bioRxiv Subject Collection: Neuroscience's Journal

Closed-loop microstimulations of the orbitofrontal cortex during real-life gaze interaction enhance dynamic social attention
The prefrontal cortex is extensively involved in social exchange. During dyadic gaze interaction, multiple prefrontal areas exhibit neuronal encoding of social gaze events and context-specific mutual eye contact, supported by a widespread neural mechanism of social gaze monitoring. To explore causal manipulation of real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events to three prefrontal areas in monkeys. Microstimulations of orbitofrontal cortex (OFC), but not dorsomedial prefrontal or anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing distance of gaze fixations relative to the eyes of the partner monkey. In the temporal dimension, microstimulations of OFC reduced the inter-looking interval for attending to another agent and the latency to reciprocate the directed gaze by the partner. These findings demonstrate that primate OFC serves as a functionally accessible node in controlling dynamic social attention and suggest its potential for a therapeutic brain interface.

Transcriptional signatures of fentanyl use in the mouse ventral tegmental area
Synthetic opioids such as fentanyl contribute to the vast majority of opioid-related overdose deaths, but fentanyl use remains broadly understudied. Like other substances with misuse potential, opioids cause lasting molecular adaptations to brain reward circuits, including neurons in the ventral tegmental area (VTA). The VTA contains numerous cell types that play diverse roles in opioid use and relapse, however it is unknown how fentanyl experience alters the transcriptional landscape in specific subtypes. Here, we performed single nuclei RNA sequencing to study transcriptional programs in fentanyl experienced mice. Male and female C57/BL6 mice self-administered intravenous fentanyl (1.5 mcg/kg/infusion) or saline for 10 days. After 24 hr abstinence, VTA nuclei were isolated and prepared for sequencing on the 10X platform. We identified different patterns of gene expression across cell types. In dopamine neurons, we found enrichment of genes involved in growth hormone signaling. In dopamine-glutamate-GABA combinatorial neurons, and some GABA neurons, we found enrichment of genes involved in Pi3k-Akt signaling. In glutamate neurons, we found enrichment of genes involved in cholinergic signaling. We identified transcriptional regulators for the differentially expressed genes in each neuron cluster, including downregulation of transcriptional repressor Bcl6, and upregulation of Wnt signaling partner Tcf4. We also compared the fentanyl-induced gene expression changes identified in mouse VTA with a published rat dataset in bulk VTA, and found overlap in genes related to GABAergic signaling and extracellular matrix interaction. Together, we provide a comprehensive picture of how fentanyl self-administration alters the transcriptional landscape of the mouse VTA, that serves for the foundation for future mechanistic studies.

Neural codes for visual numerosity independent of other quantities are present both in the dorsal and in the ventral stream of the human brain
Representing the number of items in sets (numerosity) is a core and evolutionary ancient ability. In a recent fMRI study Castaldi et al. (eLife 2019) showed that visual numerosity is represented independently from other visual features starting from early visual areas and progressively amplified along the dorsal stream hierarchy up to parietal areas. However, because in this study we recorded the brain activity from a restricted brain volume, and performed the analyses only in a series of retinotopically organized regions of interest along the dorsal stream, we still miss an exhaustive picture of the full network of regions encoding pure numerosity across the whole brain. In this research advance, we extend the findings of Castaldi et al. in two significant ways. First, we recorded the whole brain which allowed us to characterize the neural responses to numerosity beyond the dorsal stream using a searchlight analysis in addition to an ROIs approach. Second, in addition to the classical model-based analytical approach, such as RSA, we compared the neural representational geometries across the different regions using multi-dimensional scaling, an hypothesis-free approach capable of unveiling latent neural dimensions that might otherwise go unnoticed. Our results confirm that numerosity is represented over and above other visual features in early visual areas and progressively enhanced in associative areas of the dorsal stream but also, notably, of the ventral stream. We also found that numerosity representations in association areas differ substantially from those of early visual areas, and that in associative regions of both streams numerosity is represented on a similar manifold akin to a curved number line, a structure suggestive of their similar involvement in numerosity-based decision making. Taken together, these results call for an important revision of the existing neurocognitive models of number cognition.

The dynamics of oligodendrocyte populations following permanent ischemia promotes long-term spontaneous remyelination of damaged area.
Stroke is a major public health concern, whit limited clinically approved interventions available to enhance sensorimotor recovery beyond reperfusion. Remarkably, spontaneous recovery is observed in certain stroke patients, suggesting the existence of a self-brain repair mechanism not yet fully understood. In a rat model of permanent cerebral ischemia, we described an increase in oligodendrocytes expressing 3RTau in damaged area. Considering that restoration of myelin integrity ameliorates symptoms in many neurodegenerative diseases, here we hypothesize that this cellular response could trigger remyelination. Our results revealed after ischemia an early recruitment of OPCs to damaged area, followed by their differentiation into 3RTau+ pre-myelinating cells and subsequent into remyelinating oligodendrocytes. Using rat brain slices and mouse primary culture we confirmed the presence of 3RTau in pre-myelinating oligodendrocytes and a subset of mature. The myelin status analysis confirmed long-term remyelination in the damaged area. Postmortem samples from stroke subjects showed a reduction in oligodendrocytes, 3RTau+ cells, and myelin complexity in subcortical white matter. In conclusion, the dynamics of oligodendrocytes populations after ischemia reveals a spontaneous brain self-repair mechanism which restores the functionality of neuronal circuits long-term by remyelination of damage area. This is evidenced by the improvement of sensorimotor functions in ischemic rats. A deep understanding of this mechanism could be valuable in the search for alternative oligodendrocyte-based, therapeutic interventions to reduce the effects of stroke.

Novel in vivo TDP-43 stress reporter models to accelerate drug development in ALS.
The development of therapies to combat neurodegenerative diseases is widely recognised as a research priority, with conditions like Alzheimers, Amyotrophic lateral sclerosis (ALS) and Parkinsons set to place an ever-heavier burden on healthcare systems in the near future. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility of in vivo reporters of cytoprotective pathways (e.g. NRF2, p53) as surrogate early biomarkers of the ALS degenerative disease progression. We hypothesized that cellular stress observed in a model of ALS may precede overt cellular damage and could activate our cytoprotective pathway reporters. To test this hypothesis, we generated novel ALS-reporter mice by crossing the hTDP-43tg model into our oxidative stress/inflammation (Hmox1; NRF2 pathway) and DNA damage (p21; p53 pathway) stress reporter models. Histological analysis of reporter expression in a homozygous hTDP-43tg background demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with ALS. The activation occurs in Purkinje neurons and other parvalbumin-positive (PV+) cells within the cerebellum of mice, before moderate clinical signs are observed. In addition, reporter expression in hTDP-43tg hom peripheral tissues was not observed at the tested mouse ages (15 and 17 days postnatally). Further work is warranted to determine the specific mechanisms by which TDP-43 accumulation leads to reporter activation and whether therapeutic intervention modulates reporters expression. Our current studies suggest that these reporters may represent a powerful approach to accelerate preclinical studies targeting TDP-43 pathologies. We anticipate the reporter strategy could be of great value in developing treatments for a range of degenerative disorders.

