bioRxiv Subject Collection: Neuroscience's Journal

Longitudinal trajectories of aperiodic EEG activity in early to middle childhood
Background: Emerging evidence suggests that aperiodic EEG activity may follow a nonlinear growth trajectory in childhood. However, existing studies are limited by small assessment windows and cross-sectional samples that are unable to fully capture these patterns. The current study aimed to characterize the developmental trajectories of aperiodic activity longitudinally from infancy to middle childhood. We examined potential trajectory differences by sex and brain region. We further investigated whether different developmental trajectories resulted in differential associations between aperiodic activity and maternal anxiety symptoms. Methods: A community sample of children and their parents (N=391) enrolled in a longitudinal study of emotion processing were assessed at infancy, and at ages 3 years, 5 years, and 7 years. Analyses included individual growth curve and mixed effect models. Developmental trajectories of the aperiodic slope and offset were investigated across whole brain, frontal, central, temporal, and posterior regions. Associations of whole brain slope and offset with maternal anxiety symptoms were also examined. Results: Developmental trajectories for both slope and offset were generally characterized by a relative increase in early childhood and a subsequent decrease or stabilization by age 7, with variation by brain region. Females showed relatively steeper slopes at some ages, and males showed relatively greater offset at certain ages. Maternal anxiety was negatively associated with slope at 3 years and positively associated with slope at 7 years. Conclusions: The longitudinal developmental trajectory of aperiodic slope in early childhood is nonlinear and shows variation by sex and brain region. The magnitude and direction of associations with maternal anxiety varied by age, corresponding with changes in trajectories. Developmental stage should be considered when interpreting findings related to aperiodic activity in childhood.

Distinct roles of general anesthesia activated CeA neurons in acute versus late phase of neuropathic pain
A previous study discovered a distinct population of GABAergic neurons in the central amygdala (CeA) that can be activated by general anesthesia (CeA-GA) and exert analgesic functions (Hua et al., 2020). To independently reproduce these prior findings and to investigate the electrophysiological properties of CeA-GA neurons, we first used 1.2 percent isoflurane to induce c-Fos activation in the mouse brain and validated the Fos expression by RNAscope in situ hybridization. Indeed, isoflurane induced robust Fos expression in CeA and these Fos+ CeA-GA neurons are GABAergic neurons (Vgat+). We next used Fos-TRAP2 method (different from the CANE method used in the prior study) to label CeA-GA neurons (tdTomato+). Our ex vivo electrophysiological recordings in brain slices revealed that compared to Fos-negative CeA neurons, CeA-GA neurons had significantly higher excitability and exhibited distinct patterns of action potentials. Chemogenetic activation of Fos-TRAPed CeA-GA neurons was effective at increasing pain thresholds in naive mice and mice with early-phase neuropathic pain 2 weeks after spared nerve injury (SNI). However, the same chemogenetic activation of CeA-GA neurons only had modest analgesia in the late phase of SNI at 8 weeks, although it was highly effective in reducing chronic pain-associated anxiety behaviors at this stage. We found that Fos-negative CeA neurons, but not CeA-GA neurons, exhibited increased excitability in the late-phase of SNI, suggesting that chronic pain causes a shift in the relative activity of the CeA microcircuit. Interestingly, Fos-negative neurons exhibited much higher expression of K/Cl cotransporter-2 (KCC2), and KCC2 expression was downregulated in the CeA in the late-phase of neuropathic pain. These results support the idea that targeting CeA-GA neurons may provide therapeutic benefits for pain relief and chronic pain-associated anxiety. Our findings also suggest distinct roles of CeA-GA neurons in regulating physiological pain, acute pain, and chronic pain with a possible involvement of KCC2.

Anisotropy of object non-rigidity: High-level perceptual consequences of cortical anisotropy
This study investigates a compelling instance where variations in a complex, higher-level perceptual phenomenon. Specifically, the anisotropy in object non-rigidity are explained by the distribution of low-level neural properties in the primary visual cortex. Through a combination of mathematical derivations and computational simulations, we replicate psychophysical experiment results that explore the perception of non-rigidity in what should be rigidly rotating objects. Specifically, we examine the visual interpretation of two connected circular rings in rotation. When these rigidly connected rings rotate horizontally, observers predominantly perceive rigid rotation. However, when the image is rotated by 90 degrees, observers perceive only non-rigid wobbling. Additionally, vertically elongated rings appear narrower and longer compared to their horizontal counterparts. Our analysis first shows that these perceived shape changes can be decoded from V1 outputs by considering anisotropies in orientation-selective cells. We then empirically demonstrate that even when the vertically rotating ellipses are widened or the horizontally rotating ellipses are elongated to match shapes, the perceived difference in non-rigidity is reduced, but increased non-rigidity persists in vertical rotations, suggesting that the motion mechanism also plays role. By incorporating cortical anisotropies into motion flow computations, we found that the motion gradients for vertical rotations more closely align with physical wobbling, while horizontal rotations fall between wobbling and rigid rotation. This suggests that intrinsic cortical anisotropies contribute to the heightened perception of non-rigidity when orientation shifts from horizontal to vertical. The study underscores the importance of these cortical anisotropies in shaping perceptual outcomes and raises intriguing questions about their evolutionary significance, particularly regarding their impact on shape constancy and motion perception.

Pathogenic microbiota disrupts the intact structure of cerebral organoids by altering energy metabolism
This study investigated the impact of different bacterial populations on the biomolecular structures of cerebral organoids (COs) at various levels. COs were co-cultured with non- pathogenic (NM) and pathogenic (PM) bacterial populations. PM reduced the number of TUJ1+ neurons and disrupted the intact structure of COs. In addition, PM was found to induce changes in the transcript profile of COs, including a decrease in the activity of the glycolysis pathway and an increase in the pentose phosphate pathway, leading to deterioration in cellular energy metabolism, which is linked to neurodegenerative diseases. Proteomic analysis revealed a unique cluster of proteins in COs. PM exposure upregulated proteins related to neurological diseases, consistent with RNA-seq data. Communication between bacteria and neural cells was demonstrated using 18O-stable isotope labeling (SIL)-based metabolic flux analysis. COs showed higher 18O-enrichment of TCA cycle intermediates when co-cultured with NM and PM, indicating increased oxidative phosphorylation activity upon exposure to bacteria. This study provides a useful platform to monitor metabolic signals and communication between microbiotas and human brain cells. The findings suggest that pathogenic bacteria release metabolites that alter biomolecular structures in brain organoids, potentially contributing to neurodegenerative diseases.

Influence of the Glymphatic System on α-Synuclein Propagation: Role of Aquaporin-4 and the Dystrophin-Associated Protein Complex
Propagation and aggregation of prion proteins, such as tau and -synuclein (Syn), are key pathological features of neurodegenerative diseases. Extracellular clearance pathways, such as the glymphatic system, may play a crucial role in the removal of these toxic proteins from the brain. Primarily active during sleep, this system relies on aquaporin-4 (AQP4) water channel expression and polarisation to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated in Parkinsons disease, however the precise mechanisms underlying the pathogenic effect of this dysfunction remain unclear. This includes how impaired glymphatic function influences Syn propagation dynamics, and the role of propagating Syn itself on glymphatic function. In this study, we used a mouse model of Syn propagation to elucidate the impact of Syn aggregation on glymphatic function, by measuring CSF-ISF exchange and assessing AQP4 and associated endfoot complex proteins in the brain over time and across different regions. Our results show that direct injection of Syn pre-formed fibrils leads to reduced expression of the AQP4 endfoot complex, but propagation of endogenous Syn induces an enhancement of glymphatic function suggesting compensatory upregulation in response to increasing endogenous Syn burden. To determine the influence of glymphatic dysfunction on Syn propagation dynamics, we then employed a pharmacological approach to inhibit glymphatic function in this model. Acute glymphatic inhibition significantly reduced brain to CSF Syn clearance, and chronic treatment exacerbated Syn pathology, neurodegeneration, and motor behavioural deficits in mice. Together our findings show that Syn clearance and propagation are modulated by glymphatic function and suggest that AQP4 complex dysregulation may contribute to glymphatic impairment associated with Parkinsons diseases.

Validity of a New Stress Induction Protocol using Speech Improvisation (IMPRO)
This paper proposes a novel stress induction protocol utilizing speech improvisation -- Interactive Multitask Performance Response Observation (IMPRO) -- in front of an audience. This approach aims to induce stress through a combination of public speaking, cognitive effort, and challenge to maintain a spontaneous narrative. We investigate the validity of this novel approach by examining physiological responses of 35 healthy participants aged 18 to 38. Saliva cortisol was measured as the ground truth for mental stress assessment. In addition, electrodermal activity (EDA) was used as a non-invasive measure of sympathetic activation, offering real-time data with high resolution. Functional near-infrared spectroscopy (fNIRS) measurement was performed to assess the cortical hemodynamic responses induced by the IMPRO protocol. We focused on hemodynamics in the prefrontal cortex (PFC), a region associated with stress processing. We found that cortisol levels and EDA significantly increased in response to the stress task compared to the baseline. We also observed a significant change in PFC hemodynamic levels in a set of channels compared to the baseline, with a higher overall increase in the right frontopolar area compared to the left. In conclusion, our findings validated IMPRO as an effective and easy to perform method for mental stress induction.

