bioRxiv Subject Collection: Neuroscience's Journal

Macrovascular blood flow and microvascular cerebrovascular reactivity are regionally coupled in adolescence
Cerebrovascular imaging assessments are particularly challenging in adolescent cohorts, where not all modalities are appropriate, and rapid brain maturation alters hemodynamics at both macro- and microvascular scales. In a preliminary sample of healthy adolescents (n=12, 8-25 years), we investigated relationships between 4D flow MRI-derived blood velocity and blood flow in bilateral anterior, middle, and posterior cerebral arteries and BOLD cerebrovascular reactivity in associated vascular territories. As hypothesized, higher velocities in large arteries are associated with an earlier response to a vasodilatory stimulus (cerebrovascular reactivity delay) in the downstream territory. Higher blood flow through these arteries is associated with a larger BOLD response to a vasodilatory stimulus (cerebrovascular reactivity amplitude) in the associated territory. These trends are consistent in a case study of adult moyamoya disease. In our small adolescent cohort, macrovascular-microvascular relationships for velocity/delay and flow/CVR change with age, though underlying mechanisms are unclear. Our work emphasizes the need to better characterize this key stage of human brain development, when cerebrovascular hemodynamics are changing, and standard imaging methods offer limited insight into these processes. We provide important normative data for future comparisons in pathology, where combining macro- and microvascular assessments may better help us prevent, stratify, and treat cerebrovascular disease.

pNet: A toolbox for personalized functional networks modeling
Personalized functional networks (FNs) derived from functional magnetic resonance imaging (fMRI) data are useful for characterizing individual variations in the brain functional topography associated with the brain development, aging, and disorders. To facilitate applications of the personalized FNs with enhanced reliability and reproducibility, we develop an open-source toolbox that is user-friendly, extendable, and includes rigorous quality control (QC), featuring multiple user interfaces (graphics, command line, and a step-by-step guideline) and job-scheduling for high performance computing (HPC) clusters. Particularly, the toolbox, named personalized functional network modeling (pNet), takes fMRI inputs in either volumetric or surface type, ensuring compatibility with multiple fMRI data formats, and computes personalized FNs using two distinct modeling methods: one method optimizes the functional coherence of FNs, while the other enhances their independence. Additionally, the toolbox provides HTML-based reports for QC and visualization of personalized FNs. The toolbox is developed in both MATLAB and Python platforms with a modular design to facilitate extension and modification by users familiar with either programming language. We have evaluated the toolbox on two fMRI datasets and demonstrated its effectiveness and user-friendliness with interactive and scripting examples. pNet is publicly available at https://github.com/MLDataAnalytics/pNet.

Control of OPC proliferation and repopulation by the intellectual disability gene PAK1 under homeostatic and demyelinating conditions
Appropriate proliferation and repopulation of oligodendrocyte progenitor cells (OPCs) determine successful (re)myelination in homeostatic and demyelinating brains. Activating mutations in p21-activated kinase 1 (PAK1) cause intellectual disability, neurodevelopmental abnormality, and white matter anomaly in children. It remains unclear if and how PAK1 regulates oligodendroglial development. Here, we report that PAK1 controls proliferation and regeneration of OPCs. Unlike differentiating oligodendrocytes, OPCs display high PAK activity which maintains them in a proliferative state by modulating PDGFRa-mediated mitogenic signaling. PAK1-deficient or kinase-inhibited OPCs reduce their proliferation capacity and population expansion. Mice carrying OPC-specific PAK1 deletion or kinase inhibition are populated with fewer OPCs in the homeostatic and demyelinated CNS than control mice. Together, our findings suggest that kinase-activating PAK1 mutations stall OPCs in a progenitor state, impacting timely oligodendroglial differentiation in the CNS of affected children and that PAK1 is a potential molecular target for replenishing OPCs in demyelinating lesions.

Developmental origins of Parkinson's disease risk: perinatal exposure to the organochlorine pesticide dieldrin leads to sex-specific DNA modifications in critical neurodevelopmental pathways in the mouse midbrain
Epidemiological studies show that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Animal studies support a link between developmental dieldrin exposure and increased neuronal susceptibility in the -synuclein preformed fibril (-syn PFF) and MPTP models in adult male C57BL/6 mice. In a previous study, we showed that developmental dieldrin exposure was associated with sex-specific changes in DNA modifications within genes related to dopaminergic neuron development and maintenance at 12 weeks of age. Here, we used capture hybridization-sequencing with custom baits to interrogate DNA modifications across the entire genetic loci of the previously identified genes at multiple time points - birth, 6 weeks, 12 weeks, and 36 weeks old. We identified largely sex-specific dieldrin-induced changes in DNA modifications at each time point that annotated to pathways important for neurodevelopment, potentially related to critical steps in early neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, synaptic plasticity, and glial-neuron interactions. Despite large numbers of age-specific DNA modifications, longitudinal analysis identified a small number of DMCs with dieldrin-induced deflection of epigenetic aging. The sex-specificity of these results adds to evidence that sex-specific responses to PD-related exposures may underly sex-specific differences in disease. Overall, these data support the idea that developmental dieldrin exposure leads to changes in epigenetic patterns that persist after the exposure period and disrupt critical neurodevelopmental pathways, thereby impacting risk of late life diseases, including PD.

Unveiling microstructural dynamics: Somatosensory-evoked response induces extensive diffusivity and kurtosis changes associated with neural activity in rodents
Diffusion MRI (dMRI) facilitates the exploration of microstructural features within the brain owing to its sensitivity to restrictions and hindrances in the form of cell membranes or subcellular structures. As such, alterations in cell morphology and water transport mechanisms linked to neuronal activity are inherently embedded in the dMRI signal. In this context, the goal of our study was to investigate changes in Mean Diffusivity (MD) and Mean Kurtosis (MK) across the rat brain upon unilateral forepaw electrical stimulation and compare them to BOLD-fMRI mapping of brain activity. The positive BOLD response in the contralateral primary somatosensory cortex, forelimb region (S1FL) was accompanied by a significant decrease in MD in the same region, described in the literature as the result of cellular swelling and increased tortuosity in the extracellular space. For the first time, we also report a paired decrease in MK during stimulation in S1FL, most likely indicative of increased membrane permeability, as suggested by the slight decrease in exchange time estimated from kurtosis time-dependence analyses. The primary motor (M1) and the secondary somatosensory (S2) cortices, part of the cortical somatosensory processing and integration pathways, also displayed a positive BOLD response during stimulation, albeit with a lower amplitude, while MD and MK had differentiated dynamics in these two areas. In M1, the trends of MD and MK mirrored those observed in S1FL, whereas in S2, the opposite pattern was identified, that is MD and MK increased. Subcortical regions implicated in somatosensory information processing and integration, such as the thalamus and hippocampus, also exhibited an increase in MD and MK as in S2, remarkably in the absence of a discernible BOLD response. In the striatum a marginal negative BOLD response coincided with an increase in MD and MK. These findings highlight the capacity of dMRI to offer complementary functional insights into excitatory and inhibitory neural activity, potentially below the BOLD detection threshold.