Ketamine potentiates a glutamatergic presynapse
Ketamine is a NMDA receptor blocker with rapid antidepressant effects that are mediated by increased glutamatergic signalling. It remains unclear whether ketamine increases presynaptic function itself or acts via postsynaptic or network-level- mechanisms. Using presynaptic capacitance measurements at acute brain slices, we show that ketamine enhances presynaptic function within minutes. The presynaptic potentiation persisted >30 minutes after washout of ketamine and did not occur with MK-801, another NMDA receptor blocker. Mechanistically, ketamine increased both calcium influx and the number of release-ready vesicles. Our data uncover a rapid effect of ketamine on key presynaptic properties of glutamatergic signalling.

Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis
Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease that targets mature oligodendrocytes (MOLs) and their myelin. MOLs are transcriptionally heterogeneous and can transition to immune-like states in the context of MS. However, the intricacies of their dynamics throughout disease progression remain poorly understood. Here, we employed simultaneous single-cell multiome ATAC and RNA sequencing targeting oligodendroglia (OLGs) from the experimental autoimmune encephalomyelitis (EAE) MS mouse model at different stages of the disease course. We found that the transition to immune OLG states appear already at the early stages of EAE and persist to the late stages of the disease. Interestingly, transcription factor activity suggested immunosuppression in MOLs at early stages of EAE and we also observed a transitory activation of a regenerative program in MOLs at this stage. Importantly, different MOLs exhibit a differential responsiveness to EAE, with MOL2 exhibiting a stronger transcriptional immune response than MOL5/6. Moreover, we observed divergent responses at the epigenetic level of MOL2 and MOL5/6 during disease evolution. Thus, our single-cell multiomic resource highlights dynamic and distinct responses of OLG subpopulations to the evolving environment in EAE, which might modulate their response to regenerative therapeutic interventions in MS.

Orbitofrontal Cortex Modulates Auditory Cortical Sensitivity and Sound Perception
Sensory perception is dynamic, quickly adapting to sudden shifts in environmental or behavioral context. Though decades of work have established that these dynamics are mediated by rapid fluctuations in sensory cortical activity, we have a limited understanding of the brain regions and pathways that orchestrate these changes. Neurons in the orbitofrontal cortex (OFC) encode contextual information, and recent data suggest that some of these signals are transmitted to sensory cortices. Whether and how these signals shape sensory encoding and perceptual sensitivity remains uncertain. Here, we asked whether the OFC mediates context-dependent changes in auditory cortical sensitivity and sound perception by monitoring and manipulating OFC activity in freely moving animals under two behavioral contexts: passive sound exposure and engagement in an amplitude modulation (AM) detection task. We found that the majority of OFC neurons, including the specific subset that innervate the auditory cortex, were strongly modulated by task engagement. Pharmacological inactivation of the OFC prevented rapid context-dependent changes in auditory cortical firing, and significantly impaired behavioral AM detection. Our findings suggest that contextual information from the OFC mediates rapid plasticity in the auditory cortex and facilitates the perception of behaviorally relevant sounds.

Automating literature screening and curation with applications to computational neuroscience
Objective: ModelDB (https://modeldb.science) is a discovery platform for computational neuroscience, containing over 1800 published model codes with standardized metadata. These codes were mainly supplied from unsolicited model author submissions, but this approach is inherently limited. We estimate we have captured only around one-third of NEURON models and lower fractions for other simulators. To more completely characterize the state of computational neuroscience modeling work, we aim to identify works containing results derived from computational neuroscience approaches and their standardized associated metadata (e.g. cell types, research topics). Materials and Methods: Known computational neuroscience work from ModelDB and identified neuroscience work queried from PubMed were included in our study. After pre-screening with SPECTER2, GPT-3.5 and GPT-4 were used to identify likely computational neuroscience work and their relevant metadata. Results: SPECTER2, GPT-4, and GPT-3.5 demonstrated varied but high abilities in identification of computational neuroscience work. GPT-4 achieved 96.9% accuracy and GPT-3.5 improved from 54.2% to 85.5% through instruction-tuning and Chain of Thought. GPT-4 also showed high potential in identifying relevant metadata annotations. Discussion: Due to computational limitations, we only used each paper's title and abstract, partially leading to false negatives. Further efforts should be devoted to including more training data and further improving current LLMs through fine-tuning approaches. Conclusion: NLP and LLM techniques can be added to ModelDB to facilitate further model discovery, and will contribute to a more standardized and comprehensive framework for establishing domain-specific resources.

SleepEEGpy: a Python-based package for the preprocessing, analysis, and visualization of sleep EEG data
Sleep research uses electroencephalography (EEG) to infer brain activity in health and disease. Beyond standard sleep scoring, there is increased interest in advanced EEG analysis that investigates activities at specific times, frequencies, and scalp locations. Such analysis requires preprocessing to improve the signal-to-noise ratio, and dedicated analysis algorithms and visualizations. While many EEG software packages exist, sleep research has specific considerations (e.g., avoiding particular artifacts, analysis, and visualization in an ongoing non-epoch nature, detection of characteristic oscillatory events, and interface with sleep staging) that require dedicated tools. Currently, sleep investigators typically use available libraries for specific tasks in a 'fragmented' configuration that is inefficient, prone to errors, and requires the burdensome learning of multiple software environments. Here, we present SleepEEGpy, an open-source Python package for sleep EEG data preprocessing and analysis, including (i) cleaning, (ii) independent component analysis, (iii) analysis of sleep events, (iv) analysis of spectral features, and associated visualization tools. SleepEEGpy builds upon MNE-Python, YASA, and SpecParam (formerly FOOOF) tools to provide an all-in-one package for comprehensive yet straightforward sleep EEG research. We demonstrate the SleepEEGpy pipeline and its functionalities by applying it to overnight high-density EEG data in healthy participants, revealing multiple characteristic activity signatures typical of each vigilance state. These include alpha oscillations in wakefulness, sleep spindle and slow wave activities in NREM sleep, and theta activity in REM sleep. We hope that this package will be embraced and further developed by the sleep research community, allowing investigators to focus more on science and improve reproducibility among research groups.

Interleukin-1α links peripheral CaV2.2 channel activation to rapid adaptive increases in heat sensitivity in skin
Neurons have the unique capacity to adapt output in response to changes in their environment. Within seconds, sensory nerve endings can become hypersensitive to stimuli in response to potentially damaging events. The underlying neuroinflammatory response is well studied, but several of the key signaling molecules that mediate sensory hypersensitivity remain unknown. We previously discovered that peripheral voltage-gated CaV2.2 channels in nerve endings in skin are essential for the rapid, transient increase in sensitivity to heat, but not to mechanical stimuli, that accompanies intradermal capsaicin. Here, we report that the cytokine interleukin-1 (IL-1), an alarmin, is necessary and sufficient to trigger rapid heat and mechanical hypersensitivity in skin. Of 20 cytokines screened, only IL-1 was consistently detected in hind paw interstitial fluid in response to intradermal capsaicin and, similar to behavioral sensitivity to heat, IL-1 levels were also dependent on peripheral CaV2.2 channel activity. Neutralizing IL-1 in skin significantly reduced capsaicin-induced changes in hind paw sensitivity to radiant heat and mechanical stimulation. Intradermal IL-1 enhances behavioral responses to stimuli and, in culture, IL-1 enhances the excitability of Trpv1-expressing sensory neurons. Together, our data suggest that IL-1 is the key cytokine that underlies rapid and reversible neuroinflammatory response in skin.