Operant conditioning of cortical waves through a brain-machine interface
At the surface of the cerebral cortex, activity dynamics measured at a mesoscopic (about 0.1 to 1 mm in mouse cortex) scale are characterized by both spontaneous and behavior-related dynamical waves of synchronized neuronal activity. These waves are thought to participate in information propagation and processing, but remain poorly understood. To assess if such mesoscopic coordinated neuronal dynamics can be controlled in a goal-directed manner, we implemented a task in which mice are trained to generate waves with specific trajectories in order to obtain rewards. We tracked propagating waves at the surface of the somatosensory-motor cortex of head-fixed mice in real time by means of wide field calcium imaging, and conditioned the delivery of rewards to the detection of wave trajectories responding to specific spatiotemporal criteria. We found that the majority of the trained mice significantly increased their performance, mainly by increasing the frequency of rewardable waves. As the mice learned to achieve this task, we observed changes in the spatiotemporal patterns of the cortical waves. By revealing that, upon learning, neuronal activity can be shaped at the mesoscopic scale to generate specific waves patterns, our work opens up new perspectives for brain-machine interfacing.

Protective variant in PLCgamma2 mitigates Alzheimer's disease associated pathology via enhancing beneficial microglia functions
PLCgamma2-P522R (phospholipase C gamma 2, proline 522 to arginine) is a protective variant that reduces the risk for late onset Alzheimer's disease (LOAD). Recently, it was shown to decrease beta-amyloid pathology in 5XFAD mouse model of AD. In this study, our goal was to investigate the protective functions of PLCgamma2-P522R variant in less aggressive mouse model of AD as well as to assess underlying mechanisms at the molecular and cellular level using mouse and human microglia models. The effects of the protective PLCgamma2-P522R variant on microglia activation, AD-related beta-amyloid and neuronal pathologies, as well as behavioral changes were investigated in PLCgamma2-P522R knock-in mice crossbred with an APP/PS1 mouse model of AD. Transcriptomic, proteomic, and functional studies were carried out in cultured and acutely isolated adult PLCgamma2-P522R mouse microglia to study molecular mechanisms. Finally, microglia-like cell models generated from blood and skin biopsy samples of the PLCgamma2-P522R variant carriers were employed to translate the key findings in human cells. Our results demonstrate that the PLCgamma2-P522R variant reduces brain beta-amyloid plaque burden of APP/PS1 mice. Simultaneously, PLCgamma2-P522R variant increased non-proinflammatory microglia activation and microglia clustering around beta-amyloid plaques, leading to reduced beta-amyloid plaque-associated neuronal dystrophy. In cultured mouse primary microglia, PLCgamma2-P522R variant decreased accumulation of large lipid droplets, reduced cell stress, and increased acute response to strong inflammatory stimuli. Transcriptomic and proteomic analyses in acutely isolated adult mouse microglia as well as in human monocyte-derived microglial cells showed that PLCgamma2-P522R upregulates mitochondrial fatty acid oxidation and downregulates inflammatory/interferon signaling pathways. Accordingly, PLCgamma2-P522R increased mitochondrial respiration in iPSC -derived microglial cells. Together, these findings suggest that PLCgamma2-P522R variant exerts protection against AD-associated beta-amyloid and neuronal pathologies via enhancing microglial barrier formation around beta-amyloid plaques, but suppressing pro-inflammatory activation. Observed changes in fatty acid metabolism and mitochondrial flexibility as well as the downregulation of genes involved in inflammatory signaling pathways suggest that these protective effects of the PLCgamma2-P522R variant are mediated through an anti-ageing mechanism.

Adult oligodendrogenesis gates arcuate neuronal glucose sensing through remodelling of the blood-hypothalamus barrier via ADAMTS4
Brain glucose sensing is critical for survival during hypoglycaemia and tunes the level of defended blood glucose, which goes up in diabetes. Neuronal glucose sensing neurons and mechanisms have been identified, but how these neurons access blood concentrations of glucose to adjust their output and maintain glucose homeostasis is unclear. Here, we demonstrate that adult oligodendrogenesis in the median eminence (ME) is modulated by changes in circulating glucose levels and rapidly upregulated by hypoglycaemia. We show that genetic blockade of new OL production in adult mice impairs the regulation of glucose homeostasis, the integrity of the ME blood-hypothalamus barrier, and neuronal glucose sensing in the arcuate nucleus of the hypothalamus (ARH). Unexpectedly, functional integrity of adult-formed myelin is not required for the maintenance of glucose homeostasis. Instead, newly formed OLs exert their glucoregulatory actions via the synthesis of A disintegrin and metallopeptidase with thrombospondin motifs 4 (ADAMTS4), a metallopeptidase expressed exclusively by OLs and dependent on adult OL genesis to maintain its expression in the ME. Both lack of Adamts4 and ADAMTS4 gain-of-function are associated with impaired glucose homeostasis and remodelling of the blood-hypothalamus barrier, indicating that optimal ADAMTS4 expression is required for the integrity of vascular permeability and normal glycaemic control. Finally, we show that ME ADAMTS4 expression is regulated by changes in peripheral glycaemia and is dysregulated in diabetes, providing a mechanism by which ME OLs contribute to the regulation of glucose homeostasis.

Predicting Task Activation Maps from Resting-State Functional Connectivity using Deep Learning
Recent work has shown that deep learning is a powerful tool for predicting brain activation patterns evoked through various tasks using resting state features. We replicate and improve upon this recent work to introduce two models, BrainSERF and BrainSurfGCN, that perform at least as well as the state-of-the-art while greatly reducing memory and computational footprints. Our performance analysis observed that low predictability was associated with a possible lack of task engagement derived from behavioral performance. Furthermore, a deficiency in model performance was also observed for closely matched task contrasts, likely due to high individual variability confirmed by low test-retest reliability. Overall, we successfully replicate recently developed deep learning architecture and provide scalable models for further research.

Boosting forward connectivity between primary visual and body selective cortex reduces interference of task irrelevant dimensions on body judgements
We effortlessly categorise other people along socially relevant categories such as sex, age, and emotion. A core question in social vision relates to whether we perceive these categories independently or in relation to each other. Here, we investigated categorisation of sex and emotion from the body, finding that participants generally fail to fully ignore task-irrelevant variations of sex while judging body emotional expressions. In contrast, sex categorisation was unaffected by variations in emotional expression. We propose that this asymmetric interaction between sex and emotion may arise because of bottom-up visual processing, due to partially shared visual features used for both judgments, or because of top-down, categorical associations between sex and emotion categories. To disentangle these possibilities, we used cortico-cortical paired associative stimulation (ccPAS) to modulate the connectivity between primary visual cortex and the extrastriate body area. We posited that boosting forward connectivity between these regions would increase efficiency of feature-based processing, while boosting feedback connectivity would enhance the separability of semantic categories related to sex and emotion. We found that boosting forward connectivity eliminated the interference of the irrelevant variation of body sex on body emotion judgments, while the same interference remained unaffected with modulation of feedback connectivity. These findings suggest that interactions between sex and emotion in body perception emerge during the perceptual analysis of the stimuli, and add to our understanding of person perception and social categorization.

Pro-inflammatory mediators sensitise Transient Receptor Potential Melastatin 3 cation channel (TRPM3) signalling in mouse sensory neurons
Pro-inflammatory mediators can directly activate pain-sensing neurons, known as nociceptors. Additionally, these mediators can potentiate or sensitise ion channels and receptors expressed by these cells through transcriptional and post-translational modulation, leading to nociceptor hypersensitivity. A well-characterised group of ion channels that subserve nociceptor sensitisation is the transient receptor potential (TRP) superfamily of cation channels. For example, the roles of TRP channels vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in nociceptor sensitisation and inflammatory pain have been extensively documented. In the case of TRP melastatin 3 (TRPM3), however, despite the increasing recognition of this channel's role in inflammatory pain, the mechanisms driving its sensitisation during inflammation remain poorly understood. Here, we found that an inflammatory soup of bradykinin, interleukin 1{beta} (IL-1{beta}) and tumour necrosis factor (TNF) sensitised TRPM3 function in isolated mouse sensory neurons; IL-1{beta} and TNF, but not bradykinin, independently potentiated TRPM3 function. TRPM3 expression and translocation to the membrane remained unchanged upon individual or combined exposure to these inflammatory mediators, which suggests post-translational modification occurs. Finally, using the model of complete Freund's adjuvant-induced knee inflammation, we found that pharmacological blockade of TRPM3 does not alleviate inflammatory pain, which contrasts with previous reports using different pain models. We propose that the nuances of the immune response may determine the relative contribution of TRPM3 to nociceptive signalling in different neuro-immune contexts. Collectively, our findings improve insight into the role of TRPM3 sensitisation in inflammatory pain.

Operation of spinal sensorimotor circuits controlling phase durations during tied-belt and split-belt locomotion after a lateral thoracic hemisection
Locomotion is controlled by spinal circuits that interact with supraspinal drives and sensory feedback from the limbs. These sensorimotor interactions are disrupted following spinal cord injury. The thoracic lateral hemisection represents an experimental model of an incomplete spinal cord injury, where connections between the brain and spinal cord are abolished on one side of the cord. To investigate the effects of such an injury on the operation of the spinal locomotor network, we used our computational model of cat locomotion recently published in eLife (Rybak et al., 2024) to investigate and predict changes in cycle and phase durations following a thoracic lateral hemisection during treadmill locomotion in tied-belt (equal left-right speeds) and split-belt (unequal left-right speeds) conditions. In our simulations, the hemisection was always applied to the right side. Based on our model, we hypothesized that following hemisection, the contralesional (intact, left) side of the spinal network is mostly controlled by supraspinal drives, whereas the ipsilesional (hemisected, right) side is mostly controlled by somatosensory feedback. We then compared the simulated results with those obtained during experiments in adult cats before and after a mid-thoracic lateral hemisection on the right side in the same locomotor conditions. Our experimental results confirmed many effects of hemisection on cat locomotion predicted by our simulations. We show that having the ipsilesional hindlimb step on the slow belt, but not the fast belt, during split-belt locomotion substantially reduces the effects of lateral hemisection. The model provides explanations for changes in temporal characteristics of hindlimb locomotion following hemisection based on altered interactions between spinal circuits, supraspinal drives, and somatosensory feedback.