Delving into the claustrum: insights into memory formation, stabilization and updating in mice
The claustrum is a brain structure that remains shrouded in mystery due to the limited understanding of its cellular structure, neural pathways, functionality and physiological aspects. Significant research has unveiled connections spanning from the claustrum to the entire cortex as well as subcortical areas. This widespread connectivity has led to speculations of its role in integrating information from different brain regions, possibly contributing to processes such as attention, consciousness, learning and memory. Our working hypothesis posits that claustrum neural activity contributes to the formation, stabilization and updating of long-term memories in mice. We found evidence in CF-1 mice of a decline in behavioral performance in an inhibitory avoidance task due to intra-claustral administration of 2% lidocaine immediately after a training session or memory recall. Nevertheless, this does not seem to be the case for the acquisition or retrieval of this type of memory, although its neural activity is significantly increased after training, evaluated through c-Fos expression. Moreover, inhibition of the claustrum's synaptic activity appears to impair stabilization but not the acquisition or retrieval of an unconditioned memory formed in a nose-poke habituation task.

Variation in the Distribution of Large-scale Spatiotemporal Patterns of Activity Across Brain States
A few large-scale spatiotemporal patterns of brain activity (quasiperiodic patterns or QPPs) account for most of the spatial structure observed in resting state functional magnetic resonance imaging (rs-fMRI). The QPPs capture well-known features such as the evolution of the global signal and the alternating dominance of the default mode and task positive networks. These widespread patterns of activity have plausible ties to neuromodulatory input that mediates changes in nonlocalized processes, including arousal and attention. To determine whether QPPs exhibit variations across brain conditions, the relative magnitude and distribution of the three strongest QPPs were examined in two scenarios. First, in data from the Human Connectome Project, the relative incidence and magnitude of the QPPs was examined over the course of the scan, under the hypothesis that increasing drowsiness would shift the expression of the QPPs over time. Second, using rs-fMRI in rats obtained with a novel approach that minimizes noise, the relative incidence and magnitude of the QPPs was examined under three different anesthetic conditions expected to create distinct types of brain activity. The results indicate that both the distribution of QPPs and their magnitude changes with brain state, evidence of the sensitivity of these large-scale patterns to widespread changes linked to alterations in brain conditions.

The muscarinic acetylcholine receptor in dermal papilla cells regulates hair growth
The role of cholinergic system in hair biology is poorly understood. In M4 muscarinic receptor (mAChR) knockout mice, the hair follicles have a prolonged telogen phase and failed to produce hair shafts. Here, we reported that hair growth was regulated by cholinergic system via mAChRs. Dermal papilla cells expressed different cholinergic biomarkers. Inhibiting AChE or stimulating mAChR in dermal papilla cells, culture vibrissae and skin epidermis promoted the hair growth. In cultured papilla cells treated with bethanechol, an agonist of mAChR, an activation of Wnt/{beta}-catenin signalling was illustrated by various indicative biomarkers, including phosphorylation of GSK-3{beta} and mRNA expression of various molecules for Wnt/{beta}-catenin signalling. Activation of Wnt/{beta}-catenin signalling was mediated by PI3K/AKT and ERK signalling upon the stimulation of bethanechol. In addition, an increase in hair shaft elongation was observed in mouse vibrissae upon the treatment of bethanechol, suggesting the cholinergic role in hair growth.

Mimicking opioid analgesia in cortical pain circuits
The anterior cingulate cortex plays a pivotal role in the cognitive and affective aspects of pain perception. Both endogenous and exogenous opioid signaling within the cingulate mitigate cortical nociception, reducing pain unpleasantness. However, the specific functional and molecular identities of cells mediating opioid analgesia in the cingulate remain elusive. Given the complexity of pain as a sensory and emotional experience, and the richness of ethological pain-related behaviors, we developed a standardized, deep-learning platform for deconstructing the behavior dynamics associated with the affective component of pain in mice, LUPE (Light aUtomated Pain Evaluator). LUPE removes human bias in behavior quantification and accelerated analysis from weeks to hours, which we leveraged to discover that morphine altered attentional and motivational pain behaviors akin to affective analgesia in humans. Through activity-dependent genetics and single-nuclei RNA sequencing, we identified specific ensembles of nociceptive cingulate neuron-types ex-pressing mu-opioid receptors. Tuning receptor expression in these cells bidirectionally modulated morphine analgesia. Moreover, we employed a synthetic opioid receptor promoter-driven approach for cell-type specific optical and chemical genetic viral therapies to mimic morphine's pain-relieving effects in the cingulate, without reinforcement. This approach offers a novel strategy for precision pain management by targeting a key nociceptive cortical circuit with on-demand, non-addictive, and effective analgesia.

Brain-wide arousal signals are segregated from movement planning in the superior colliculus
The superior colliculus (SC) is traditionally considered a brain region that functions as an interface between processing visual inputs and generating eye movement outputs. Although its role as a primary reflex center is thought to be conserved across vertebrate species, evidence suggests that the SC has evolved to support higher-order cognitive functions including spatial attention. When it comes to oculomotor areas such as the SC, it is critical that high precision fixation and eye movements are maintained even in the presence of signals related to ongoing changes in cognition and brain state, both of which have the potential to interfere with eye position encoding and movement generation. In this study, we recorded spiking responses of neuronal populations in the SC while monkeys performed a memory-guided saccade task and found that the activity of some of the neurons fluctuated over tens of minutes. By leveraging the statistical power afforded by high-dimensional neuronal recordings, we were able to identify a low-dimensional pattern of activity that was correlated with the subjects' arousal levels. Importantly, we found that the spiking responses of deep-layer SC neurons were less correlated with this brain-wide arousal signal, and that neural activity associated with changes in pupil size and saccade tuning did not overlap in population activity space with movement initiation signals. Taken together, these findings provide a framework for understanding how signals related to cognition and arousal can be embedded in the population activity of oculomotor structures without compromising the fidelity of the motor output.