Diverging roles of TRPV1 and TRPM2 in warm-temperature detection
The accurate perception of innocuous temperatures, particularly those experienced as pleasantly warm, is essential for achieving thermal comfort and maintaining thermoregulatory balance. Warm-sensitive neurons (WSN) innervating the skin play a central role in non-painful warmth detection. The TRP ion channels TRPV1 and TRPM2 have been suggested as sensors of warm temperature in WSNs. However, the precise contribution of these channels to the process of warmth detection is not fully understood. A significant challenge in analysing WSNs lies in their scarcity: fewer than 10% of sensory neurons in the rodent dorsal root ganglion (DRG) respond to innocuous warm temperatures. In this study, we examined >20,000 cultured mouse DRG neurons using calcium imaging and discovered distinct contributions of TRPV1 and TRPM2 to warm-temperature sensitivity. TRPV1 and TRPM2 affect the abundance of WSNs, with TRPV1 mediating the rapid, dynamic response to warmth. By carefully tracking animal movement in a whole-body thermal preference paradigm, we observe that these cellular differences correlate with nuanced thermal behaviours. Utilizing a drift-diffusion model to quantitatively analyse the decision-making process of animals exposed to different environmental temperatures, we found that: TRPV1 primarily impairs the precision of evidence accumulation, whereas TRPM2 significantly increases the total duration of exposure to uncomfortably warm environments. Our findings provide valuable insights into the distinct molecular responses to warmth stimuli, and underpin the subtle aspects of thermal decision-making when encountering minor temperature variations.

Ca2+ Oscillation in Vascular Smooth Muscle Cells Control Myogenic Spontaneous Vasomotion and Counteract Post-ischemic No-reflow
Ischemic stroke produces the highest adult disability. Despite successful recanalization, no-reflow, or the futile restoration of the cerebral perfusion after ischemia, is a major cause of brain lesion expansion. However, the vascular mechanism underlying this hypoperfusion is largely unknown, and no approach is available to actively promote optimal reperfusion to treat no-reflow. Here, by combining two-photon laser scanning microscopy (2PLSM) and a mouse middle cerebral arteriolar occlusion (MCAO) model, we found myogenic vasomotion deficits correlated with post-ischemic cerebral circulation interruptions and no-reflow. Transient occlusion-induced transient loss of mitochondrial membrane potential ({Delta}{Psi}m) permanently impaired mitochondria-endoplasmic reticulum (ER) contacts and abolished Ca2+ oscillation in smooth muscle cells (SMCs), the driving force of myogenic spontaneous vasomotion. Furthermore, tethering mitochondria and ER by specific overexpression of ME-Linker in SMCs restored cytosolic Ca2+ homeostasis, remotivated myogenic spontaneous vasomotion, achieved optimal reperfusion, and ameliorated neurological injury. Collectively, the maintaining of arteriolar myogenic vasomotion and mitochondria-ER contacts in SMCs, are of critical importance in preventing post-ischemic no-reflow.

EFEMP1 contributes to light-dependent ocular growth in zebrafish
Myopia (short-sightedness) is the most common ocular disorder. It generally develops after over-exposure to aberrant visual environments, disrupting emmetropization mechanisms that should match eye growth with optical power. A pre-screening of strongly associated myopia-risk genes identified through human genome-wide association studies implicates efemp1 in myopia development, but how this gene impacts ocular growth remains unclear. Here, we modify efemp1 expression specifically in the retina of zebrafish. We found that under normal lighting, efemp1 mutants developed axial myopia, enlarged eyes, reduced spatial vision and altered retinal function. However, under myopia-inducing dark-rearing, compared to control fish, mutants remained emmetropic and showed changes in retinal function. Efemp1 modification changed the expression of efemp1, egr1, tgfb1a, vegfab and rbp3 genes in the eye, and changes the inner retinal distributions of myopia-associated EFEMP1, TIMP2 and MMP2 proteins. Efemp1 modification also impacted dark-rearing-induced responses of vegfab and wnt2b genes and above-mentioned myopia-associated proteins. Together, we provided robust evidence that light-dependent ocular growth is regulated by efemp1.

A functional parcellation of the whole brain in individuals with autism spectrum disorder reveals atypical patterns of network organization
BACKGROUND: Researchers studying autism spectrum disorder (ASD) lack a comprehensive map of the functional network topography in the ASD brain. We used high-quality resting state functional MRI (rs-fMRI) connectivity data and a robust parcellation routine to provide a whole-brain map of functional networks in a group of seventy individuals with ASD and a group of seventy typically developing (TD) individuals. METHODS: The rs-fMRI data were collected using an imaging sequence optimized to achieve high temporal signal-to-noise ratio (tSNR) across the whole-brain. We identified functional networks using a parcellation routine that intrinsically incorporates stability and replicability of the networks by keeping only network distinctions that agree across halves of the data over multiple random iterations in each group. The groups were tightly matched on tSNR, in-scanner motion, age, and IQ. RESULTS: We compared the maps from each group and found that functional networks in the ASD group are atypical in three seemingly related ways: 1) whole-brain connectivity patterns are less stable across voxels within multiple functional networks, 2) the cerebellum, subcortex, and hippocampus show weaker differentiation of functional subnetworks, and 3) subcortical structures and the hippocampus are atypically integrated with the neocortex. CONCLUSIONS: These results were statistically robust and suggest that patterns of network connectivity between the neocortex and the cerebellum, subcortical structures, and hippocampus are atypical in ASD individuals.

Within-Individual Organization of the Human Cognitive Cerebellum: Evidence for Closely Juxtaposed, Functionally Specialized Regions
The human cerebellum possesses multiple regions linked to cerebral association cortex. Here we mapped the cerebellum using precision functional MRI within individual participants (N=15), first estimating regions using connectivity and then prospectively testing functional properties using independent task data. Network estimates in all participants revealed a Crus I / II cerebellar megacluster of five higher-order association networks often with multiple, discontinuous regions for the same network. Seed regions placed within the megaclusters, including the disjointed regions, yielded spatially selective networks in the cerebral cortex. Compelling evidence for functional specialization within the cerebellar megaclusters emerged from the task responses. Reflecting functional distinctions found in the cerebrum, domain-flexible cerebellar regions involved in cognitive control dissociated from distinct domain-specialized regions with differential responses to language, social, and spatial / episodic task demands. These findings provide a clear demonstration that the cerebellum encompasses multiple zones dedicated to cognition, featuring juxtaposed regions specialized for distinct processing domains.