Vibrotactile auricular vagus nerve stimulation alters limbic system connectivity in humans: A pilot study
Vibration offers a potential alternative modality for transcutaneous auricular vagus nerve stimulation (taVNS). However, mechanisms of action are not well-defined. The goal of this study was to evaluate the potential of vibrotactile stimulation as a method for activating central brain regions akin to other vagal nerve stimulation methodologies. To do so, intracranial electrophysiological signals were recorded in human subjects to perform a parametric characterization of vibrotactile taVNS and investigate changes in coherence across key brain regions. We hypothesized that vibrotactile taVNS would increase coherence between limbic brain areas, similar to areas activated by classic electrical VNS approaches. Our specific regions of interest included the orbitofrontal cortex, anterior cingulate cortex, amygdala, hippocampus, and parahippocampal gyrus. Patients with intractable epilepsy undergoing stereotactic electroencephalography (sEEG) monitoring participated in the study. Vibrotactile taVNS was administered across five vibration frequencies following a randomized stimulation on/off pattern, and sEEG signals were recorded throughout. Spectral coherence in response to stimulation was defined across four canonical frequency bands, theta, alpha, beta, and broadband gamma. At the group level, vibrotactile taVNS resulted in significantly increased global low-frequency coherence. Anatomically, multiple limbic brain regions exhibited notably increased coherence during taVNS compared to baseline. The percentage of total electrode pairs demonstrating increased coherence was also quantified at the individual level. 20 Hz vibration resulted in the highest percentage of responder pairs across low-frequency coherence measures, but notable inter-subject variability was present. Overall, vibrotactile taVNS induced significant low-frequency coherence increases involving several limbic system structures. Further, parametric characterization revealed the presence of inter-subject variability in terms of identifying the optimal vibration frequency. These findings encourage continued research into vibrotactile stimulation as an alternative modality for noninvasive vagus nerve stimulation.

Meta-awareness, mind-wandering, and the control of 'default' external and internal orientations of attention
The "default mode" of cognition usually refers to an automatic tendency to simulate past, future, and hypothetical experiences, rather than attending to external events in the moment. "Mind-wandering" usually refers to moments when attention drifts from external tasks to become engaged in internal, default-mode cognition. Both definitions are perhaps limited: the mind can be caught by external objects when attending internally, and objects in the external world can be just as captivating as internal thought, causing attention to drift. To explore the relationship between prepotent internal and external default modes and the bi-directionality of mind-wandering, we measured brain activity in forty participants using fMRI during performance of a focused attention task. Naturalistic movie clips were presented four times in sequence. When subjects tried to focus attention on the videos, more mind-wandering events (distractions from the externally-focused task) occurred as the videos became less interesting with each repetition, and when less engaging videos were presented. When subjects focused internally on their own breath, more mind-wandering events (distractions from the internally-focused task) occurred when videos were most interesting (i.e. on the first repetition) and when more engaging videos were presented. In the whole-brain fMRI data and also in focused analyses of sensory areas and default mode areas, inter-subject correlation analysis revealed cortical signals of attention that corroborated the behavioral results. We suggest that whether the default state is internal or external, and whether the sources that disrupt it are internal or external, depend on context.

Purkinje cells in Crus I and II encode the visual stimulus and the impending choice as monkeys learn a reinforcement based visuomotor association task
Visuomotor association involves linking an arbitrary visual cue to a well-learned movement. Transient inactivation of Crus I/II impairs primates' ability to learn new associations and delays motor responses without affecting the kinematics of the movement. The simple spikes of Purkinje cells in the Crus regions signal cognitive errors as monkeys learn to associate specific fractal stimuli with movements of the left or right hand. Here we show that as learning progresses, the simple spike activity of individual neurons becomes more selective for stimulus-response associations, with selectivity developing closer to the appearance of visual stimuli. Initially, most neurons respond to both associations, irrespective of the identity of the stimulus and the associated movement, but as learning advances, more neurons distinguish between specific stimulus-hand associations. Using a linear decoder, it was found that in early learning stages, the visual stimulus can be decoded only when the choice can also be decoded. As learning improves, the visual stimulus is decoded earlier than the choice. A simple model can replicate the observed simple spike signals and the monkeys' behavior in both the early and late learning stages.

Deep learning for classifying neuronal morphologies: combining topological data analysis and graph neural networks
The shape of neuronal morphologies plays a critical role in determining their dynamical properties and the functionality of the brain. With an abundance of neuronal morphology reconstructions, a robust definition of cell types is important to understand their role in brain functionality. However, an objective morphology classification scheme is hard to establish due to disagreements on the definition of cell types, on which subjective views of field experts show significant differences. The robust grouping of neurons based on their morphological shapes is important for generative models and for establishing a link between anatomical properties and other modalities, such as biophysical and transcriptomic information. We combine deep learning techniques with a variety of mathematical descriptions of neurons and evaluate the classification accuracy of different methods. We demonstrate that various methodologies, including graph neural networks, topological morphology descriptors, and morphometrics, consistently perform with the highest accuracy for a variety of datasets. Based on these methods, we present a robust classification of both inhibitory and excitatory cell types in the rodent cortex and propose a generalized scheme for a consistent classification of neurons into classes.

Beyond EEG Onset Transients: Sensitisation and Habituation of Hyper-excitation to Constant Presentation and Offset ofPattern-Glare Stimuli
Pattern-glare, characterised by visual distortions, discomfort, and stress when viewing striped patterns, has been associated with cortical hyperexcitability, particularly in individuals with visually induced epilepsy, migraines, and visual stress. While previous studies have explored the onset transients of such stimuli, this research investigates the sensitisation and habituation effect to the constant presentation and offset of pattern-glare stimuli. We analysed the temporal characteristics of the Event Related Potentials (ERPs) in healthy participants to find correlates of cortical hyperexcitability over two time granularities: a fine granularity (over seconds) and a coarser granularity (across the time-course of the entire experiment). We looked for habituation and sensitization effects across these time periods. Our results suggest that brain responses to pattern-glare stimuli are correlated to participants' sensitivity to visual discomfort with statistically significant effects observed for this factor and for its interaction with changes over time. This study improves our understanding of how the brain adapts to persistent visual stimuli and provides insights that may inform treatments for conditions like migraine and epilepsy.

A systems model of alternating theta sweeps via firing rate adaptation
Place and grid cells provide a neural system for self-location and tend to fire in sequences within each cycle of the hippocampal theta rhythm when rodents run on a linear track. These sequences correspond to the decoded location of the animal sweeping forward from its current location ('theta sweeps'). However recent findings in open-field environments show alternating left-right theta sweeps, and propose a circuit for their generation. Here, we present a computational model of this circuit, comprising head direction cells, conjunctive grid x direction cells, and pure grid cells, based on continuous attractor dynamics, firing rate adaptation, and modulated by the medial-septal theta rhythm. Due to firing rate adaptation, the head-direction ring attractor exhibits left-right sweeps coding for internal direction, providing an input to the grid cell attractor network shifted along the internal direction, via an intermediate layer of conjunctive grid x direction cells, producing left-right sweeps of position by grid cells. Our model explains the empirical findings, including the alignment of internal position and direction sweeps and the dependence of sweep length on grid spacing. It makes predictions for theta-modulated head-direction cells, including specific relationships between theta phase precession during turning, theta skipping, anticipatory firing and directional tuning width. These predictions are verified in experimental data from anteroventral thalamus. The model also makes several predictions for the relationships between position and direction sweeps, running speed and dorsal-ventral location within the entorhinal cortex. Overall, a simple intrinsic mechanism explains the complex theta dynamics of the spatial circuit, with testable predictions.

Preventive Effects of Pomegranate Seed Oil on Transient Middle Cerebral Artery Occlusion via the Keap1/Nrf2/NQO1 Pathway in the rats Cortex
Ischemic stroke remains a pressing challenge that needs to be solved. Energy metabolic failure is a critical factor contributing to mitochondrial dysfunction and oxidative stress in the pathogenesis of brain ischemia, leading to the generation of excessive reactive oxygen species. Pomegranate seed oil (PSO) exhibits antioxidant properties; however, its protective effects against cerebral ischemia/reperfusion injury and the underlying mechanisms remain unclear. In this study, a transient middle cerebral artery occlusion (tMCAO) rat model was employed to simulate cerebral ischemia/reperfusion injury. We investigated the mechanisms by which different concentrations of PSO modulate oxidative damage caused by cerebral ischemia/reperfusion injury through the Keap1/Nrf2/NQO1 pathway in cortex. SD male rats were randomly divided into four groups: Control, tMCAO+NaCl, tMCAO+LO (low concentration of PSO), tMCAO+MO (medium concentration of PSO), and tMCAO+HO (high concentration of PSO). Our findings suggest that low concentration of PSO exerts neuroprotective effects by activating Nrf2 and NQO1, thereby reducing oxidative stress. Furthermore, LO significantly improved neurological scores and reduced neuronal edema. Additionally, the results demonstrated an increase in superoxide dismutase (SOD) levels and a decrease in malondialdehyde (MDA) levels. In contrast, MO and HO exhibited suboptimal effects. To sum up, these results indicate that PSO activates neuroprotective pathways against oxidative stress following cerebral ischemia/reperfusion injury via the Keap1/Nrf2/NQO1 pathway, providing novel insights into potential preventive therapies for cerebral ischemia/reperfusion.