Spinal cord perfusion impairments in the M83 mouse model of Parkinson's disease
Metabolism and bioenergetics in the central nervous system play important roles in the pathophysiology of Parkinson's disease (PD). Here, we employed a multimodal imaging approach to assess oxygenation changes in the spinal cord of a transgenic M83 murine model of PD in comparison to non-transgenic littermates at 9-12 months-of-age. A lower oxygen saturation (SO2)SVOT was detected in vivo with spiral volumetric optoacoustic tomography (SVOT) in the spinal cord of M83 mice compared to non-transgenic littermate mice. Ex-vivo high-field T1-weighted magnetic resonance imaging (MRI) and immunostaining for alpha-synuclein (phospho-S129) and vascular organisation (CD31 and GLUT1) were used to investigate the nature of the abnormalities detected via in vivo imaging. Ex-vivo analysis showed that the vascular network in the spinal cord was not impaired in the spinal cord of M83 mice. Ex-vivo MRI assisted with deep learning-based automatic segmentation showed no volumetric atrophy in the spinal cord of M83 mice compared to non-transgenic littermates, whereas nuclear alpha-synuclein phosphorylated at Ser129 site could be linked to early pathology and metabolic dysfunction. The proposed and validated non-invasive high-resolution imaging tool to study oxygen saturation in the spinal cord of PD mice holds promise for assessing early changes preceding motor deficits in PD mice.

Translational modelling of low and medium intensity transcranial magnetic stimulation from rodents to humans
Background: Rodent models using subthreshold intensities of transcranial magnetic stimulation (TMS) have provided insight into the biological mechanisms of TMS but often differ from human studies in the intensity of the electric field (E-field) induced in the brain. Objective: To develop a finite element method model as a guide for translation between low and medium intensity TMS rodent studies and high intensity TMS studies in humans. Methods: FEM models using three head models (mouse, rat, and human), and eight TMS coils were developed to simulate the magnetic flux density (B-field) and E-field values induced by three intensities. Results: In the mouse brain, maximum B-fields ranged from 0.00675 T to 0.936 T and maximum E-field of 0.231 V/m to 60.40 V/m E-field. In the rat brains maximum B-fields ranged from of 0.00696 T to 0.567 T and maximum E-fields of 0.144 V/m to 97.2 V/m. In the human brain, the S90 Standard coil could be used to induce a maximum B-field of 0.643 T and E-field of 241 V/m, while the MC-B70 coil induced 0.564 T B-field and 220 V/m E-field. Conclusions: We have developed a novel FEM modelling tool that can help guide the replication of rodent studies using low intensity E-fields to human studies using commercial TMS coils. Modelling limitations include lack of data on dielectric values and CSF volumes for rodents and simplification of tissue geometry impacting E-field distribution, methods for mitigating these issues are discussed. A range of additional cross-species factors affecting the translation of E-fields were identified that will aid TMS E-field modelling in both humans and rodents. We present data that describes to what extent translation of brain region-specific E-field values from rodents to humans is possible and detail requirements for future improvement. A graphical abstract of the translational modelling pipeline from this study is provided below (Figure A.1).

Information on Oral Temperature is More Robustly Encoded Than Taste in Neurons of the Mouse Gustatory Cortex
The gustatory cortex (GC) has traditionally been studied for its role in processing taste stimuli at a fixed temperature. The GC neurons respond to compounds representing different taste qualities and their hedonic value with time-varying and lick-related patterns of activity. However, a growing body of experimental work indicates that GC neurons can also respond to non-gustatory components of oral stimuli, including temperature, a prominent feature of the sensory properties of food and beverages. In this study, our objective is to evaluate the neural saliency of GC neurons in encoding chemosensory taste information at room temperature compared to their responsiveness to oral thermal information, specifically deionized water in the absence of classical taste qualities. To address this question, we recorded spiking activity from over 900 single GC neurons in mice allowed to freely lick to receive four liquid gustatory stimuli at room temperature or deionized water at different non-nociceptive temperatures. We then used a Bayesian analysis approach to determine classification scores for spike trains, considering both the rate and phase codes in response to the different stimuli. Our findings suggest that a classification approach that relies primarily on rate information, with a secondary contribution from phase, is optimal to distinguish between gustatory stimuli or water temperature. Surprisingly, we also observed that the number of GC neurons correctly classifying the stimulus is larger for thermal stimuli than for chemosensory stimuli, indicating that fluid temperature is more strongly encoded and thus more neurally salient than taste information.

Drosophila Glue Expulsion and Spreading Behavior is Modulated by Neuropeptidergic Mip-SPR Signaling from a Descending Command Neuron
At the end of their growth phase, Drosophila larvae remodel their bodies, firmly glue themselves to a substrate, and harden their cuticle in preparation for metamorphosis. This process is termed pupariation and it is triggered by a surge in the steroid hormone ecdysone. Substrate attachment is achieved by a recently-described pupariation subprogram called glue expulsion and spreading behavior (GSB). An epidermis-to-CNS Dilp8-Lgr3 relaxin signaling event that occurs downstream of ecdysone after pupariation initiation is critical for unlocking progression of the pupariation program towards GSB, but the factors and circuits acting downstream of Lgr3 signaling remain unknown. Here, we screened for such factors using cell type-specific RNA interference (RNAi) and behavioral monitoring. We identify Myoinhibiting peptide (Mip) and its highly conserved neuronal receptor, Sex peptide receptor (SPR), as a critical neuropeptidergic signaling pathway required to trigger and modulate multiple action components of GSB. In addition, we find that Mip is specifically required in a pair of descending neurons, whose neurogenetic silencing completely abrogates GSB without overtly affecting other pupariation components. This strongly suggests that these descending Mip neurons are GSB command neurons. Dissection of the GSB action components via muscle calcium-level monitoring coupled with cell-type specific RNAi indicates that Mip acts on multiple SPR-positive neuronal populations, which collectively define and pattern the sequence and timing of GSB actions. Hence, we have identified a pair of descending command neurons that utilize both synaptic transmission and neuropeptidergic signaling to trigger and modulate a complex innate behavior in Drosophila. Our results advance our molecular and cellular understanding of pupariation control, reveal the complexity of glue expulsion and spreading behavior control, provide insight into conserved aspects of Mip-SPR signaling in animals, and contribute to the understanding of how multi-step innate behaviors are coordinated in time through command neurons and neuropeptidergic signaling.