Fluvoxamine maleate ameliorates Alzheimer disease pathology by mitigating amyloid-beta load and neuroinflammation in 5XFAD mice
Background: Alzheimer pathology (AD) is accompanied by the deposition of amyloid beta (A{beta}) and chronic neuroinflammation, where NLRP3 inflammasome is particularly involved. In this study, we found that the OCD drug fluvoxamine maleate (FXN) can potently ameliorate AD pathology in 5XFAD mice by autophagy-mediated clearance of A{beta} and inhibition of NLRP3 inflammasome. Methods: We used mice primary astrocytes to establish the mechanism of action of FXN against NLRP3 inflammasome by using various techniques like ELISA, Western blotting, confocal microscopy, Immunofluorescence, etc. The validation of the anti-AD activity of FXN was done in transgenic 5XFAD mice after two months of treatment followed by behavior analysis and studying inflammatory and autophagy proteins along with immunohistochemistry analysis for A{beta} load in the hippocampi. Results: Our data showed that FXN induces autophagy to inhibit NF-{kappa}B and NLRP3 inflammasome at a low concentration of 78 nM apart from directly inhibiting NLRP3 inflammasome in primary astrocytes. FXN activated the PRKAA2 pathway through CAMKK2 signaling, which led to the induction of autophagy in primary astrocytes. FXN inhibited the ATP-mediated NLRP3 inflammasome through autophagic degradation of NF-{kappa}B and thus caused the downregulation of pro-IL-1{beta} and NLRP3. The anti-NLRP3 inflammasome effect of FXN was reversed when autophagy was inhibited either by genetic knockdown of the PRKAA2 pathway or by bafilomycin A1. Furthermore, FXN treatment led to improved AD pathology in 5XFAD mice, which displayed a significant improvement in multiple behavior parameters like working memory and neuromuscular coordination and they behaved more like wild-type animals. We found that FXN improved behavior in 5XFAD mice by clearing the A{beta} deposits from the hippocampi along with a significant reduction in multiple inflammatory proteins, including NF-{kappa}B, GFAP, IBA1, IL-1{beta}, TNF-, and IL-6 associated with NF-{kappa}B and NLRP3 inflammasome in the brain. Moreover, these changes were accompanied by increased expression of autophagic proteins. Conclusion: Our data suggest that to ameliorate AD pathology, FXN simultaneously targets two key pathological features of AD that is A{beta} deposits and neuroinflammation. Being an approved drug, FXN can be pushed as a potential drug candidate for human studies against AD.

Reduced Lateralization of Multiple Functional Brain Networks in Autistic Males
Background: Autism spectrum disorder has been linked to a variety of organizational and developmental deviations in the brain. One such organizational difference involves hemispheric lateralization, which may be localized to language-relevant regions of the brain or distributed more broadly. Methods: In the present study, we estimated brain hemispheric lateralization in autism based on each participant's unique functional neuroanatomy rather than relying on group-averaged data. Additionally, we explored potential relationships between the lateralization of the language network and behavioral phenotypes including verbal ability, language delay, and autism symptom severity. We hypothesized that differences in hemispheric asymmetries in autism would be limited to the language network, with the alternative hypothesis of pervasive differences in lateralization. We tested this and other hypotheses by employing a cross-sectional dataset of 118 individuals (48 autistic, 70 neurotypical). Using resting-state fMRI, we generated individual network parcellations and estimated network asymmetries using a surface area-based approach. A series of multiple regressions were then used to compare network asymmetries for eight significantly lateralized networks between groups. Results: We found significant group differences in lateralization for the left-lateralized Language (d = -0.89), right-lateralized Salience/Ventral Attention-A (d = 0.55), and right-lateralized Control-B (d = 0.51) networks, with the direction of these group differences indicating less asymmetry in autistic individuals. These differences were robust across different datasets from the same participants. Furthermore, we found that language delay stratified language lateralization, with the greatest group differences in language lateralization occurring between autistic individuals with language delay and neurotypical individuals. Limitations: The generalizability of our findings is restricted due to the male-only sample and greater representation of individuals with high verbal and cognitive performance. Conclusions: These findings evidence a complex pattern of functional lateralization differences in autism, extending beyond the Language network to the Salience/Ventral Attention-A and Control-B networks, yet not encompassing all networks, indicating a selective divergence rather than a pervasive one. Furthermore, a differential relationship was identified between Language network lateralization and specific symptom profiles (namely, language delay) of autism.

Effects of novelty and temporal distance on post-experience reactivation of hippocampal place cells encoding multiple environments
The hippocampus plays a crucial role in consolidating episodic memories from diverse experiences that encompass spatial, temporal, and novel information. This study analyzed the spike patterns of hippocampal place cells in the CA3 and CA1 areas of rats that sequentially foraged in five rooms, including familiar and novel rooms, followed by a rest period. Across multiple rooms, the generation of place fields by CA1 place cells was coordinated with other place cells. In the subsequent rest period, CA3 place cells that encoded novel environments exhibited stronger and more coordinated reactivation during sharp wave ripples (SWRs) than CA1 place cells. In contrast, CA1 place cells that encoded more recent environments exhibited stronger SWR-associated reactivation, independent of spikes of other cells, with weaker influences from novelty compared to CA3 place cells. These results suggest that post-experience SWR-associated reactivation of CA3 and CA1 neurons primarily processes novelty-related and temporal distance-related aspects of memory, respectively.

A pilot study of the impact of smells on the behavior of level 3 autistic children and adolescents during an ongoing task
The present pilot study aims to perform a first evaluation of the effect of smells on the behavior of autistic children and adolescents (level 3) while they are performing a routine task and are going through a more or less intense crisis situation. To do this, we developed a protocol adapted for a field study in the familiar environment (specialized school) of 8 autistic children and adolescents, where the effect of odors on the behaviors of screaming, agitation, and aggression was assessed. First, it was possible to carry out this protocol on this level 3 autistic population. Second, the results acquired on subjective data collected by the experimenter suggest that odors may reduce certain behavioral traits such as agitation or screaming. These data should be considered as proof-of-concept, with results that need to be confirmed in a larger sample of autistic individuals.

Evaluating Augmentation Approaches for Deep Learning-based Major Depressive Disorder Diagnosis with Raw Electroencephalogram Data
While deep learning methods are increasingly applied in research contexts for neuropsychiatric disorder diagnosis, small dataset size limits their potential for clinical translation. Data augmentation (DA) could address this limitation, but the utility of EEG DA methods remains relatively underexplored in neuropsychiatric disorder diagnosis. In this study, we train a model for major depressive disorder diagnosis. We then evaluate the utility of 6 EEG DA approaches. Importantly, to remove the bias that could be introduced by comparing performance for models trained on larger augmented training sets to models trained on smaller baseline sets, we also introduce a new baseline trained on duplicate training data to better. We lastly examine the effects of the DA approaches upon representations learned by the model with a pair of explainability analyses. We find that while most approaches boost model performance, they do not improve model performance beyond that of simply using a duplicate training set without DA. The exception to this is channel dropout augmentation, which does improve model performance. These findings suggest the importance of comparing EEG DA methods to a baseline with a duplicate training set of equal size to the augmented training set. We also found that some DA methods increased model robustness to frequency (Fourier transform surrogates) and channel (channel dropout) perturbation. While our findings on EEG DA efficacy are restricted to our dataset and model, we hope that future studies on deep learning for small EEG datasets and on new EEG DA methods will find our findings helpful.