BRD4 expression in microglia supports recruitment of T cells into the CNS and exacerbates EAE
In EAE, a mouse model of multiple sclerosis, immunization with MOG autoantigen results in the generation of Th1/Th17 T cells in the periphery. MOG-specific T cells then invade into the central nervous system (CNS), resulting in neuronal demyelination. Microglia, innate immune cells in the CNS are known to regulate various neuronal diseases. However, the role of microglia in EAE has remained elusive. BRD4 is a BET protein expressed in microglia, whether BRD4 in microglia contributes to EAE has not been determined. We show that EAE pathology was markedly reduced with microglia-specific Brd4 conditional knockout (cKO). In these mice, microglia- T cell interactions were greatly reduced, leading to the lack of T cell reactivation. Microglia specific transcriptome data showed downregulation of genes required for interaction with and reactivation of T cells in Brd4 cKO samples. In summary, BRD4 plays a critical role in regulating microglia function in normal and EAE CNS.

The role of feedback in responding to gradual and abrupt visuo-proprioceptive cue conflict
When people observe conflicting visual and proprioceptive cues about their static hand position, visuo-proprioceptive recalibration results. Recalibration also occurs during gradual or abrupt visuomotor adaptation, in response to both the cue conflict and sensory prediction errors experienced as the hand reaches to a target. Here we asked whether creating a cue conflict gradually vs. abruptly, or providing error feedback, affects recalibration in a static hand. We examined participants' responses to a 70 mm visuo-proprioceptive conflict, imposed by shifting the visual cue forward from the proprioceptive cue (static left hand). Participants pointed with their unseen right hand to indicate perceived bimodal and unimodal cue positions. Conflict was introduced gradually (groups 1 and 2) or abruptly (groups 3 and 4), with performance feedback present (groups 2 and 4) or absent (groups 1 and 3). For abrupt groups, most behavioral change occurred immediately after the conflict began. No-feedback groups (1 and 3) showed comparable magnitudes of overall recalibration, indicating that abrupt and gradual conflicts result in similar recalibration but with different timings. Motor adaptation was evident in the indicator hand with performance feedback (groups 2 and 4). However, performance on a static ruler task suggests proprioceptive recalibration also occurred despite the presence of feedback. Control groups confirmed accurate performance on the pointing task despite the visual cue shift. These findings highlight the distinct timing of recalibration mechanisms for gradual versus abrupt cue conflicts and potential smaller contribution of error mechanisms for a static conflict.

A high-speed OLED monitor for precise stimulation in vision, eye-tracking, and EEG research
The recent introduction of organic light-emitting diode (OLED) monitors with refresh rates of 240 Hz or more opens new possibilities for their use as precise stimulation devices in vision research, experimental psychology, and electrophysiology. These affordable high-speed monitors, targeted at video gamers, promise several advantages over the cathode ray tube (CRT) and liquid crystal display (LCD) monitors commonly used in these fields. Unlike LCDs, OLED displays have self-emitting pixels that can show true black, resulting in superior contrast ratios, a broad color gamut, and good viewing angles. More importantly, the latest gaming OLEDs promise excellent timing properties with minimal input lags and rapid transition times. However, OLED technology also has potential drawbacks, notably Auto-Brightness Limiting (ABL) behavior, where the local luminance of a stimulus can change with the number of currently illuminated pixels. This study characterized a 240 Hz OLED monitor, the ASUS PG27AQDM, in terms of its timing properties, spatial uniformity, viewing angles, warm-up times, and ABL behavior. We also compared its responses to those of CRTs and LCDs. Results confirm the monitor's excellent temporal properties with CRT-like transition times (around 0.3 ms), wide viewing angles, and decent spatial uniformity. Additionally, we found that ABL could be prevented with appropriate settings. We illustrate the monitor's benefits in two time-critical paradigms: Rapid "invisible" flicker stimulation (RIFT) and the gaze-contingent presentation of stimuli during eye movements. Our findings suggest that the newest gaming OLEDs are precise and cost-effective stimulation devices for visual experiments that have several key advantages over CRTs and LCDs.

Decreased GABA levels during development result in increased connectivity in the larval zebrafish tectum
{gamma}-aminobutyric acid (GABA) is an abundant neurotransmitter that plays multiple roles in the vertebrate central nervous system (CNS). In the early developing CNS, GABAergic signaling acts to depolarize cells. It mediates several aspects of neural development, including cell proliferation, neuronal migration, neurite growth, and synapse formation, as well as the development of critical periods. Later in CNS development, GABAergic signaling acts in an inhibitory manner when it becomes the predominant inhibitory neurotransmitter in the brain. This behavior switch occurs due to changes in chloride/cation transporter expression. Abnormalities of GABAergic signaling appear to underlie several human neurological conditions, including seizure disorders. However, the impact of reduced GABAergic signaling on brain development has been challenging to study in mammals. Here we take advantage of zebrafish and light sheet imaging to assess the impact of reduced GABAergic signaling on the functional circuitry in the larval zebrafish optic tectum. Zebrafish have three gad genes: two gad1 paralogs known as gad1a and gad1b, and gad2. The gad1b and gad2 genes are expressed in the developing optic tectum. Null mutations in gad1b significantly reduce GABA levels in the brain and increase electrophysiological activity in the optic tectum. Fast light sheet imaging of genetically encoded calcium indicator (GCaMP)-expressing gab1b null larval zebrafish revealed patterns of neural activity that were different than either gad1b-normal larvae or gad1b-normal larvae acutely exposed to pentylenetetrazole (PTZ). These results demonstrate that reduced GABAergic signaling during development increases functional connectivity and concomitantly hyper-synchronization of neuronal networks.

High distinctness of circadian rhythm is related to negative emotionality and enhanced neural processing of punishment-related information in men
For years, research on the human biological clock has focused primarily on chronotype (phase of the circadian rhythm). However, a second dimension - distinctness (subjective amplitude) of the rhythm, has so far been overlooked. This study aimed to explore the intricate interplay between psychometric traits and reward-punishment processing, considering both chronotype and distinctness. Circadian rhythmicity characteristics of 37 healthy men (aged 20-30) were measured using the Morningness-Eveningness-Stability-Scale improved (MESSi) questionnaire. We also employed a battery of psychometric questionnaires and used functional magnetic resonance (fMRI) during the Monetary Incentive Delay task, which is a common method of assessing reward-punishment processing. We found a positive association between distinctness and the activity in the bilateral Superior Frontal Gyrus (SFG), Supplementary Motor Area (SMA), and Ventral Tegmental Area (VTA) during processing of punishment cues. These results are consistent with psychometric findings - a significant positive association between distinctness and sensitivity to punishment, neuroticism, behavioral inhibition system (BIS), attention deficits, and negative emotionality. As regards eveningness, we found its negative association only with sensitivity to punishment and BIS. These results highlight the crucial role of distinctness in human functioning, especially in terms of punishment processing and negative emotionality.

Transcranial electrical brain stimulation modulates the vestibular system
Transcranial electrical stimulation (tES) techniques are widely used to modulate brain excitability, though their mechanisms remain unclear. This study demonstrates that tES can directly activate the vestibular system, which may contribute to its observed effects. Using computational modelling, we showed that tES with a C3-Fp2 montage generates electric fields in the vestibular system, with strengths similar to those generated by electrical vestibular stimulation (EVS). Experiments in three participants with 4 Hz alternating current revealed that C3-Fp2 tES induces body sway at 4 Hz, comparable to the effect of EVS. A 2 mA tES produced a sway response equivalent to 1 mA EVS, suggesting both activate the vestibular system. These findings indicate that direct activation of the vestibular system may interfere with the interpretation of tES studies. The effect is likely to exist for wide range of typical tES frequencies and current intensities.

Early intrinsic plasticity of ACC engram neurons defines memory formation and precision
Learning induces an early tag of prefrontal cortex neurons implicated in long-term memory storage, but this tag's nature, functional role, and time course are unknown. Using a c-fos dependent genetic and viral system for the labeling and manipulation of putative engram neurons of the anterior cingulate cortex (ACC) together with behavior and in vitro electrophysiology, we found that contextual fear learning triggered an increase in the neuron-wide intrinsic excitability specifically of ACC engram neurons. This plasticity was expressed over several days during the early memory phase and required for enduring memory storage. Pharmacogenetic manipulation of the engram neurons' intrinsic excitability during its plastic phase altered the strength and context-precision of enduring fear memories. Moreover, this manipulation prevented the memory decline usually caused by an interference event. In contrast, excitability manipulation or interference during remote memory phases did not influence long-term memory retrieval; their impact is thus strongly correlating with the time course of intrinsic plasticity. These findings shed light on the functional role of intrinsic plasticity of ACC engram neurons in long-term memory storage. Associative learning strongly engages ACC engram neurons and triggers neuron-wide intrinsic plasticity. This plasticity is transiently expressed and necessary for the consolidation and specificity of long-term memory.

AAV-mediated expression of proneural factors stimulates neurogenesis from adult Müller glia in vivo.
The lack of regeneration in the human central nervous system (CNS) has major health implications. To address this, we previously used transgenic mouse models to show that neurogenesis can be stimulated in the adult mammalian retina by driving regeneration programs that other species activate following injury. Expression of specific proneural factors in adult Muller glia causes them to re-enter the cell cycle and give rise to new neurons following retinal injury. To bring this strategy closer to clinical application, we now show that neurogenesis can also be stimulated when delivering these transcription factors to Muller glia using adeno-associated viral (AAV) vectors. AAV-mediated neurogenesis phenocopies the neurogenesis we observed from transgenic animals, with different proneural factor combinations giving rise to distinct neuronal subtypes in vivo. Vector-borne neurons are morphologically, transcriptomically and physiologically similar to bipolar and amacrine/ganglion-like neurons. These results represent a key step forward in developing a cellular reprogramming approach to regenerative medicine in the CNS.