A Computational Model of Deep Brain Stimulation for Parkinsons Disease Tremor
Parkinsons Disease (PD) is a progressive neurological disorder that is typically characterized by a range of motor dysfunctions and its impact extends beyond physical abnormalities into emotional well-being and cognitive symptoms. The loss of dopaminergic neurons in the Substantia nigra pars compacta (SNc) leads to an array of dysfunctions in the functioning of Basal Ganglia (BG) circuitry that manifests into PD. While active research is being carried out in finding the root cause of SNc cell deaths, various therapeutic techniques are prevalent to manage the symptoms of PD. The most common approach in managing the symptoms is replenishing the lost dopamine in the form of taking dopaminergic medications such as Levodopa amidst its long-term complications. Another commonly used intervention for PD is deep brain stimulation (DBS), which is a invasive technique where an electrode is surgically inserted into the skull and a high frequency current of appropriate characteristics is delivered to the brain region. DBS is most commonly used when levodopa medication efficacy reduces and also in combination with levodopa medication that will help reducing the required dosage of medication prolonging the therapeutic effect. DBS is also a go to option when motor complications such as dyskinesias emerge as a side effect of medication. Several studies have also reported that though DBS is found to be effective in suppressing severe motor symptoms such as tremor and rigidity, it has adverse effect on cognitive capabilities. Henceforth it is important to understand the exact mechanism of DBS in alleviating the motor symptoms. A computational model of DBS stimulation for motor symptoms will offer great insights in understanding the mechanisms underlying the DBS and in this line in our current study we model a cortico-basal ganglia circuitry of arm reaching where we simulate healthy controls (HC) and PD symptoms as well as the DBS effect on the PD tremor. With DBS current characteristics of 220 pA, 130 Hz and 100 microseconds pulse-width we were able to see maximum therapeutic effect using our model. This model can be extended to accommodate cognitive dynamics in future so as to study the impact of DBS on cognitive symptoms and optimizing the parameters to get optimal performance effect across modalities.

Insights into dynamic sound localisation: A direction-dependent comparison between human listeners and a Bayesian model.
Self-motion is an essential but often overlooked component of sound localisation. While the directional information of a source is implicitly contained in head-centred acoustic cues, that acoustic input needs to be continuously combined with sensorimotor information about the head orientation in order to decode these cues to a world-centred frame of reference. On top of that, the use of head movement significantly reduces ambiguities in the directional information provided by the incoming sound. In this work, we evaluate a Bayesian model that predicts dynamic sound localisation, by comparing its predictions to human performance measured in a behavioural sound-localisation experiment. Model parameters were set a-priori, based on results from various psychoacoustic and sensorimotor studies, i.e., without any post-hoc parameter fitting to behavioral results. In a spatial analysis, we evaluated the model's capability to predict spatial localisation responses. Further, we investigated specific effects of the stimulus duration, the spatial prior and sizes of various model uncertainties on the predictions. The spatial analysis revealed general agreement between the predictions and the actual behaviour. The altering of the model uncertainties and stimulus duration revealed a number of interesting effects providing new insights on modelling the human integration of acoustic and sensorimotor information in a localisation task.

Sequential predictive learning is a unifying theory for hippocampal representation and replay
The mammalian hippocampus contains a cognitive map that represents an animal's position in the environment and generates offline "replay" for the purposes of recall, planning, and forming long term memories. Recently, it's been found that artificial neural networks trained to predict sensory inputs develop spatially tuned cells, aligning with predictive theories of hippocampal function. However, whether predictive learning can also account for the ability to produce offline replay is unknown. Here, we find that spatially tuned cells, which robustly emerge from all forms of predictive learning, do not guarantee the presence of a cognitive map with the ability to generate replay. Offline simulations only emerged in networks that used recurrent connections and head-direction information to predict multi-step observation sequences, which promoted the formation of a continuous attractor reflecting the geometry of the environment. These offline trajectories were able to show wake-like statistics, autonomously replay recently experienced locations, and could be directed by a virtual head direction signal. Further, we found that networks trained to make cyclical predictions of future observation sequences were able to rapidly learn a cognitive map and produced sweeping representations of future positions reminiscent of hippocampal theta sweeps. These results demonstrate how hippocampal-like representation and replay can emerge in neural networks engaged in predictive learning, and suggest that hippocampal theta sequences reflect a circuit that implements a data-efficient algorithm for sequential predictive learning. Together, this framework provides a unifying theory for hippocampal functions and hippocampal-inspired approaches to artificial intelligence.

Laminar fMRI in the locked-in stage of amyotrophic lateral sclerosis shows preserved activity in layer Vb of primary motor cortex
Amyotrophic lateral sclerosis (ALS) affects the cerebral cortex layer-dependently, most notably by the foremost targeting of upper motor neurons (UMNs) sited in layer Vb. Previous studies have shown a retained ability of paralysed patients to activate residual cortical motor networks, even in late-stage ALS. However, it is currently unknown whether such activation reflects a retained capacity to process sensorimotor inputs or if it is a result of actual motor output. Given the distinct function of individual cortical layers, layer-specific functional measurements may provide insight to this question. In this study, using submillimetre resolution laminar fMRI, we assessed the layer-dependent activation associated with attempted (motor) and passive (somatosensory) movements in a locked-in stage ALS patient. We found robust activation in both superficial and deep layers of primary motor cortex. The peak activation in deep layers was localised to layer Vb. These findings demonstrate preserved activity in deep output layers of M1, possibly reflecting a retained ability to engage residual UMNs despite years of paralysis. Our study underscores the capacity of laminar fMRI to discern subtle cortical activity and elucidates a promising pathway for probing in vivo human ALS pathology with unprecedented resolution.

Investigating the Triple Code Model in Numerical Cognition Using Stereotactic Electroencephalography
The ability to conceptualize numerical quantities is an essential human trait. According to the Triple Code Model (TCM) in numerical cognition, distinct neural substrates encode the processing of visual, auditory, and nonsymbolic numerical representations. While our contemporary understanding of human number cognition has benefited greatly from advances in clinical imaging, limited studies have investigated the intracranial electrophysiological correlates of number processing. In this study, 13 subjects undergoing stereotactic electroencephalography for epilepsy participated in a number recognition task. Drawing upon postulates of the TCM, we presented subjects with numerical stimuli varying in representation type (symbolic vs. non-symbolic) and mode of stimuli delivery (visual vs. auditory). Time-frequency spectrograms were dimensionally reduced with principal component analysis and passed into a linear support vector machine classification algorithm to identify regions associated with number perception compared to inter-trial periods. Across representation formats, the highest classification accuracy was observed in the bilateral parietal lobes. Auditory (spoken and beeps) and visual (Arabic) number formats preferentially engaged the superior temporal cortices and the frontoparietal regions, respectively. The left parietal cortex was found to have the highest classification for number dots. Notably, the putamen exhibited robust classification accuracies in response to numerical stimuli. Analyses of spectral feature maps revealed that non-gamma frequency below 30 Hz held greater than chance classification value and could be potentially used to characterize format specific number representations. Taken together, our findings obtained from intracranial recordings provide further support and expand on the TCM model for numerical cognition.

