ultrasonic vocalization emissions, mediated by hippocampal ventral CA1 and dopamine receptor expressing neurons in the nucleus accumbens.

Emergence of multiple spontaneous coherent subnetworks from a single configuration of human connectome-coupled oscillators model
Large-scale brain models with biophysical or biophysically inspired parameters generate brain-like dynamics with multi-state metastability. Multi-state metastability reflects the capacity of the brain to transition between different network configurations and cognitive states in response to changing environments or tasks, thus relating to cognitive flexibility. To study this phenomenon, we used a Kuramoto network of oscillators corresponding to a human brain atlas of 90 nodes, each with an intrinsic frequency of 40 Hz. The networks nodes were interconnected based on the structural connectivity strengths and delays found in the human brain. We identified global coupling and delay scale parameters corresponding to maximum spectral entropy, a proxy for maximal multi-state metastability. At this point, we show that multiple coherent (functional) sub-networks spontaneously emerge across multiple oscillatory modes, and persist in time for periods between 140 and 4389 ms. Most nodes in the network exhibit broad frequency spectra away from their intrinsic frequency, and switch between modes, in a manner similar to that reported in empirical resting-state neuroimaging data. We suggest that the obtained dynamics at maximum metastability is a suitable model of the awake brain. Further, we show that global coupling and delay scale parameters away from maximum metastability yield dynamical features similar to other brain states such as sleep and anesthesia. Therefore, spectral entropy also correlates with wakefulness and the synchrony of functional networks.

Prefrontal cortical dynorphin peptidergic transmission constrains threat-driven behavioral and network states
Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing fear-related behavioral states. Dynorphin (Dyn) has been implicated in mediating negative affect and mal-adaptive behaviors induced by severe threats and is expressed in limbic circuits, including the vmPFC. However, there is a critical knowledge gap in our understanding of how vmPFC Dyn-expressing neurons and Dyn transmission detect threats and regulate expression of defensive behaviors. Here, we demonstrate that Dyn cells are broadly activated by threats and release Dyn locally in the vmPFC to limit passive defensive behaviors. We further demonstrate that vmPFC Dyn-mediated signaling promotes a switch of vmPFC networks to a fear-related state. In conclusion, we reveal a previously unknown role of vmPFC Dyn neurons and Dyn neuropeptidergic transmission in suppressing defensive behaviors in response to threats via state-driven changes in vmPFC networks.

Highlights[bullet] vmPFCDyn neurons are activated by threats and threat-predictive cues
[bullet]Characterization of a genetically-encoded kappa-opioid receptor sensor
[bullet]vmPFCDyn neurons rapidly release Dyn in response to threats and their predictors
[bullet]vmPFCDyn signaling opposes threat-induced passive defensive behaviors
[bullet]Dyn signaling promotes threat-evoked state transitions in vmPFC networks

Dopaminergic Changes in the Subgenual Cingulate Cortex in Dementia with Lewy Bodies Associates with Presence of Depression
In addition to the core clinical features of fluctuating cognition, visual hallucinations, and parkinsonism, individuals with dementia with Lewy bodies (DLB) frequently experience chronic and debilitating major depression. Treatment of depression in DLB is hampered by a lack of available effective therapies and standard serotonergic medication for major depressive disorder (MDD) is typically ineffective. Dysfunction of dopaminergic neurotransmission contributing to anhedonia and loss of motivation has been described in MDD. The subgenual anterior cingulate (sgACC) is important in mood regulation and in the symptomatic expression of depression, displaying structural, functional and metabolic abnormalities in MDD. To assess dopaminergic and serotonergic synaptic changes in DLB, post mortem sgACC tissue from DLB donors with and without depression was investigated using high-resolution stimulated emission depletion (STED) microscopy, as well as Western and dot blotting techniques. STED imaging demonstrated the presence of -synuclein within individual dopaminergic terminals in the sgACC, -synuclein presence showing a significant positive correlation with increased SNAP25 volumes in depressed DLB cases. A reduction in dopaminergic innervation in the sgACC was observed in DLB cases with depression, along with reduced levels of multiple dopaminergic markers and receptors. Limited alterations were observed in serotonergic markers. Our work demonstrates a role for dopaminergic neurotransmission in the aetiology of depression in DLB. Careful and selective targeting of dopaminergic systems may be a therapeutic option for treatment of depression in DLB.