Single voxel autocorrelation reflects hippocampal function in temporal lobe epilepsy
We have previously shown that analyses of autocorrelation of BOLD signal applied to single voxels in healthy controls can identify gradients of temporal dynamics throughout the hippocampal long-axis that are related to behavior. A question that remains is how changes in functional and structural integrity in the brain affect single voxel autocorrelation. In this study we investigate how hippocampal autocorrelation is affected by structural and functional hippocampal dysfunction by investigating a population of patients with unilateral temporal lobe epilepsy (TLE). Many patients with TLE have mesial temporal sclerosis (MTS), characterized by scarring and neuronal loss particularly in the anterior hippocampus. Here we compared patients with left and right TLE, some with and without MTS, to healthy controls. We applied our single voxel autocorrelation method and data-driven clustering approach to segment the hippocampus based on the autocorrelation. We found that patients with left TLE had slower signal dynamics (i.e., higher autocorrelation) compared to controls, particularly in the anterior-medial portion of the hippocampus. This was true for both the epileptogenic and non-epileptogenic hemispheres. We also evaluated the extent of cluster preservation (i.e., spatial overlap with controls) of patient autocorrelation clusters and the relationship to verbal and visuospatial memory. We found that patients with greater cluster preservation in the anterior-medial hippocampus had better memory performance. Surprisingly, we did not find any effect of MTS on single voxel autocorrelation, despite the structural changes associated with the condition. These results suggest that single voxel autocorrelation may be related to functional, rather than structural, integrity.

The effect of long-term sleep disruption on the brain - looking beyond amyloid
The mechanism underlying the possible causal association between long-term sleep disruption and Alzheimer's disease remains unclear [1]. A hypothesised pathway through increased brain amyloid load was not confirmed in previous work in our cohort of maritime pilots with long-term work-related sleep disruption [2]. Here, using functional MRI, T2-FLAIR and Arterial Spin Labeling MRI scans, we explored alternative neuroimaging biomarkers related to both sleep disruption and AD: resting-state network co-activation and between-network connectivity of the default mode network (DMN), salience network (SAL) and frontoparietal network (FPN), vascular damage and cerebral blood flow (CBF). We acquired data of 16 maritime pilots (56 +/- 2.3 years old) with work-related long-term sleep disruption (23 +/- 4.8 working years) and 16 healthy controls (59 +/- 3.3 years old), with normal sleep patterns (Pittsburgh Sleep Quality Index less than or equal to 5). Maritime pilots did not show altered co-activation in either the DMN, FPN, or SAL and no differences in between-network connectivity. We did not detect increased markers of vascular damage in maritime pilots, and additionally, maritime pilots did not show altered CBF-patterns compared to healthy controls. In summary, maritime pilots with long-term sleep disruption did not show neuroimaging markers indicative of preclinical AD compared to healthy controls. These findings do not resemble those of short-term sleep deprivation studies. This could be due to resiliency to sleep disruption or selection bias, as participants have already been exposed to and were able to deal with sleep disruption for multiple years, or to compensatory mechanisms [3]. This suggests the relationship between sleep disruption and AD is not as strong as previously implied in studies on short-term sleep deprivation, which would be beneficial for all shift workers suffering from work-related sleep disruptions.

Amyloid precursor protein induces reactive astrogliosis
We present in vitro and in vivo evidence demonstrating that Amyloid Precursor Protein (APP) acts as an essential instigator of reactive astrogliosis. Cell-specific overexpression of APP in cultured astrocytes led to remodelling of the intermediate filament network, enhancement of cytokine production and activation of cellular programs centred around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion in cultured astrocytes abrogated remodelling of the intermediate filament network and blunted expression of IFN stimulated gene (ISG) products in response to lipopolysaccharide (LPS). Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein (GFAP) observed canonically in astrocytes in response to TBI. Thus, APP represents a molecular inducer and regulator of reactive astrogliosis.

DDHD2 is necessary for activity-driven fatty acid fueling of nerve terminal function
HSP54, a hereditary spastic paraplegia associated with cognitive impairment, is caused by mutations in the neuron-specific triglyceride (TG) lipase DDHD2. Loss of DDHD2 function results in lipid accumulation in human brains1 and lipid droplets (LDs) in mouse neurons2. In metabolically demanding tissues, TG lipases generate a fatty acid (FA) flux from LDs to fuel mitochondrial ATP production, but neurons are considered unable to use fat as an energy source. Thus, the basis for cognitive impairment driven by DDHD2 loss remains enigmatic. To resolve this paradox, we took advantage of presynaptic sensitivity to metabolic perturbations to determine if FAs derived from LDs could power local {beta}-oxidation to support synaptic functions and whether DDHD2 activity would be required in the process. We demonstrate that nerve terminals are enriched with DDHD2 and blocking its activity leads to presynaptic accumulation of LDs. Moreover, we show that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion and drive local mitochondrial ATP production allowing nerve terminals to sustain function in the complete absence of glucose. Our data demonstrate that neurons and their nerve terminals can make use of LDs during electrical activity to provide metabolic support when glucose is in short supply.

Comparative basolateral amygdala connectomics reveals dissociable single-neuron projection patterns to frontal cortex in macaques and mice
The basolateral amygdala (BLA) projects to the frontal cortex (FC) in both rodents and primates, but the comparative organization of single-neuron BLA-FC projections is unknown. Using a barcoded connectomic approach, we found that BLA neurons are more likely to project to multiple distinct parts of FC in mice than in macaques. Further, while single BLA neuron projections to nucleus accumbens are similarly organized in mice and macaques, BLA-FC connections differ.

The molecular basis of sugar detection by an insect taste receptor
Animals crave sugars because of their energy potential and the pleasurable sensation of tasting sweetness. Yet all sugars are not metabolically equivalent, requiring mechanisms to detect and differentiate between chemically similar sweet substances. Insects use a family of ionotropic gustatory receptors to discriminate sugars, each of which is selectively activated by specific sweet molecules. To gain insight into the molecular basis of sugar selectivity, we determined structures of Gr9, a gustatory receptor from the silkworm Bombyx mori (BmGr9), in the absence and presence of its sole activating ligand, D-fructose. These structures, along with structure-guided mutagenesis and functional assays, illustrate how specificity for D-fructose is seemingly achieved by a ligand-binding pocket that precisely matches the overall shape and pattern of chemical groups in D-fructose. However, our computational docking and experimental binding assays revealed that other sugars also bind BmGr9, yet they are unable to activate the receptor. We identified the conformational change required to open the channel gate that provides an additional layer of receptor tuning in BmGr9; only D-fructose can both fit into the pocket and simultaneously engage a bridge of two conserved aromatic residues that connects the pocket to the ion conducting pore. Thus, chemical specificity does not depend solely on the selectivity of the ligand-binding pocket, but it is an emergent property arising from a combination of receptor-ligand interactions and allosteric coupling. Our results support a model whereby coarse receptor tuning is derived from the size and chemical characteristics of the pocket, whereas fine-tuning of receptor activation is achieved through the selective engagement of an allosteric pathway that regulates ion conduction.