Different behaviourally relevant stimuli evoke different forms of adaptation in the olfactory system
Sensory neurons are continuously exposed to a large diversity of stimuli and adjust their response according to the recent stimulation history, in a process called adaptation. Recent studies have demonstrated that many sensory neurons not only depress (decrease their response to repetitive sensory stimulation) but some neurons exhibit facilitation: a small initial response followed by increase in response amplitude. Adaptation has been mainly studied with neutral stimuli and it is not known whether different behaviourally relevant stimuli evoke adaptation with similar or different properties. Here we used ethologically relevant stimuli to study adaptation in the zebrafish olfactory system. We found that repetitive presentation of food odour caused a variety of adaptations ranging from very strong depression to facilitation, but depression was the predominant dynamic. On the other hand, a different behaviourally-relevant stimulus, alarm substance, evoked much stronger facilitation and also decreased the amplitude of responses to food presentation. Other sensory modalities, aversive mechanosensory and attractive visual stimuli, also caused adaptation with different properties in the same brain area. Different forms of adaptation may therefore be used for processing sensory stimuli evoking different behavioural reactions.

Glial alterations in the glutamatergic and GABAergic signaling pathways in a mouse model of Lafora disease, a severe form of progressive myoclonus epilepsy
Lafora disease (LD; OMIM#254780) is a rare form of progressive myoclonus epilepsy characterized by the accumulation of insoluble deposits of aberrant glycogen (polyglucosans), named Lafora bodies (LBs), in the brain but also in peripheral tissues. It is assumed that the accumulation of LBs is related to the appearance of the characteristic pathological features of the disease. In mouse models of LD, we and others have reported an increase in the levels of reactive astrocytes and activated microglia, which triggers the expression of the different pro-inflammatory mediators. Recently, we have demonstrated that the TNF and IL-6 inflammatory signaling pathways are the main mediators of the neuroinflammatory phenotype associated with the disease. In this work, we present evidence that the activation of these pathways produces a dysregulation in the levels of different subunits of the excitatory ionotropic glutamatergic receptors (phopho-GluN2B, phospho-GluA2, GluK2) and also an increase in the levels of the GABA transporter GAT1 in the hippocampus of the Epm2b-/- mice. In addition, we present evidence of the presence of activated forms of the Src and Lyn protein kinases in this area. These effects may increase the excitatory glutamatergic signaling and decrease the inhibitory GABAergic tone, leading to hyper-excitability. More importantly, the enhanced production of these subunits occurs in non-neuronal cells such as activated microglia and reactive astrocytes, pointing out a key role of glia in the pathophysiology of LD.

Correlated and Anticorrelated Binocular Disparity Modulate GABA+ and Glutamate/glutamine Concentrations in the Human Visual Cortex
Binocular disparity is used for perception and action in three dimensions. Neurons in the primary visual cortex respond to binocular disparity in random dot patterns, even when the contrast is inverted between eyes (false depth cue). In contrast, neurons in the ventral stream largely cease to respond to false depth cues. This study evaluated whether GABAergic inhibition is involved in suppressing false depth cues in the human ventral visual cortex. We compared GABAergic inhibition (GABA+) and glutamatergic excitation (Glx) during the viewing of correlated and anticorrelated binocular disparity in 18 participants using single voxel proton magnetic-resonance spectroscopy (MRS). Measurements were taken from the early visual cortex (EVC) and the lateral occipital cortex (LO). Three visual conditions were presented per voxel location: correlated binocular disparity; anticorrelated binocular disparity; or a blank grey screen with a fixation cross. To identify differences in neurochemistry, GABA+ or Glx levels were compared across viewing conditions. In EVC, correlated disparity increased Glx over anticorrelated and rest conditions, also mirrored in the Glx/GABA+ ratio. In LO, anticorrelated disparity decreased GABA+ and increased Glx. Joint effects on GABA+ and Glx were summarised by the Glx/GABA+ ratio, which showed increased excitatory over inhibitory drive to anticorrelated disparity in LO. Glx during viewing of anticorrelation in LO was predictive of its object-selective BOLD-activity. We provide evidence that early and ventral visual cortices change GABA+ and Glx concentrations during presentation of correlated and anticorrelated disparity, suggesting a contribution of cortical excitation and inhibition in disparity selectivity.

Abnormal mu rhythm state-related cortical and corticospinal responses in chronic stroke
The motor cortex's activity is state-dependent. Specifically, the sensorimotor mu rhythm phase relates to fluctuating levels of primary motor cortex (M1) excitability, previously demonstrated in young and healthy volunteers. However, it is unknown whether this observation is generalizable to individuals with brain lesions after a stroke. We investigated the phase relationship between the mu rhythm and cortical excitability by combining real-time processing of electroencephalography (EEG) signals and transcranial magnetic stimulation (TMS) of M1. In 11 chronic subcortical stroke survivors and 12 similar-aged healthy volunteers, we applied TMS to M1 at the peak, falling, trough, and rising phase of the sensorimotor mu oscillation. As outcome measures, we investigated the M1-to-muscle excitability by measuring motor-evoked potentials (MEPs) and local cortical activation by measuring TMS-evoked potentials (TEPs). We found that M1-to-muscle excitability in stroke survivors and older volunteers shows a phase-dependency similar to that in young healthy adults. That is, MEPs were increased and decreased at the trough and peak of the mu rhythm, respectively. However, individuals with stronger stroke-related motor symptoms showed a decreased phase preference. Further, phase-dependency was abolished in the local cortical activity, as measured with EEG, in the stroke-affected hemisphere, in contrast to the non-affected hemisphere as well as either hemisphere in healthy volunteers. Altogether, these results shed light on the state-dependency of motor cortex excitability after stroke. Our results indicate that the strength of phase preference of TMS motor responses could indicate the severity of motor impairment. These results could enable the development of improved TMS paradigms for recovery of motor impairment after stroke.

Dynamical Modulation of Hippocampal Replay Sequences through Firing Rate Adaptation
During periods of immobility and sleep, the hippocampus generates diverse self-sustaining sequences of "replay" activity, exhibiting stationary, diffusive, and super-diffusive dynamical patterns. However, the neural mechanisms underlying this diversity in hippocampal sequential dynamics remain largely unknown. Here, we propose such a mechanism demonstrating that modulation of firing rate adaptation in a continuous attractor model of place cells causes the emergence of different types of replay. Our model makes several key predictions. First, more diffusive replay sequences positively correlate with longer theta sequences across animals (both reflecting stronger adaptation). Second, replay diffusivity varies within an animal across behavioural states that affect adaptation (such as wake and sleep). Third, increases in neural excitability, incorporated with firing rate adaptation, reduce the step size of decoded movements within individual replay sequences. We provide new experimental evidence for all three predictions. These insights suggested that the diverse replay dynamics observed in the hippocampus can be reconciled through a simple yet effective neural mechanism, shedding light on its role in hippocampal-dependent cognitive functions and its relationship to other aspects of hippocampal electrophysiology.

Learning-related oscillatory dynamics in the human cortico-basal ganglia network during motor sequence initiation in Parkinson's Disease
Learning fine motor sequences is crucial to quality of life and can be altered in Parkinson's Disease (PD). It may be partially driven by the optimization of motor preparation and initiation, but neither pre-movement neural activity nor its optimization is well understood. One theory of general motor initiation posits that network beta ({beta}) desynchronization releases motor cortical excitability, reflected as delta ({delta}) phase response, which in turn facilitates sequence-specific motor cortical ensemble activity to produce voluntary movement. With motor sequence learning, increases in cortico-basal ganglia {delta} synchrony may facilitate enhanced recruitment of both cortical and basal ganglia neural ensembles, increasing the reliability of their firing patterns. As gamma ({gamma}) activity can correlate with spiking population dynamics, this model predicts learning-dependent pre-movement sequence-specific {gamma} activity, alongside {beta}[->]{delta}[->]{gamma} interactions and cortico-basal ganglia {delta} phase synchrony--any of which could differ in PD. We test this model in four subjects with PD, on dopaminergic medication without deep brain stimulation, by leveraging invasive cortico-basal ganglia field potential recordings during a multi-day, multi-sequence typing task. Possibly indicative of PD-related neuropathophysiology, there was no consistent evidence for a full cascade of {beta}[->]{delta}[->]{gamma} gating of general motor initiation. However, subjects who improved with practice did demonstrate 1) practice-driven increases in the discriminability of sequence-specific {gamma} activity and 2) cortico-basal ganglia {delta} synchrony that appeared to reflect a framework for learning-dependent {delta}-{beta} and {delta}-{gamma} coupling. In subjects who did not improve, discriminability of sequence-specific {gamma} activity rather decreased with practice, and basal ganglia was functionally disconnected from cortex, instead dominated by ongoing subcortical {delta} oscillations. These findings suggest a model in which phase-responsiveness of basal ganglia {delta} to cortex is a predictor of motor learning.

Track-A-Worm 2.0: A Software Suite for Quantifying Properties of C. elegans Locomotion, Bending, Sleep, and Action Potentials
Comparative analyses of locomotor behavior and cellular electrical properties between wild-type and mutant C. elegans are crucial for exploring the gene basis of behaviors and the underlying cellular mechanisms. Although many tools have been developed by research labs and companies, their application is often hindered by implementation difficulties or lack of features specifically suited for C. elegans. Track-A-Worm 2.0 addresses these challenges with three key components: WormTracker, SleepTracker, and Action Potential (AP) Analyzer. WormTracker quantifies a comprehensive set of locomotor and body bending properties, distinguishes between the ventral and dorsal sides, tracks the animal using a motorized stage, and integrates external devices, such as a light source for optogenetic stimulation. SleepTracker detects and quantifies sleep-like behavior in freely moving animals. AP Analyzer assesses the resting membrane potential, afterhyperpolarization level, and various AP properties, including threshold, amplitude, mid-peak width, rise and decay times, and maximum and minimum slopes. Importantly, it addresses the challenge of AP threshold quantification posed by the absence of a pre-upstroke inflection point. Track-A-Worm 2.0 is potentially a valuable tool for many C. elegans research labs due to its powerful functionality and ease of implementation.