Do Topographic Deep ANN Models of the Primate Ventral Stream Predict the Perceptual Effects of Direct IT Cortical Interventions?
Ever-advancing artificial neural network (ANN) models of the ventral visual stream capture core object recognition behavior and the neural mechanisms underlying it with increasing precision. These models take images as input, propagate through simulated neural representations that resemble biological neural representations at all stages of the primate ventral stream, and produce simulated behavioral choices that resemble primate behavioral choices. We here extend this modeling approach to make and test predictions of neural intervention experiments. Specifically, we enable a new prediction regime for topographic deep ANN (TDANN) models of primate visual processing through the development of perturbation modules that translate micro-stimulation, optogenetic suppression, and muscimol suppression into changes in model neural activity. This unlocks the ability to predict the behavioral effects from particular neural perturbations. We compare these predictions with the key results from the primate IT perturbation experimental literature via a suite of nine corresponding benchmarks. Without any fitting to the benchmarks, we find that TDANN models generated via co-training with both a spatial correlation loss and a standard categorization task qualitatively predict all nine behavioral results. In contrast, TDANN models generated via random topography or via topographic unit arrangement after classification training predict less than half of those results. However, the models quantitative predictions are consistently misaligned with experimental data, over-predicting the magnitude of some behavioral effects and under-predicting others. None of the TDANN models were built with separate model hemispheres and thus, unsurprisingly, all fail to predict hemispheric-dependent effects. Taken together, these findings indicate that current topographic deep ANN models paired with perturbation modules are reasonable guides to predict the qualitative results of direct causal experiments in IT, but that improved TDANN models will be needed for precise quantitative predictions.

Enhancement of Mediodorsal Thalamus Rescues Aberrant Belief Dynamics in a Novel Mouse Model for Schizophrenia
Optimizing behavioral strategy requires belief updating based on new evidence, a process that engages higher cognition. In schizophrenia, aberrant belief dynamics may lead to psychosis, but the mechanisms underlying this process are unknown, in part, due to lack of appropriate animal models and behavior readouts. Here, we address this challenge by taking two synergistic approaches. First, we generate a mouse model bearing point mutation in Grin2a (Grin2aY700X+/-), a gene that confers high-risk for schizophrenia and was recently identified by large-scale exome sequencing. Second, we develop a computationally-trackable foraging task, in which mice form and update belief-driven strategies in a dynamic environment. We found that Grin2aY700X+/- mice perform less optimally than their wild-type (WT) littermates, showing unstable behavioral states and a slower belief update rate. Using functional ultrasound imaging, we identified the mediodorsal (MD) thalamus as hypofunctional in Grin2aY700X+/- mice, and in vivo task recordings showed that MD neurons encoded dynamic values and behavioral states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopied Grin2aY700X+/- mice, and enhancing MD activity rescued task deficits in Grin2aY700X+/- mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction, and a potential target for future therapeutics.

Timing the cerebellum and its connectivity within the social brain
The posterior cerebellum is a recently discovered hub of the affective and social brain, with different subsectors contributing to different social functions. However, very little is known about when the posterior cerebellum plays a critical role in social processing. Due to its location and anatomy, it has been difficult to use traditional approaches to directly study the chronometry of the cerebellum. To address this gap in cerebellar knowledge, here we investigated for the first time the causal contribution of the posterior cerebellum to social processing using a chronometric transcranial magnetic stimulation (TMS) approach. We show that the posterior cerebellum is recruited at an early stage of the emotional processing (starting from 100 ms after stimulus onset), simultaneously with the posterior superior temporal sulcus (pSTS), a key node of the emotional-social brain. Moreover, using a condition-and-perturb TMS approach, we found that the recruitment of the pSTS in emotional processing is dependent on cerebellar activation. Our results are the first to shed light on chronometric aspects of cerebellar function and its causal connectivity with other nodes of the social brain.

Structured behavioral data format: An NWB extension standard for task-based behavioral neuroscience experiments
Understanding brain function necessitates linking neural activity with corresponding behavior. Structured behavioral experiments are crucial for probing the neural computations and dynamics underlying behavior; however, adequately representing their complex data is a significant challenge. Currently, a comprehensive data standard that fully encapsulates task-based experiments, integrating neural activity with the richness of behavioral context, is lacking. We designed a data model, as an extension to the NWB neurophysiology data standard, to represent structured behavioral neuroscience experiments, spanning stimulus delivery, timestamped events and responses, and simultaneous neural recordings. This data format is validated through its application to a variety of experimental designs, showcasing its potential to advance integrative analyses of neural circuits and complex behaviors. This work introduces a comprehensive data standard designed to capture and store a spectrum of behavioral data, encapsulating the multifaceted nature of modern neuroscience experiments.