Acute stress yields a sex-dependent facilitation of signaled active avoidance in rats
Post-traumatic stress disorder (PTSD) is a debilitating disorder characterized by excessive fear, hypervigilance, and avoidance of thoughts, situations or reminders of the trauma. Among these symptoms, relatively little is known about the etiology of pathological avoidance. Here we sought to determine whether acute stress influences avoidant behavior in adult male and female rats. We used a stress procedure (unsignaled footshock) that is known to induce long-term sensitization of fear and potentiate aversive learning. Rats were submitted to the stress procedure and, one week later, underwent two-way signaled active avoidance conditioning (SAA). In this task, rats learn to prevent an aversive outcome (shock) by performing a shuttling response when exposed to a warning signal (tone). We found that acute stress significantly enhanced SAA acquisition rate in females, but not males. Female rats exhibited significantly greater avoidance responding on the first day of training relative to controls, reaching similar levels of performance by the second day. Males that underwent the stress procedure showed similar rates of acquisition to controls but exhibited resistance to extinction. This was manifest as both elevated avoidance and intertrial responding across extinction days relative to non-stressed controls, an effect that was not observed in females. In a second experiment, acute stress sensitized footshock unconditioned responses in males, not females. However, males and females exhibited similar levels of stress-enhanced fear learning (SEFL), which was expressed as sensitized freezing to a shock-paired context. Together, these results reveal that acute stress facilitates SAA performance in both male and female rats, though the nature of this effect is different in the two sexes. We did not observe sex differences in SEFL, suggesting that the stress-induced sex difference in performance was selective for instrumental avoidance. Future work will elucidate the neurobiological mechanisms underlying the differential effect of stress on instrumental avoidance in male and female rats.

Lesions that Cause Psychosis Map to a Common Brain Circuit in the Hippocampus
Identifying the anatomy of circuits causal of psychosis could inform treatment targets for schizophrenia. We identified 155 published case reports of brain lesions that caused new-onset psychosis. We mapped connectivity of these lesions using a normative human fMRI connectome. Lesions causing psychosis mapped to a common brain circuit defined by functional connectivity to the posterior subiculum of the hippocampus. This circuit was consistent both across individual symptoms of psychosis (delusions, hallucinations, and thought disorders), and when excluding lesions that touched the hippocampus. In an independent observational study (n=181), lesions connected to this circuit were preferentially associated with psychotic symptoms. A location in the rostromedial prefrontal cortex with high connectivity to this psychosis circuit was identified as a potential target for transcranial magnetic stimulation. Based on these results, we conclude that lesions that cause psychosis have common functional connections to the posterior subiculum of the hippocampus.

Structure-Function Relationship in Electrical and Hemodynamic Brain Networks: Insights from EEG and fNIRS during Rest and Task States
Identifying relationships between structural and functional networks is crucial for understanding the large-scale organization of the human brain. The potential contribution of emerging techniques like functional near-infrared spectroscopy to investigate the structure-functional relationship has yet to be explored. In our study, we characterize global and local structure-function coupling using source-reconstructed Electroencephalography (EEG) and Functional near-infrared spectroscopy (fNIRS) signals in both resting state and motor imagery tasks, as this relationship during task periods remains underexplored. Employing the mathematical framework of graph signal processing, we investigate how this relationship varies across electrical and hemodynamic networks and different brain states. Results show that fNIRS structure-function coupling resembles slower-frequency EEG coupling at rest, with variations across brain states and oscillations. Locally, the relationship is heterogeneous, with greater coupling in the sensory cortex and increased decoupling in the association cortex, following the unimodal to transmodal gradient. Discrepancies between EEG and fNIRS are noted, particularly in the frontoparietal network. Cross-band representations of neural activity revealed lower correspondence between electrical and hemodynamic activity in the transmodal cortex, irrespective of brain state while showing specificity for the somatomotor network during a motor imagery task. Overall, these findings initiate a multimodal comprehension of structure-function relationship and brain organization when using affordable functional brain imaging.

Contribution of statistical learning to mitigating the curse of dimensionality in reinforcement learning
Natural environments are abundant with patterns and regularities. It has been demonstrated that learning these regularities, especially through statistical learning, can greatly influence perception, memory, and other cognitive functions. Using a novel experimental paradigm involving two orthogonal tasks, we investigated whether regularities in the environment can enhance reward learning. In one task, human participants predicted the next stimulus in a sequence by recognizing regularities in a feature. In a separate, multidimensional learning task, they learned the predictive value of a different set of stimuli, based on reward feedback received after choosing between pairs of stimuli. Using both model-free and model-based approaches, we found that participants used regularities about features from the sequence-prediction task to bias their behavior in the learning task, resulting in the values associated with the regular feature having a greater influence. Fitting of choice behavior revealed that these effects were more consistent with attentional modulations of learning, rather than decision making, due to regularity manipulation. Specifically, the learning rates for the feature with regularity were higher, especially when learning from the forgone option during unrewarded trials. This demonstrates that feature regularities can intensify the confirmation bias observed in reward learning. Our results suggest that by enhancing learning about certain features, detecting regularities in the environment can reduce dimensionality and thus mitigate the curse of dimensionality in reward learning. Such interactions between statistical and reward learning have important implications for learning in naturalistic settings.

Enhancement of spatial learning by 40 Hz visual stimulation requires parvalbumin interneuron-dependent hippocampal neurogenesis
Acute and short-term rhythmic 40 Hz light flicker stimulation has shown promising results in alleviating cognitive impairments in mouse models of Alzheimer's disease (AD), stroke, and autism spectrum disorders (ASD). Understanding the long-term impacts and underlying mechanisms is crucial to progress this approach for potential human therapeutic applications. Here, we show that prolonged exposure to 40 Hz light flicker (1 hour per day for 30 days) significantly improved spatial learning and neurogenesis in the dentate gyrus (DG) without harmful behavioral side effects. Mice with transgenic deletion of doublecortin-positive cells (DCXDTR) in the adult hippocampus failed to exhibit enhanced neurogenesis and spatial learning with 40 Hz stimulation. Inactivation or knockout of GABAergic parvalbumin (PV) interneurons reduced the effects of 40 Hz entrainment and neurogenesis enhancement. Mechanistically, the stimulation did not alter the regional microvessel blood flow but significantly raised PV excitability and GABA levels and enhanced inhibitory transmission in the DG. Blocking GABAA receptors reversed the improvements in spatial learning and neurogenesis. These data showed that long-term exposure to 40 Hz light flicker enhances spatial learning through PV-dependent adult neurogenesis, which requires elevated GABA as a critical neurochemical mechanism for sustaining adult neurogenesis.

Development of thalamocortical connectivity during the third trimester
Thalamocortical connections are crucial for relaying sensory information in the brain and facilitate essential functions including motor skills, emotion, and cognition. Emerging evidence suggests that thalamocortical connections are organised along spatial gradients that may reflect their sequential formation during early brain development. However, this has not been extensively characterised in humans. To examine early thalamocortical development, we analysed diffusion MRI data from 345 infants, scanned between 29-45 weeks gestational age. Using diffusion tractography, we mapped thalamocortical connectivity in each neonate and used Principal Component Analysis to extract shared spatial patterns of connectivity. We identified a primary axis of connectivity that varied along an anterior/medial to posterior/lateral gradient within the thalamus, with corresponding projections to cortical areas varying along a rostral-caudal direction. The primary patterns of thalamocortical connectivity were present at 30 weeks gestational age and gradually refined during gestation. This refinement was largely driven by the maturation of connections between the thalamus and cortical association areas. Differences in thalamocortical connectivity between preterm and term neonates were only weakly related to primary thalamocortical gradients, suggesting a relative preservation of these features following premature birth. Overall, our results indicate that the organisation of structural thalamocortical connections are highly conserved across individuals, develop early in gestation and gradually mature with age.