Virally-Mediated Enhancement of Efferent Inhibition Reduces Acoustic Trauma in Wild Type Murine Cochleas.
Noise-induced hearing loss (NIHL) poses an emerging global health problem with only ear protection or sound avoidance as preventive strategies. In addition, however, the cochlea receives some protection from medial olivocochlear (MOC) efferent neurons, providing a potential target for therapeutic enhancement. Cholinergic efferents release ACh (Acetylycholine) to hyperpolarize and shunt the outer hair cells (OHCs), reducing sound-evoked activation. The (9)2(10)3 nicotinic ACh receptor (nAChR) on the OHCs mediates this effect. Transgenic knock-in mice with a gain-of-function nAChR (9L9'T) suffer less NIHL. 9 knockout mice are more vulnerable to NIHL but can be rescued by viral transduction of the 9L9'T subunit. In this study, an HA-tagged gain-of-function 9 isoform was expressed in wildtype mice in an attempt to reduce NIHL. Synaptic integration of the virally-expressed nAChR subunit was confirmed by HA-immunopuncta in the postsynaptic membrane of OHCs. After noise exposure, 9L9'T-HA injected mice had less hearing loss (auditory brainstem response (ABR) thresholds and threshold shifts) than did control mice. ABRs of 9L9'T-HA injected mice also had larger wave1 amplitudes and better recovery of wave one amplitudes post noise exposure. Thus, virally-expressed 9L9'T combines effectively with native 9 and 10 subunits to mitigate NIHL in wildtype cochleas.

Quantifying the influence of biophysical factors in shaping brain communication through remnant functional networks
Functional connectivity (FC) reflects brain wide communication crucial for cognition, yet the role of underlying biophysical factors, physical and molecular, in shaping FC remains unclear. We quantify the influence of physical factors, structural connectivity (SC) and spatial autocorrelation (DC), capturing anatomical wiring and distance between regions and molecular factors, gene expression similarity (GC) and neuroreceptor congruence (RC), capturing similarity in the neurobiological make up on the organizational features of fMRI derived resting state FC. We assess the impact of these factors on graph-theoretic and topological features, capturing both pairwise and higher order interactions between brain regions. We develop a simple test using remnant functional networks generated by selectively removing connections aligned with specific biophysical factors. Our findings reveal that molecular factors, particularly RC, predominantly shape graph-theoretic features, while topological features are influenced by a mix of molecular and physical factors, notably GC and DC. Surprisingly, SC plays a minor role in FC organization. Additionally, we link FC alterations to specific biophysical factors in neuropsychiatric conditions such as schizophrenia, bipolar disorder, and ADHD, with physical factors more effectively differentiating these groups. These insights are crucial for understanding and modeling FC across various applications. Our analysis offers a robust method to examine how underlying factors dynamically influence FC in different contexts beyond resting state, including during a task, development, and clinical conditions.

Repetitive magnetic stimuli over the motor cortex impair consolidation of a balance task by suppressing up-regulation of intracortical inhibition
Low-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) was shown to impair short-term consolidation of a balance task, emphasizing the importance of M1 in balance skill consolidation. However, the disruptive mechanisms of rTMS on neural consolidation processes and their persistence across multiple balance acquisition sessions remain unclear. GABAergic processes are crucial for motor consolidation and, at the same time, are up-regulated when learning balance skills. Therefore, this study investigated the impact of rTMS on GABA-mediated short-interval intracortical inhibition (SICI) and consolidation of balance performance. Participants (n=31) underwent six balance acquisition sessions on a rocker board, each followed by rTMS (n=15) or sham-rTMS (n=16). In the PRE-measurement, SICI was assessed at baseline and after balance acquisition with subsequent rTMS/sham-rTMS. In the POST-measurement, this procedure was repeated to assess the influence of motor memory reactivation on SICI. In addition, SICI-PRE and SICI-POST were compared to assess long-term processes. Both groups achieved similar improvements within the balance acquisition sessions. However, they did not consolidate equally well indicated by significant declines in performance for the rTMS group (p = 0.006) in the subsequent sessions. Both short- (p = 0.014) and long-term (p = 0.038) adaptations in SICI were affected by rTMS: while the sham-rTMS group up-regulated SICI, rTMS led to reductions in inhibition. The interfering effect of rTMS on both balance consolidation and up-regulation of SICI suggests that increased intracortical inhibition is an important factor to protect and consolidate the newly acquired motor memory.

Intracortical injection of immune checkpoint inhibitor promotes monocyte/macrophage infiltration and restores microglial function and neuronal activity in an AD mouse model
Understanding the intricate interplay among immune responses and homeostatic cell function in Alzheimer's disease (AD) remains challenging. Here, we present a novel strategy to mitigate AD pathology by directly modulating the immune checkpoint PD-1/PD-L1 signaling pathway in the brain, where elevated levels of microglial PD-1 and astrocytic PD-L1 have been observed. We found that a single intracortical injection of anti-PD-L1 antibody facilitates the infiltration of peripheral immune cells into the brain, including IL-10-secreting Ly6C+ monocytes. Subsequently, this leads to the restoration of microglial homeostatic functions including an increase in P2RY12 expression, which enhances microglial process extension. This cascade of events following anti-PD-L1 injection is crucial for regulating abnormally hyperactive neurons and reducing amyloid-beta plaques. These findings suggest that the direct application of immune checkpoint blockade in the brain could offer a new approach to managing the delicate cell-cell interactions among neurons, glial cells, and peripheral immune cells in the AD brain.

Isotonic and minimally invasive optical clearing media for live cell imaging ex vivo and in vivo
Tissue clearing has been widely used for fluorescence imaging of fixed tissues, but not for live tissues due to its toxicity. Here we develop minimally invasive optical clearing media for fluorescence imaging of live mammalian tissues. Light scattering is minimized by adding spherical polymers with low osmolarity to the extracellular medium. A clearing medium containing bovine serum albumin (SeeDB-Live) is minimally invasive to live cells, allowing for structural and functional imaging of live tissues, such as spheroids, organoids, acute brain slices, and the mouse brain in vivo. SeeDB-Live minimally affects the electrophysiological properties and sensory responses of neurons. We demonstrate its utility for widefield imaging of subcellular voltage dynamics, such as backpropagating action potentials, in acute brain slices. We also utilize SeeDB-Live for widefield voltage imaging of dozens of dendrites in vivo, demonstrating population dynamics. Thus, SeeDB-Live expands the scale and modalities of fluorescence imaging of live mammalian tissues.

Cross-sectional brain age assessments are limited in predicting future brain change
The concept of brain age (BA) describes an integrative imaging marker of brain health, often suggested to reflect ageing processes. However, the degree to which cross-sectional MRI features, including BA, reflect past, ongoing and future brain changes across different tissue types from macro- to microstructure remains controversial. Multimodal imaging data of 39,325 UK Biobank participants, aged 44-82 years at baseline and 2,520 follow-ups within 1.12-6.90 years, provide insufficient evidence that BA reflects the rate of brain ageing.

SMN deficiency induces an early non-atrophic myopathy with alterations in the contractile and excitatory coupling machinery of skeletal myofibers in the SMN{triangleup}7 mouse model of spinal muscular atrophy
Spinal muscular atrophy (SMA) is caused by a deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. The main pathological hallmark of SMA is the degeneration of lower motor neurons (MNs) with subsequent denervation and atrophy of skeletal muscle. However, increasing evidence indicates that low SMN levels not only are detrimental to the central nervous system but also directly affect other peripheral tissues and organs, including skeletal muscle. To better understand the potential primary impact of SMN deficiency in muscle, we explored the cellular, ultrastructural, and molecular basis of SMA myopathy in the SMN{Delta}7 mouse model of severe SMA at an early postnatal period (P0-7) prior to muscle denervation and MN loss (preneurodegenerative [PND] stage). This period contrasts with the neurodegenerative (ND) stage (P8-14), in which MN loss and muscle atrophy occur. At the PND stage, we found that SMN{triangleup}7 mice displayed early signs of motor dysfunction with overt myofiber alterations in the absence of atrophy. Focal and segmental lesions in the myofibrillar contractile apparatus were noticed in myofibers. These lesions were observed in association with specific myonuclear domains and included abnormal accumulations of actin-thin myofilaments, sarcomere disruption, and the formation of minisarcomeres. The sarcoplasmic reticulum and triads also exhibited ultrastructural alterations, suggesting decoupling during the excitation-contraction process. Finally, changes in intermyofibrillar mitochondrial organization and dynamics, indicative of mitochondrial biogenesis overactivation, were also found. Overall, our results demonstrated that SMN deficiency induces early and MN loss-independent alterations in myofibers that essentially contribute to SMA myopathy. This strongly supports the view of an intrinsic alteration of skeletal muscle in SMA, suggesting that this peripheral tissue is a key therapeutic target for the disease.