Early Intervention with Electrical Stimulation Reduces Neural Damage After Stroke in Non-human Primates
Ischemic stroke is a neurological condition that results in significant mortality and long-term disability for adults, creating huge health burdens worldwide. For stroke patients, acute intervention offers the most critical therapeutic opportunity as it can reduce irreversible tissue injury and improve functional outcomes. However, currently available treatments within the acute window are highly limited. Although emerging neuromodulation therapies have been tested for chronic stroke patients, acute stimulation is rarely studied due to the risk of causing adverse effects related to ischemia-induced electrical instability. To address this gap, we combined electrophysiology and histology tools to investigate the effects of acute electrical stimulation on ischemic neural damage in non-human primates. Specifically, we induced photothrombotic lesions in the monkey sensorimotor cortex while collecting electrocorticography (ECoG) signals through a customized neural interface. Gamma activity in ECoG was used as an electrophysiological marker to track the effects of stimulation on neural activation. Meanwhile, histological analysis including Nissl, cFos, and microglial staining was performed to evaluate the tissue response to ischemic injury. Comparing stimulated monkeys to controls, we found that theta-burst stimulation administered directly adjacent to the ischemic infarct at 1 hour post-stroke briefly inhibits peri-infarct neuronal activation as reflected by decreased ECoG gamma power and cFos expression. Meanwhile, lower microglial activation and smaller lesion volumes were observed in animals receiving post-stroke stimulation. Together, these results suggest that acute electrical stimulation can be used safely and effectively as an early stroke intervention to reduce excitotoxicity and inflammation, thus mitigating neural damage and enhancing stroke outcomes.

Male-specific features of C. elegans neuronal aging
Aging is a complex biological process, with sexually dimorphic aspects. For example, men and women differ in their vulnerabilities in cognitive decline, suggesting biological sex may contribute to the heterogeneous nature of aging. Although we know a great deal about the cognitive aging of hermaphrodites of the model systemm C. elegans, less is known about cognitive decline in males. Through behavioral analyses, we found that the cognitive aging process has both sex-shared and sex-dimorphic characteristics. Through neuron-specific sequencing, we identified neuronal age-associated sex-differential targets. In addition to sex-shared neuronal aging genes, males differentially downregulate mitochondrial metabolic genes and upregulate GPCR genes with age. In addition, the X chromosome exhibits increased gene expression in hermaphrodites and altered dosage compensation complex expression with age, indicating possible X-chromosomal dysregulation that contributes to sexual dimorphism in cognitive aging. Finally, we found that the sex-differentially expressed gene hrg-7, which encodes an aspartic-type endopeptidase, regulates male behavior during cognitive aging but does not affect hermaphrodite behaviors. Overall, these results suggest that males and hermaphrodites exhibit different age-related neuronal changes. This study will strengthen our understanding of sex-specific vulnerability and resilience and help identify new pathways to target with novel treatments that could benefit both sexes.

Vision sculpts a continuum of L2/3 cell types in the visual cortex during the critical period
We previously reported that vision specifies Layer 2/3 (L2/3) glutamatergic cell-type identity in the primary visual cortex (V1). Using unsupervised clustering of single-nucleus RNA-sequencing data, we identified molecularly distinct L2/3 cell types in normal-reared (NR) and dark-reared (DR) mice, but the two sets exhibited poor correspondence. Here, we show that classification of cell types was confounded in DR by vision-dependent gene programs that are orthogonal to gene programs underlying cell-type identity. A focused clustering analysis successfully matches cell types between DR and NR, suggesting that cell identity-defining gene programs persist under vision deprivation but are overshadowed by vision-dependent transcriptomic variation. Using multi-tasking theory we show that L2/3 cell types form a continuum between three cell-archetypes. Visual deprivation markedly shifts this distribution along the continuum. Thus, dark- rearing markedly influences cell states thereby masking cell-type-identities and changes the distribution of L2/3 types along a transcriptomic continuum.

Isolectin B4 (IB4)-conjugated streptavidin for the selective knockdown of proteins in IB4-positive (+) nociceptors
In vivo analysis of protein function in nociceptor subpopulations using antisense oligonucleotides and short interfering RNAs is limited by their nonselective cellular uptake. To address the need for selective transfection methods, we covalently linked isolectin B4 (IB4) to streptavidin and analyzed whether it could be used to study protein function in IB4 positive nociceptors. Rats treated intrathecally with IB4 conjugated streptavidin complexed with biotinylated antisense oligonucleotides for protein kinase C epsilon (PKCe) mRNA were found to have: a) less PKCe in dorsal root ganglia (DRG), b) reduced PKCe expression in IB4 positive but not IB4 negative DRG neurons, and c) fewer transcripts of the PKCe gene in the DRG. This knockdown in PKCe expression in IB4 positive DRG neurons is sufficient to reverse hyperalgesic priming, a rodent model of chronic pain that is dependent on PKCe in IB4 positive nociceptors. These results establish that IB4 streptavidin can be used to study protein function in a defined subpopulation of nociceptive C fiber afferents.

Learning Image Memorability with Feedback-Based Training
Memorability, or the likelihood that an image is later remembered, is an intrinsic stimulus property that is remarkably consistent across viewers. Despite this consistency in what people remember and forget, previous findings suggest a lack of consistency in what individuals subjectively believe to be memorable and forgettable. We aimed to improve the ability of participants to judge memorability using a feedback-based training paradigm containing face images (Experiment 1) or scene images (Experiment 2 and its replication and control experiments). Overall, participants were fairly accurate at categorizing the memorability of images. In response to the training, participants were able to improve their memorability judgments of scenes, but not faces. Those who used certain strategies to perform the task, namely relying on characteristic features of the scenes, showed greater learning. Although participants improved slightly over time, they never reached the level of ResMem, the leading DNN for estimating image memorability. These results suggest that with training, human participants can better their understanding of image memorability, but may be unable to access its full variance.

Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner
Epidemiological studies link neurodevelopmental disorders (NDDs) with exposure to maternal viral infection in utero. It is hypothesized that the mechanism governing this link involves the activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17. While IL-17 is implicated as a major driver of fetal brain abnormalities, this inflammation-induced TH17 pathway has not been thoroughly examined in models of live viral infection during pregnancy. Influenza A virus (IAV) infection is consistently linked to offspring NDDs and can result in host intestinal dysregulation. Therefore, it is possible that intestinal TH17 cells and subsequent production of IL-17 could drive fetal brain abnormalities during gestational IAV infection. To test this, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-dose IAV group, despite a lack of IL-17 signaling. Profiling fetal microglia and border-associated macrophages (BAMs) --potential cellular mediators of IAV-induced cortical abnormalities --revealed dose-dependent differences in the numbers of BAMs but not microglia. Overall, our data support the idea of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, confirming the use of live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.