The chromatin remodeler CHD3 is highly expressed in mature neurons and regulates genes involved in synaptic development and function
Changes in the dynamics of chromatin state that control spatiotemporal gene expression patterns are crucial during brain development. CHD3 is a chromatin remodeler that is highly expressed during neurogenesis and that functions as a core member of the NuRD complex, a large multiprotein complex mediating chromatin state. Genetic disruptions in CHD3 have been implicated in a neurodevelopmental disorder characterized by intellectual disability, macrocephaly and severe speech deficits. To study the roles of CHD3 during early human brain development, we generated induced pluripotent stem cells with heterozygous and homozygous loss-of-function mutations, differentiated them into unguided neural organoids and cortical neurons, and analyzed these by immunohistochemistry, bulk RNA-, single-cell RNA-, and ChIP-sequencing. Loss of CHD3 expression had no detectable effects on early neuroepithelium formation and organoid growth, nor did it significantly affect cell type composition or neuronal differentiation speed. Instead, upon loss of CHD3, we observed dysregulation of genes related to axon guidance and synapse development across all datasets, identifying a novel role for the protein as a regulator that facilitates neurogenesis, in particular neuronal maturation. Our results based on genetically engineered knockout organoids pave the way for future studies modeling the neurobiological pathways affected in CHD3-related disorder.

A central role for Numb/Nbl in multiple Shh-mediated axon repulsion processes
Sonic hedgehog (Shh) is an axon guidance molecule that can act as either a chemorepellent or a chemoattractant, depending on the neuron type and their developmental stage. In the developing spinal cord, Shh initially attracts commissural axons to the floor plate and later induces their repulsion after they cross the midline. In the developing visual system, Shh repels ipsilateral retinal ganglion cell (iRGC) axons at the optic chiasm. Although Shh requires the endocytic adaptor Numb for attraction of commissural neurons, the molecular mechanisms underlying Shh's dual function in attraction and repulsion are still unclear. In this study, we investigate whether Numb also regulates repulsive axon guidance. We show that Numb is essential for two Shh-mediated repulsion processes: iRGC axon repulsion at the optic chiasm and antero-posterior commissural axon repulsion in the spinal cord. Therefore, Numb is required for Shh-mediated attraction and repulsion. These results position Numb as a central player in the non-canonical Shh signalling pathway mediating axon repulsion.

Paraventricular Thalamus Neuronal Ensembles Encode Early-life Adversity and Mediate the Consequent Sex-dependent Disruptions of Adult Reward Behaviors
Early-life adversity increases risk for mental illnesses including depression and substance use disorders, disorders characterized by dysregulated reward behaviors. However, the mechanisms by which transient ELA enduringly impacts reward circuitries are not well understood. In mice, ELA leads to anhedonia-like behaviors in males and augmented motivation for palatable food and sex-reward cues in females. Here, the use of genetic tagging demonstrates robust, preferential and sex-specific activation of the paraventricular nucleus of the thalamus (PVT) during ELA and a potentiated reactivation of these PVT neurons during a reward task in adult ELA mice. Chemogenetic manipulation of specific ensembles of PVT neurons engaged during ELA identifies a role for the posterior PVT in ELA-induced aberrantly augmented reward behaviors in females. In contrast, anterior PVT neurons activated during ELA were required for the anhedonia-like behaviors in males. Thus, the PVT encodes adverse experiences early-in life, prior to the emergence of the hippocampal memory system, and contributes critically to the lasting, sex-modulated impacts of ELA on reward behaviors.

Molecular and neural mechanisms of behavioural integration in the extended-amygdala
Integration of diverse stimuli is crucial for organisms to adapt and communicate effectively, enabling overall homeostasis and survival. Studies have been performed on identifying specific neuronal encoding of individual behaviours, but how neurons integrate diverse behaviours across contexts remains elusive. Here we use Ca2+ imaging in freely moving mice to identify neural ensembles in the extended amygdala encoding behaviours across six distinct contexts. We found extensive flexibility in these ensemble encodings that may act as reserves for behavioural integration, with those encoding aversive stimuli showing greater specificity. Finally, we identified differential gene expression profiles between ensembles that are enriched in associations with human psychiatric and neurodegenerative disorders. Overall, our results demonstrate the molecular mechanisms behind behavioural integration, and their potential implications in health and disease.

Partial FAM19A5 Deficiency in Mice Leads to Disrupted Spine Maturation, Hyperactivity and Altered Fear Response
The FAM19A5 polypeptide, encoded by the TAFA5 gene, is evolutionarily conserved among vertebral species. This protein is predominantly expressed in the brain, highlighting its crucial role in the central nervous system (CNS). Here, we investigated the potential roles of FAM19A5 in brain development and behavior using a FAM19A5-LacZ KI mouse model. This model exhibited a partial reduction in the FAM19A5 protein level. FAM19A5-LacZ KI mice displayed no significant alterations in gross brain structure but alterations in dendritic spine distribution, with a bias towards immature forms. These mice also showed lower body weights. Behavioral tests revealed that compared with their wild-type littermates, FAM19A5-LacZ KI mice displayed hyperactivity and a delayed innate fear response. These findings suggest that FAM19A5 plays a role in regulating spine formation and maintenance, thereby contributing to neural connectivity and behavior.

Cell-type-specific fluorescent tagging of endogenous target proteins reveals synaptic enrichment and dynamic regulations of dopamine receptors
Dopamine can play opposing physiological roles depending on the receptor subtype. In the fruit fly Drosophila melanogaster, Dop1R1 and Dop2R encode the D1- and D2-like receptors, respectively, and are reported to oppositely regulate intracellular cAMP levels. Here, we profiled the expression and subcellular localization of endogenous Dop1R1 and Dop2R in specific cell types in the mushroom body circuit. For cell-type-specific visualization of endogenous proteins, we employed reconstitution of split-GFP tagged to the receptor proteins. We detected dopamine receptors at both presynaptic and postsynaptic sites in multiple cell types. Quantitative analysis revealed enrichment around the active zones, particularly for Dop2R. The presynaptic localization of Dop1R1 and Dop2R in dopamine neurons suggests dual feedback regulation as autoreceptors. Furthermore, we discovered a starvation-dependent, bidirectional modulation of the presynaptic receptor expression in the PAM and PPL1 clusters, two distinct subsets of dopamine neurons, suggesting regulation of appetitive behaviors. Our results highlight the significance of the co-expression of the two antagonizing dopamine receptors in the spatial and conditional regulation of dopamine responses in neurons.