Ndufs4 inactivation in glutamatergic neurons reveals swallow-breathing discoordination in a mouse model of Leigh Syndrome
Swallowing, both nutritive and non-nutritive, is highly dysfunctional in children with Leigh Syndrome (LS) and contributes to the need for both gastrostomy and tracheostomy tube placement. Without these interventions aspiration of food, liquid, and mucus occur resulting in repeated bouts of respiratory infection. No study has investigated whether mouse models of LS, a neurometabolic disorder, exhibit dysfunctions in neuromuscular activity of swallow and breathing integration. We used a genetic mouse model of LS in which the NDUFS4 gene is knocked out (KO) specifically in Vglut2 or Gad2 neurons. We found increased variability of the swallow motor pattern, disruption in breathing regeneration post swallow, and water-induced apneas only in Vglut2 KO mice. These physiological changes likely contribute to weight loss and premature death seen in this mouse model. Following chronic hypoxia (CH) exposure, swallow motor pattern, breathing regeneration, weight, and life expectancy were not changed in the Vglut2-Ndufs4-KO CH mice compared to control, indicating a rescue of phenotypes. These findings show that like patients with LS, Ndufs4 mouse models of LS exhibit swallow impairments as well as swallow-breathing dyscoordination alongside the other phenotypic traits described in previous studies. Understanding this aspect of LS will open roads for the development of future more efficacious therapeutic intervention for this illness.

Visually-evoked activity and variable modulation of auditory responses in the macaque inferior colliculus
How multisensory cues affect processing in early sensory brain areas is not well understood. The inferior colliculus (IC) is an early auditory structure that is visually responsive (Porter et al., 2007; Bulkin & Groh, 2012b, 2012a), but little is known about how visual signals affect the IC's auditory representation. We explored how visual cues affect both spiking and local field potential (LFP) activity in the IC of two monkeys performing a task involving saccades to auditory, visual, or combined audiovisual stimuli. We confirm that LFPs are sensitive to the onset of fixation lights as well as the onset of visual targets presented during steady fixation. The LFP waveforms evoked by combined audiovisual stimuli differed from those evoked by sounds alone. In single-unit spiking activity, responses were weak when visual stimuli were presented alone, but visual stimuli could modulate the activity evoked by sounds in a stronger way. Such modulations could involve either increases or decreases in activity, and whether increases or decreases were observed was variable and not obviously correlated with the responses evoked by visual or auditory stimuli alone. These findings indicate that visual stimuli shape the IC's auditory representation in flexible ways that differ from those observed previously in multisensory areas.

Muscle spindles provide flexible sensory feedback for movement sequences
Sensory feedback is essential for motor performance and must adapt to task demands. Muscle spindle afferents (MSAs) are a major primary source of feedback about movement, and their responses are readily modulated online by gain-controller fusimotor neurons and other mechanisms. They are therefore a powerful site for implementing flexible sensorimotor control. We recorded from MSAs innervating the jaw musculature during performance of a directed lick sequence task. Jaw MSAs encoded complex jaw-tongue kinematics. However, kinematic encoding alone accounted for less than half of MSA spiking variability. MSA representations of kinematics changed based on sequence progression (beginning, middle, or end of the sequence, or reward consumption), suggesting that MSAs are flexibly tuned across the task. Dynamic control of incoming feedback signals from MSAs may be a strategy for adaptable sensorimotor control during performance of complex behaviors.

Mindfulness-based Neurofeedback: A Systematic Review of EEG and fMRI studies
Neurofeedback concurrent with mindfulness meditation may reveal meditation effects on the brain and facilitate improved mental health outcomes. Here, we systematically reviewed EEG and fMRI studies of mindfulness meditation with neurofeedback (mbNF) and followed PRISMA guidelines. We identified 10 fMRI reports, consisting of 177 unique participants, and 9 EEG reports, consisting of 242 participants. Studies of fMRI focused primarily on downregulating the default-mode network (DMN). Although studies found decreases in DMN activations during neurofeedback, there is a lack of evidence for transfer effects, and the majority of studies did not employ adequate controls, e.g. sham neurofeedback. Accordingly, DMN decreases may have been confounded by general task-related deactivation. EEG studies typically examined alpha, gamma, and theta frequency bands, with the most robust evidence supporting the modulation of theta band activity. Both EEG and fMRI mbNF have been implemented with high fidelity in clinical populations. However, the mental health benefits of mbNF have not been established. In general, mbNF studies would benefit from sham-controlled RCTs, as well as clear reporting (e.g. CRED-NF).

Neurovascular Impulse Response Function (IRF) during spontaneous activity differentially reflects intrinsic neuromodulation across cortical regions
Ascending neuromodulatory projections from deep brain nuclei generate internal brain states that differentially engage specific neuronal cell types. Because neurovascular coupling is cell-type specific and neuromodulatory transmitters have vasoactive properties, we hypothesized that the impulse response function (IRF) linking spontaneous neuronal activity with hemodynamics would depend on neuromodulation. To test this hypothesis, we used optical imaging to measure (1) release of neuromodulatory transmitters norepinephrine (NE) or acetylcholine (ACh), (2) Ca2+ activity of local cortical neurons, and (3) changes in hemoglobin concentration and oxygenation across the dorsal surface of cerebral cortex during spontaneous neuronal activity in awake mice. A canonical convolution model with a stationary IRF (e.g., the convolution kernel) describing evolution of total hemoglobin (HbT, reflective of dilation dynamics) with respect to Ca2+, resulted in a poor fit to the data. However, the HbT time-course was well predicted, pixel-by-pixel, by a weighted sum of Ca2+ and NE time-courses. The weighting coefficients, calculated using linear regression, varied smoothly across the cortical space. Consistent with this result, modeling HbT as a weighted sum of stationary Ca2+- and NE-specific IRFs convolved with the respective time-courses dramatically improved the fit compared to the invariant IRF. In both the linear regression and the Double-IRF convolution models, Ca2+ and NE weighting was positive and negative, respectively. In contrast to NE, ACh was largely redundant with Ca2+ and therefore did not improve HbT estimation. Because NE covaried with arousal, we observed instances of the diminished hemodynamic coherence between cortical regions during high arousal despite coherent behavior of the underlying neuronal Ca2+ activity. We conclude that while neurovascular coupling with respect to neuronal Ca2+ is a dynamic and seemingly complex phenomenon, hemodynamic fluctuations can be captured by a simple linear model with stationary IRFs with respect to the underlying dilatory and constrictive forces. In the current study, these forces were captured by the positive Ca2+ (dilation) and negative NE (constriction) coefficients. Without accounting for NE neuromodulation and the associated vasoconstriction, diminished hemodynamic coherence, commonly referred to as ''functional (dys)connectivity'' in BOLD fMRI studies, can be falsely interpreted as neuronal desynchronizations.

Opponent visuospatial coding structures responses during memory recall and visual perception in medial parietal cortex
The mechanisms linking perceptual and memory representations in the brain are not yet fully understood. In early visual cortex, perception and memory are known to share similar neural representations, but how they interact beyond early visual cortex is less clear. Recent work identified that scene-perception and scene-memory areas on the lateral and ventral surfaces of the brain are linked via a shared but opponent visuospatial coding scheme, suggesting that shared visuospatial coding might provide a framework for perceptual-memory interactions. Here, we test whether the pattern in visuospatial coding within category-selective memory areas of medial parietal cortex structures responses during memory recall and visual perception. Using functional magnetic resonance imaging, we observe signatures of visuospatial coding in the form of population receptive fields (pRFs) with both positive and negative response profiles within medial parietal cortex. Crucially, the more dissimilar the timeseries of a pair of positive/negative pRFs within a region, the more dissimilar their responses during both memory recall and visual perception - tasks that place very different demands on these regions: internally oriented memory recall versus externally oriented visual perception. These data extend recent work to suggest that the interplay between pRFs with opponent visuospatial coding may play a vital role in integrating information across different representational spaces.

Thermosensory behaviors of the free-living life stages of Strongyloides species support parasitism in tropical environments
Soil-transmitted parasitic nematodes infect over 1 billion people worldwide and are a common source of neglected disease. Strongyloides stercoralis is a potentially fatal skin-penetrating human parasite that is endemic to tropical and subtropical regions around the world. The complex life cycle of Strongyloides species is unique among human-parasitic nematodes in that it includes a single free-living generation featuring soil-dwelling, bacterivorous adults whose progeny all develop into infective larvae. The sensory behaviors that enable free-living Strongyloides adults to navigate and survive soil environments are unknown. S. stercoralis infective larvae display parasite-specific sensory-driven behaviors, including robust attraction to mammalian body heat. In contrast, the free-living model nematode Caenorhabditis elegans displays thermosensory behaviors that guide adult worms to stay within a physiologically permissive range of environmental temperatures. Do S. stercoralis and C. elegans free-living adults, which experience similar environmental stressors, display common thermal preferences? Here, we characterize the thermosensory behaviors of the free-living adults of S. stercoralis as well as those of the closely related rat parasite, Strongyloides ratti. We find that Strongyloides free-living adults are exclusively attracted to near-tropical temperatures, despite their inability to infect mammalian hosts. We further show that lifespan is shorter at higher temperatures for free-living Strongyloides adults, similar to the effect of temperature on C. elegan's lifespan. However, we also find that the reproductive potential of the free-living life stage is enhanced at warmer temperatures, particularly for S. stercoralis. Together, our results reveal a novel role for thermotaxis to maximize the infectious capacity of obligate parasites and provide insight into the biological adaptations that may contribute to their endemicity in tropical climates.

Neural and verbal responses to attachment-schema narratives differ based on past and current caregiving experiences
Children's caregiving experiences impact the internal models they use to process new emotional events. Examining inter-subject functional correlation in 7- to 15-year-olds during narrative movies depicting separation and reunion, we find that secure attachment to current caregivers plays a larger role than early adversity in shaping prefrontal-amygdala connectivity. Secure attachment also decreased the emphasis in later memory on separation elements in the narrative.