Within-subject changes in DNA-methylome profile identify individual signatures of early-life adversity, with a potential to predict neuropsychiatric outcome.
Background: Adverse early-life experiences (ELA), including poverty, trauma and neglect, affect a majority of world children. Whereas the impact of ELA on cognitive and emotional health throughout the lifespan is well-established, it is not clear how distinct types of ELA influence child development, and there are no tools to predict for an individual child their vulnerability or resilience to the consequences of ELAs. Epigenetic markers including DNA-methylation profiles of peripheral cells may encode ELA and provide a predictive outcome marker. However, the rapid dynamic changes in DNA methylation in childhood and the inter-individual variance of the human genome pose barriers to identifying profiles predicting outcomes of ELA exposure. Here, we examined the relation of several dimensions of ELA to changes of DNA methylation, using a longitudinal within-subject design and a high threshold for methylation changes in the hope of mitigating the above challenges. Methods: We analyzed DNA methylation in buccal swab samples collected twice for each of 110 infants: neonatally and at 12 months. We identified CpGs differentially methylated across time, calculated methylation changes for each child, and determined whether several indicators of ELA associated with changes of DNA methylation for individual infants. We then correlated select dimensions of ELA with methylation changes as well as with measures of executive function at age 5 years. We examined for sex differences, and derived a sex-dependent impact score based on sites that most contributed to the methylation changes. Findings: Setting a high threshold for methylation changes, we discovered that changes in methylation between two samples of an individual child reflected age-related trends towards augmented methylation, and also correlated with executive function years later. Among the tested factors and ELA dimensions, including income to needs ratios, maternal sensitivity, body mass index and sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, an interaction was observed between a measure of high early-life unpredictability and methylation changes, in presaging executive function. Interpretation: These findings establish longitudinal, within-subject changes in methylation profiles as a signature of some types of ELA in an individual child. Notably, such changes are detectable beyond the age-associated DNA methylation dynamics. Future studies are required to determine if the methylation profile changes identified here provide a predictive marker of vulnerabilities to poorer cognitive and emotional outcomes.

Machine learning of brain-specific biomarkers from EEG
Electroencephalography (EEG) has a long history as a clinical tool to study brain function, and its potential to derive biomarkers for various applications is far from exhausted. Machine learning (ML) can guide future innovation by harnessing the wealth of complex EEG signals to isolate relevant brain activity. Yet, ML studies in EEG tend to ignore physiological artifacts, which may cause problems for deriving biomarkers specific to the central nervous system (CNS). We present a framework for conceptualizing machine learning from CNS versus peripheral signals measured with EEG. A common signal representation across the frequency spectrum based on Morlet wavelets allowed us to define traditional brain activity features (e.g. log power) and alternative inputs used by state-of-the-art ML approaches (covariance matrices). Using more than 2600 EEG recordings from large public databases (TUAB, TDBRAIN), we studied the impact of peripheral signals and artifact removal techniques on ML models in exemplary age- and sex-prediction analyses. Across benchmarks, basic artifact rejection improved model performance whereas further removal of peripheral signals using ICA decreased performance. Our analyses revealed that peripheral signals enable age and sex prediction. However, they explained only a fraction of the performance provided by brain signals. We show that brain signals and body signals, both reflected in the EEG, allow for prediction of personal characteristics. While these results may depend on specific prediction problems, our work suggests that great care is needed to separate these signals when the goal is to develop CNS-specific biomarkers using ML.

Whole-brain modular dynamics at rest predict sensorimotor learning performance
Predictive biomarkers of cognitive performance are informative about the neural mechanisms underlying cognitive phenomena, and have tremendous potential for the diagnosis and treatment of neuropathologies with cognitive symptoms. Among such biomarkers, the modularity (subnetwork composition) of whole-brain functional networks is especially promising, due to its longstanding theoretical foundations and recent success in predicting clinical outcomes. We used functional magnetic resonance imaging to identify whole-brain modules at rest, calculating metrics of their spatio-temporal dynamics before and after a sensorimotor learning task on which fast learning is widely believed to be supported by a cognitive strategy. We found that participants' learning performance was predicted by the strength of dynamic modularity scores (clarity of subnetwork composition), the degree of coordination of modular reconfiguration, and the strength of recruitment and integration of networks derived during the task itself. Our findings identify these whole-brain metrics as promising biomarkers of cognition, with relevance to basic and clinical neuroscience.

Interpretable deep learning framework towards understanding molecular changes in human brains with Alzheimer's disease: implication for microglia activation and sex differences in AD
INTRODUCTION: The objective of this study is to characterize the molecular changes associated with AD from gene expression data of brain tissues taking an interpretable deep learning approach which has not been fully exploited. METHODS: We trained multi-layer perceptron (MLP) models for the classification of neuropathologically confirmed AD vs. controls using the transcriptomic data of three brain regions from the ROSMAP study. The whole disease spectrum was then modeled as a progressive trajectory. SHAP (SHapley Additive exPlanations) value was derived to explain model predictions and identify significant implicated genes for subsequent network analysis of key gene modules underlying AD progression. The framework was validated using two external datasets: the Mayo RNA-seq study cohort and the Mount Sinai Brain Bank study cohort. RESULTS: The MLP models achieved superior performance in classification and prediction in external datasets. SHAP explainer revealed common and specific transcriptomic signatures from different brain regions. DISCUSSION: We identified common gene signatures in microglia and sex specific modules in neurons that are implicated in AD. This work paves the way for utilizing artificial intelligence approaches in studying AD at the molecular level.

RSPO/LGR signaling mediates astrocyte-induced proliferation of adult hippocampal neural stem cells
In the dentate gyrus of the adult hippocampus, neurogenesis from neural stem cells (NSCs) is regulated by Wnt signals from the local microenvironment. The Wnt/{beta}-catenin pathway is active in NSCs, where it regulates proliferation and fate commitment, and subsequently its activity is strongly attenuated. The mechanisms controlling this pattern of activity are poorly understood. In stem cells from adult peripheral tissues, secreted R-spondin proteins (RSPO1-4) interact with LGR4-6 receptors and control Wnt signaling strength. Here, we found that RSPO1-3 and LGR4-6 are expressed in the adult dentate gyrus and in cultured NSCs isolated from the adult mouse hippocampus. The expression of LGR4-5 decreased in NSCs upon differentiation, concomitantly with the reported decrease in Wnt activity. Treatment with RSPO1-3 increased hippocampal NSCs proliferation and the expression of the Wnt target gene Cyclin D1. Moreover, RSPO1-3 were expressed by primary cultures of dentate gyrus astrocytes, a crucial component of the neurogenic niche able to induce NSC proliferation and neurogenesis. In co-culture experiments, astrocyte-induced proliferation of NSCs was prevented by RSPO2 knockdown in astrocytes, and by LGR5 knockdown in hippocampal NSCs. Altogether, our results indicate that RSPO/LGR signaling is present in the dentate niche, where it could control Wnt activity and proliferation of NSCs.