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome
Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in the WFS1 (and WFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-old Wfs1{triangleup}exon8 mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.

The causal role of early visual cortex in vividness of visual imagery
While numerous studies have demonstrated objective accuracy in visual imagery tasks to involve the early visual cortex (V1/V2), the role of this region in imagery vividness remains unclear. We addressed this question by combining Transcranial Magnetic Stimulation (TMS) with a cross-adaptation paradigm in which visual adaptation modulates the ability to engage in visual imagery in the adapted part of the visual field. As previously shown, in the control (Vertex) condition, mental imagery accuracy was impaired when the mental image was generated in the adapted region of visual space. This effect was removed by TMS, indicating that the locus of adaptation was the early visual cortex. In contrast, analysis of vividness ratings (collected on trial-by-trial basis) showed no effects of adaptation, indicating that the imagery vividness is somewhat orthogonal to the fidelity of the mental image. The key finding was that TMS impacted vividness ratings on trials when participants performed incorrectly in the imagery task. Thus, the effects of TMS on accuracy and vividness were observed on different trial types: TMS impaired accuracy of trials associated with high baseline performance, but increased vividness on incorrect trials. Overall, our findings suggest that the early visual cortex plays a role in both accuracy and vividness of mental images, yet these processes are dissociable.

Fungi activate Toll-1 dependent immune evasion to induce cell loss in the host brain
Fungi evolve within the host, ensuring their own nutrition and reproduction, at the expense of host health. They intervene in hosts brain function, to alter host behaviour and induce neurodegeneration. In humans, fungal infections are emerging as drivers of neuroinflammation, neurodegenerative diseases and psychiatric disorders. However, how fungi alter the host brain is unknown. Fungi trigger an innate immune response mediated by the Toll-1/TLR receptor, the adaptor MyD88 and the transcription factor Dif/NFkB, that induce the expression of antimicrobial peptides (AMPs). However, in the nervous system, Toll-1/TLR could also drive an alternative pathway involving the adaptor Sarm, which causes cell death instead. Sarm is the universal inhibitor of MyD88 and could drive immune evasion. The entomopathogenic fungus Beauveria bassiana is well-known to activate Toll-1 signalling in innate immunity in Drosophila. In fruit-flies, the adaptor Wek links Toll-1 to Sarm. Thus, here we asked whether B. bassiana could damage the Drosophila brain via Toll-1, Wek and Sarm. We show that exposure to B. bassiana reduced fly lifespan and impaired locomotion. B. bassiana entered the brain and induced the up-regulation of AMPs, as well as wek and sarm, within the brain. Exposure to B. bassiana caused neuronal and glial loss in the adult Drosophila brain. Importantly, RNAi knockdown of Toll-1, wek or sarm concomitantly with infection prevented B. bassiana induced cell loss. By contrast, over-expression of wek or sarm was sufficient to cause dopaminergic neuron loss in the absence of infection. These data show that B. bassiana caused cell loss in the host brain via Toll-1/Wek/Sarm signalling driving immune evasion. We conclude that pathogens can benefit from an innate immunity receptor to damage the host brain. A similar activation of Sarm downstream of TLRs in response to fungal infections could underlie psychiatric and neurodegenerative diseases in humans.

Unifying community-wide whole-brain imaging datasets enables robust automated neuron identification and reveals determinants of neuron positioning in C. elegans
We develop a data harmonization approach for C. elegans volumetric microscopy data, still or video, consisting of a standardized format, data pre-processing techniques, and a set of human-in-the-loop machine learning based analysis software tools. We unify a diverse collection of 118 whole-brain neural activity imaging datasets from 5 labs, storing these and accompanying tools in an online repository called WormID (wormid.org). We use this repository to generate a statistical atlas that, for the first time, enables accurate automated cellular identification that generalizes across labs, approaching human performance in some cases. We mine this repository to identify factors that influence the developmental positioning of neurons. To facilitate communal use of this repository, we created open-source software, code, web-based tools, and tutorials to explore and curate datasets for contribution to the scientific community. This repository provides a growing resource for experimentalists, theorists, and toolmakers to investigate neuroanatomical organization and neural activity across diverse experimental paradigms, develop and benchmark algorithms for automated neuron detection, segmentation, cell identification, tracking, and activity extraction, and inform models of neurobiological development and function.

rsfMRI-based Brain Entropy is negatively correlated with Gray Matter Volume and Surface Area
In recent years, brain entropy (BEN) has been ossociated with a number of neurocognitive, biological, and sociodemographic variables. However, its link with brain morphology is still unknown. In this study, we use resting-state fMRI (rsfMRI) data to estimate BEN maps and investigate their associations with three metrics of brain morphology: gray matter volume (GMV), surface area (SA), and cortical thickness (CT). Separate analyses will be performed on BEN maps derived from four distinct rsfMRI runs, and using both a voxelwise and a regions of interest (ROIs) approach. Our findings consistently showed that lower BEN (i.e., higher temporal coherence of brain activity) was related to increased GMV and SA in the lateral frontal and temporal lobes, inferior parietal lobules, and precuneus. We hypothesize that lower BEN and higher SA might both reflect higher brain reserve as well as increased information processing capacity.

The gut-brain vagal axis scales hippocampal memory processes and plasticity
The vagus nerve serves as an interoceptive relay between the body and the brain. Despite its well-established role in feeding behaviors, energy metabolism, and cognitive functions, the intricate functional processes linking the vagus nerve to the hippocampus and its contribution to learning and memory dynamics remain still elusive. Here, we investigated whether and how the gut-brain vagal axis contributes to hippocampal learning and memory processes at behavioral, functional, cellular, and molecular levels. Our results indicate that the integrity of the vagal axis is essential for long-term recognition memories, while sparing other forms of memory. In addition, by combing multi-scale approaches, our findings show that the gut-brain vagal tone exerts a permissive role in scaling intracellular signaling events, gene expressions, hippocampal dendritic spines density as well as functional long-term plasticities (LTD and LTP). These results highlight the critical role of the gut-brain vagal axis in maintaining the spontaneous and homeostatic functions of hippocampal ensembles and in regulating their learning and memory functions. In conclusion, our study provides comprehensive insights into the multifaceted involvement of the gut-brain vagal axis in shaping time-dependent hippocampal learning and memory dynamics. Understanding the mechanisms underlying this interoceptive body-brain neuronal communication may pave the way for novel therapeutic approaches in conditions associated with cognitive decline, including neurodegenerative disorders.

Functional Localization of the Human Auditory and Visual Thalamus Using a Thalamic Localizer Functional Magnetic Resonance Imaging Task
Functional magnetic resonance imaging (fMRI) of the auditory and visual sensory systems of the human brain is an active area of investigation in the study of human health and disease. The medial geniculate nucleus (MGN) and lateral geniculate nucleus (LGN) are key thalamic nuclei involved in the processing and relay of auditory and visual information, respectively, and are the subject of blood-oxygen-level-dependent (BOLD) fMRI studies of neural activation and functional connectivity in human participants. However, localization of BOLD fMRI signal originating from neural activity in MGN and LGN remains a technical challenge, due in part to the poor definition of boundaries of these thalamic nuclei in standard T1-weighted and T2-weighted magnetic resonance imaging sequences. Here, we report the development and evaluation of an auditory and visual sensory thalamic localizer (TL) fMRI task that produces participant-specific functionally-defined regions of interest (fROIs) of both MGN and LGN, using 3 Tesla multiband fMRI and a clustered-sparse temporal acquisition sequence, in less than 16 minutes of scan time. We demonstrate the use of MGN and LGN fROIs obtained from the TL fMRI task in standard resting-state functional connectivity (RSFC) fMRI analyses in the same participants. In RSFC analyses, we validated the specificity of MGN and LGN fROIs for signals obtained from primary auditory and visual cortex, respectively, and benchmark their performance against alternative atlas- and segmentation-based localization methods. The TL fMRI task and analysis code (written in Presentation and MATLAB, respectively) have been made freely available to the wider research community.

A Causal Role of the Right Dorsolateral Prefrontal Cortex in Random Exploration
Our brain faces the dilemma of exploiting familiar options to gain immediate rewards or exploring new options to increase probable future rewards, in many real-life decisions, and solves it by direct and random exploration. Previous studies show that these two explorative strategies have dissociable neural correlates in the brain. Using the continuous theta burst stimulation (cTBS) and horizon task, we investigate the causal role of the right dorsolateral prefrontal cortex (rDLPFC) in direct and random exploration. Twenty-five healthy right handed adult participants underwent cTBS, and vertex stimulation sessions, and then completed the horizon tasks. Both model-free and model-based analysis showed that cTBS over rDLPFC selectively reduced random exploration, but not direct exploration. This suggests a causal role for rDLPFC especially in random exploration, and further supports dissociable neural implementations for direct and random exploration.

Effect of seizures on the severity of myelin vacuolization in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
ObjectiveMegalencephalic leukoencephalopathy with subcortical cysts (MLC) is a white matter disease characterized by myelin vacuolization and swollen perivascular astrocyte processes. Neuronal activity has been implicated as primary cause of myelin vacuolization and astrocyte swelling. Since acute and excessive increases in neuronal activity occur in MLC during seizures, we investigated whether seizure activity leads to the acute development of myelin vacuoles and swollen astrocyte processes.

MethodsGlialcam-null mice (an established MLC mouse model) and wild-type mice received repeated i.p. low dose (5 mg / kg) kainic acid (KA) injections until severe seizures developed. Following a 60-minute period of severe seizure activity, mice were terminated and brains were fixed and processed. Brain tissue was analyzed for myelin vacuolization and astrocyte process thickness using H&E and GFAP stains, respectively.

ResultsRepeated low-dose injections of KA resulted in prolonged severe seizure activity in mice of both genotypes. Total amount of seizure activity was comparable between Glialcam-null and wild-type mice. KA-induced severe seizure activity did not significantly increase myelin vacuolization in either Glialcam-null or wild-type mice. The width of perivascular astrocyte processes was also not affected by severe seizure activity.

InterpretationWe show that (i) repeatedly injecting a low dose of KA provides the opportunity to regulate seizure development and generate severe seizures in both wild-type and seizure-sensitive Glialcam-null mice, and that (ii) the two major pathological features of MLC, myelin vacuolization and swollen astrocyte endfeet, are not acutely aggravated in response to KA-induced severe seizure activity.

Disorganized Inhibitory Dynamics and Functional Connectivity in Hippocampal area CA1 of 22q11.2 Deletion Mutant Mice
Individuals with the 22q11.2 deletion syndrome, one of the strongest genetic risk factors for schizophrenia, demonstrate cognitive impairments such as episodic memory dysfunction. Place cell dynamics in the hippocampus supporting episodic memory are also impaired in a mouse model for the 22q11.2 deletion (Df(16)A+/-). While hippocampal neural dynamics are under strong inhibitory control, there is no available information about functional alterations of molecularly identified inhibitory circuits in mouse models for the 22q11.2 deletion. Here, we examined interneuron subtype-specific activity dynamics in hippocampal area CA1 of Df(16)A+/- mice performing random foraging and goal-oriented reward learning tasks. We found that Df(16)A+/- inhibitory interneurons carry markedly reduced spatial information during random foraging. Mutant mice perseverate at rewarded locations during reward learning, and multiple interneuron types exhibit aberrant responses to reward locations. We observe task-dependent changes in relational activity among multiple GABAergic subtypes, suggesting a broadly disorganized microcircuit functional connectivity in mutant mice. Overall, we identify widespread and heterogeneous subtype-specific alterations in interneuron dynamics during learning, depicting an inflexible microcircuitry in CA1. Our study provides novel biological insights into how schizophrenia-risk mutations affect local-circuit interactions among diverse cell types in the mouse hippocampus during learning.

DNA damage and senescence in the aging and Alzheimer's disease cortex are not uniformly distributed
Alzheimer's disease (AD) is a neurodegenerative illness with a typical age of onset exceeding 65 years of age. The age-dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a diagnosis of AD. The focus on DNA damage was motivated by evidence that increasing levels of irreparable DNA damage are a major driver of the aging process. The connection between aging and the loss of genomic integrity is compelling because DNA damage has also been identified as a possible cause of cellular senescence. The number of senescent cells has been reported to increase with age, and their senescence-associated secreted products are likely contributing factors to age-related illnesses. We tracked DNA damage with 53BP1 and cellular senescence with p16 immunostaining of human post-mortem brain samples. We found that DNA damage is significantly increased in the BA9 region of the AD cortex when compared to the same region of unaffected controls (UC). In the AD but not UC cases, the density of cells with DNA damage increased with distance from the pia mater up to approximately layer V then decreased in deeper areas. This pattern of DNA damage was overlaid with the pattern of cellular senescence, which also increased with cortical depth. On a cell-by-cell basis, we found that the intensity of the two markers was tightly linked in the AD, but not the UC brain. To test whether DNA damage was a causal factor in the emergence of the senescence program, we used etoposide treatment to damage the DNA of cultured mouse primary neurons. While DNA damage increased after treatment, no change in the expression of senescence-associated markers was observed. Our work suggests that DNA damage and cellular senescence are increased in the AD brain, and increasingly coupled. We propose that in vivo the relationship between the two age-related processes is more complex than previously thought.