Emotion Dynamics in Reciprocity: Deciphering the Role of Prosocial Emotions in Social Decision-making
To date, the relevance of prosocial emotions in social decisions based on reciprocity remains poorly understood. Expected and experienced emotions in interoceptive-social dimension, expected offers, and actual acceptance were measured in 476 participants during an ultimatum game consisting of fair, moderate, and unfair offers. We investigated whether participants adjust social decisions according to prediction errors on prosocial emotions and reciprocity. Participants' acceptance trajectories were explained by prediction errors in dominance, valence, and reward. Participants were categorized into 4 distinct subgroups based on their patterns of reward expectation, acceptance, and emotional experiences before and after the offer. Furthermore, the relationships between prosocial emotions, social decisions, and reciprocity varied across these subgroups. This study's measurement and analysis of multidimensional trajectories across four affect dimensions reveal that social decisions are influenced by the responder's perception of partner's reciprocity, as well as by the subsequent prediction error of basic and prosocial emotion.

Evaluating the validity of the eye movement event detection model of Ganzin Sol glasses
Eye tracking requires precise measurement of gaze data. Identifying fixations and saccades reliably is crucial for eye trackers, given these are fundamental eye movements. The present study evaluated the performance of Ganzin Sol glasses, a wearable eye tracker developed by Ganzin Technology, in detecting eye movement events. Participants performed the fixation and saccade invocation task (Komogortsev et al., 2010) and the gap paradigm (Saslow, 1967) using both Ganzin Sol and Tobii Pro 2 glasses separately at both short (50 cm) and long (300 cm) viewing distance. The fixation and saccade invocation task involved maintaining fixation on a regularly shifting visual target, enabling quantitative and qualitative analysis of participants' oculomotor behaviors. In the gap paradigm, participants executed saccades toward a peripheral target when the fixation disappeared (gap condition) or remained visible (overlap condition). Typically, saccade latency in the gap condition is shorter (i.e., the gap effect). Results revealed aligned performances with Ganzin Sol and Tobii Pro 2 glasses in the fixation and saccade invocation task and the observation of the gap effect with both eye trackers. Therefore, the validity of Ganzin Sol glasses was at least comparable to Tobii Pro 2 glasses in the present study.

The impact of speaker accent on discourse processing: a frequency investigation
Previous studies show that there are differences in native and foreign speech processing (Lev-Ari, 2018) while mixed evidence has been found regarding differences between dialectal and foreign accent processing (see: Adank et al., 2009; Floccia et al. 2006 but see also: Floccia et al., 2009; Girard et al., 2008). Within this field, two theories have been proposed. The Perceptual Distance Hypothesis states that the mechanisms underlying dialectal accent processing are attenuated versions of those of foreign (Clarke & Garrett, 2004). While, the Different Processes Hypothesis argues that the mechanisms of foreign and dialectal accent processing are qualitatively different (Floccia et al, 2009). A recent study looking at single-word EEG data, suggested that there may be flexibility in processing mechanisms (Thomas et al., 2022). The present study deepens this investigation by addressing in which frequency bands native, dialectal and foreign accent processing differ when listening to extended speech. Electroencephalographic data was recorded from 30 participants who listened to dialogues of approximately six minutes spoken in native, dialectal and foreign accents. Power spectral density estimation (1-35 hz) was performed. Linear mixed models were done in frequency windows of particular relevance to discourse processing. Frequency bands associated with phoneme [gamma], syllable [theta], and prosody [delta] were considered along with those of general cognitive mechanisms [alpha and beta]. Results show power differences in the Gamma frequency range. While in higher frequency ranges foreign accent processing is differentiated from power amplitudes of native and dialectal accent processing, in low frequencies we do not see any accent-related power amplitude modulations. This suggests that there may be a difference in phoneme processing for native accent types and foreign accent, while we speculate that top-down mechanisms during discourse processing may mitigate the effects observed with short units of speech.

Regional response to light illuminance across the human hypothalamus
Light exerts multiple non-image-forming biological effects on physiology including the stimulation of alertness and cognition. However, the subcortical circuitry underlying the stimulating impact of light is not established in humans. We used 7 Tesla functional magnetic resonance imaging to assess the impact of variations in light illuminance on the regional activity of the hypothalamus while healthy young adults (N=26; 16 women; 24.3 +- 2.9y) were completing two auditory cognitive tasks. We find that, during both the executive and emotional tasks, higher illuminance triggered an activity increase over the posterior part of the hypothalamus, which includes part of the tuberomamillary nucleus and the posterior part of the lateral hypothalamus. In contrast, increasing illuminance evoked a decrease in activity over the anterior and ventral parts of the hypothalamus, encompassing notably the suprachiasmatic nucleus and another part of the tuberomammillary nucleus. Critically, performance of the executive task was improved under higher illuminance and was negatively correlated with the activity of the posterior hypothalamus area. These findings reveal the distinct local dynamics of different hypothalamus regions that underlie the impact of light on cognition. They may suggest that light acts on the orexin and histamine system to affect the quality of wakefulness.

Vagal interoception of microbial metabolites from the small intestinal lumen
The vagus nerve is proposed to enable communication between the gut microbiome and brain, but activity-based evidence is lacking. Herein, we assess the extent of gut microbial influences on afferent vagal activity and metabolite signaling mechanisms involved. We find that mice reared without microbiota (germ-free, GF) exhibit decreased vagal afferent tone relative to conventionally colonized mice (specific pathogen-free, SPF), which is reversed by colonization with SPF microbiota. Perfusing non-absorbable antibiotics (ABX) into the small intestine of SPF mice, but not GF mice, acutely decreases vagal activity, which is restored upon re-perfusion with bulk lumenal contents or sterile filtrates from the small intestine and cecum of SPF, but not GF, mice. Of several candidates identified by metabolomic profiling, microbiome-dependent short-chain fatty acids, bile acids, and 3-indoxyl sulfate stimulate vagal activity with varied response kinetics, which is blocked by co-perfusion of pharmacological antagonists of FFAR2, TGR5, and TRPA1, respectively, into the small intestine. At the single-unit level, serial perfusion of each metabolite class elicits more singly responsive neurons than dually responsive neurons, suggesting distinct neuronal detection of different microbiome- and macronutrient- dependent metabolites. Finally, microbial metabolite-induced increases in vagal activity correspond with activation of neurons in the nucleus of the solitary tract, which is also blocked by co-administration of their respective receptor antagonists. Results from this study reveal that the gut microbiome regulates select metabolites in the intestinal lumen that differentially activate chemosensory vagal afferent neurons, thereby enabling microbial modulation of interoceptive signals for gut-brain communication.