Contribution of amygdala to dynamic model arbitration under uncertainty
Intrinsic uncertainty in the reward environment requires the brain to run multiple models simultaneously to predict outcomes based on preceding cues or actions, commonly referred to as stimulus- and action-based learning. Ultimately, the brain also must adopt appropriate choice behavior using reliability of these models. Here, we combined multiple experimental and computational approaches to quantify concurrent learning in monkeys performing tasks with different levels of uncertainty about the model of the environment. By comparing behavior in control monkeys and monkeys with bilateral lesions to the amygdala or ventral striatum, we found evidence for dynamic, competitive interaction between stimulus-based and action-based learning, and for a distinct role of the amygdala. Specifically, we demonstrate that the amygdala adjusts the initial balance between the two learning systems, thereby altering the interaction between arbitration and learning that shapes the time course of both learning and choice behaviors. This novel role of the amygdala can account for existing contradictory observations and provides testable predictions for future studies into circuit-level mechanisms of flexible learning and choice under uncertainty.

Egocentric anchoring-and-adjustment of social knowledge in the hippocampal formation
Recent work suggests the hippocampal formation(HF) assimilates relational social knowledge similar to how it transforms egocentric spatial cues into map-like representations. Yet whether hippocampal map-like representations of social knowledge still represent lingering egocentric biases is unclear. We test if a prominent egocentric bias involving an implicit reliance on self-knowledge when rating others, anchoring-and-adjustment, is present when the relative attributes of different social entities are assimilated by the HF. Participants provided likelihood ratings of partaking in everyday activities for themselves, fictitious individuals, and familiar social groups. Adapting a functional neuroimaging task from Kaplan and Friston, participants then learned a stranger's preference for an activity relative to one of the fictitious individuals and inferred how the stranger's preference related to the groups' preferences. Egocentric anchoring-and-adjustment was present when participants rated the other entities. Isolating the neural representation of egocentric anchoring-and-adjustment when flexibly comparing different social entities, the HF and dorsomedial prefrontal cortex(dmPFC) represented group-self rating discrepancy. Furthermore, the HF also reflected how well group preferences were remembered, where memory for group preferences correlates with task performance. We found the HF selectively represented group identity over other learned entities, confirming that the HF was primarily engaged by social comparisons in a more ample frame of reference. Taken together, these results imply that self-knowledge influences how the HF assimilates map-like knowledge about others.

Combined transcriptomic, connectivity, and activity profiling of the medial amygdala using highly amplified multiplexed in situ hybridization (hamFISH)
In situ transcriptomic technologies provide a promising avenue to link gene expression, connectivity, and physiological properties of neural cell types. Commercialized methods that allow the detection of hundreds of genes in situ, however, are expensive and therefore typically used for generating unimodal reference data rather than for resource-intensive multimodal analyses. A major bottleneck is the lack of a routine means to efficiently generate cell type data. Here, we have developed hamFISH (highly amplified multiplexed in situ hybridization), which enables the sequential detection of 32 genes using multiplexed branched DNA amplification. We used hamFISH to profile the projection, activity, and transcriptomic diversity of the medial amygdala (MeA), a critical node for innate social and defensive behaviors. In total, we profiled 643,834 cells and classified neurons into 16 inhibitory and 10 excitatory types, many of which were found to be spatially clustered. We then examined the organization of outputs of these cells and activation profiles during different social contexts. Therefore, by facilitating multiplexed detection of single molecule RNAs, hamFISH provides a streamlined and versatile platform for multimodal profiling of specific brain nuclei.

Age-related decline of PKA-RIIβ level in SNc dopaminergic neurons underlies PD pathogenesis
The cyclic-AMP dependent protein kinase A (Protein kinase A, PKA) regulates dopaminergic function in the substantia nigra pars compacta (SNc). However, whether PKA is involved in the pathogenesis of Parkinson's disease (PD) is unknown. Here, by collecting and analyzing the current worldwide SNc transcriptomic datasets of PD patients, we found a decline of PKA-RIIbeta subunit level in the SNc of PD patients. The decreased PKA-RIIbeta subunit level was positively correlated with decreased dopamine synthesis and increased oxidative stress in the SNc of PD patients. PKA-RIIbeta subunit is expressed in the striatum and the SNc. PKA-RIIbeta gene knockout mice (RIIbeta-KO) showed a age-related parkinsonism at 12 months of age. Using Cre-LoxP system, we observed that RIIbeta; re-expression in the SNc dopaminergic neurons rescued parkinsonism of RIIbeta-KO mice. RIIbeta re-expression in striatal neurons did not affect parkinsonism of RIIbeta-KO mice. The spontaneous parkinsonism could be developed in 12-month-old SNc dopaminergic neuron-specific RIIbeta-deficient mice. Single-nucleus RNA sequencing revealed decreased PKA activity, reduced dopamine synthesis and raised oxidative stress in the SNc dopaminergic neurons of RIIbeta-KO mice. Adeno-associated virus (AAV)-mediated gene therapy targeting PKA-RIIbeta in the SNc dopaminergic neurons rescued parkinsonism in PD mouse model. Taken together, these findings indicate that PKA-RIIbeta may be a key factor of human genetic etiologies of PD. The therapy targeting PKA-RIIbeta in the SNc dopaminergic neurons may be promising for PD treatment.

Endogenous Regulator of G protein Signaling 14 (RGS14) suppresses cocaine-induced emotionally motivated behaviors in female mice
Addictive drugs hijack the neuronal mechanisms of learning and memory in motivation and emotion processing circuits to reinforce their own use. Regulator of G-protein Signaling 14 (RGS14) is a natural suppressor of post-synaptic plasticity underlying learning and memory in the hippocampus. The present study used immunofluorescence and RGS14 knockout mice to assess the role of RGS14 in behavioral plasticity and reward learning induced by chronic cocaine in emotional-motivational circuits. We report that RGS14 is strongly expressed in discrete regions of the ventral striatum and extended amygdala in wild-type mice, and is co-expressed with D1 and D2 dopamine receptors in neurons of the nucleus accumbens (NAc). Of note, we found that RGS14 is upregulated in the NAc in mice with chronic cocaine history following acute cocaine treatment. We found significantly increased cocaine-induced locomotor sensitization, as well as enhanced conditioned place preference and conditioned locomotor activity in RGS14-deficient mice compared to wild-type littermates. Together, these findings suggest that endogenous RGS14 suppresses cocaine-induced plasticity in emotional-motivational circuits, implicating RGS14 as a protective agent against the maladaptive neuroplastic changes that occur during addiction.

Modeling Sensorimotor Processing with Physics-Informed Neural Networks
Proprioception is essential for planning and executing precise movements. Muscle spindles, the key mechanoreceptors for proprioception, are the principle sensory neurons enabling this process. Emerging evidence suggests spindles act as adaptable processors, modulated by gamma motor neurons to meet task demands. Yet, the specifics of this modulation remain unknown. Here, we present a novel, physics-informed neural network model that integrates biomechanics and neural dynamics to capture spindle function with high fidelity and efficiency, while maintaining computational tractability. Through validation across multiple experimental datasets and species, our model not only outperforms existing approaches but also reveals key drivers of variability in spindle responses, offering new insights into proprioceptive mechanisms.

Converging effects of cannabis and psychosis on the dopamine system: A longitudinal neuromelanin-sensitive MRI study in cannabis use disorder and first episode schizophrenia.
Importance: Despite evidence that individuals who use cannabis early in life are at elevated risk of psychosis and that the neurotransmitter dopamine has a role in both conditions, the mechanism linking the two conditions remains unclear. Objective: To use neuromelanin-sensitive MRI (neuromelanin-MRI), a practical, proxy measure of dopamine function, to assess whether a common alteration in the dopamine system may be implicated in cannabis use and psychosis and whether this alteration can be observed in cannabis users whether or not they have a diagnosis of first-episode schizophrenia. Design, Setting, and Participants: This longitudinal observational study recruited participants from 2019 to 2023 from an early intervention service for psychosis in London, Ontario, Canada. The sample consisted of 25 participants with cannabis use disorder (CUD) and 36 participants without CUD (nCUD), of which 28 had first-episode schizophrenia (FES). One-year follow-up was completed for 12 CUD and 25 nCUD participants. Main Outcomes and Measures: Neuromelanin-MRI contrast within the substantia nigra (SN) and within a subregion previously linked to psychosis severity (a priori psychosis region of interest) and diagnoses of schizophrenia-spectrum disorder and cannabis use disorder derived from the Structured Clinical Interview for DSM-5. Linear mixed effects analyses were performed relating neuromelanin-MRI contrast to clinical measures. Results: We found that CUD was associated with elevated neuromelanin-MRI signal in a cluster of ventral SN voxels (387 of 2060 SN voxels, pcorrected=0.027, permutation test). Furthermore, CUD was associated with elevated neuromelanin-MRI signal in an SN subregion previously documented to have elevated signal in relation to untreated psychotic symptoms (t92 =2.12, p=0.037). In contrast, FES was not associated with a significant alteration in neuromelanin-MRI signal (241 SN voxels had elevated signal, pcorrected=0.094). Conclusions and Relevance: These findings suggest that elevated dopamine function in a critical SN subregion may contribute to the risk of psychosis in people with CUD. Thus, cannabis affects the long-suspected 'final common pathway' for the clinical expression of psychotic symptoms. Imaging the dopamine system with neuromelanin-MRI may index long-term dopamine turnover.

Practice Reshapes the Geometry and Dynamics of Task-tailored Representations
Extensive practice makes task performance more efficient and precise, leading to automaticity. However, theories of automaticity differ on which levels of task representations (e.g., low-level features, stimulus-response mappings, or high-level conjunctive memories of individual events) change with practice, despite predicting the same pattern of improvement (e.g., power law of practice). To resolve this controversy, we built on recent theoretical advances in understanding computations through neural population dynamics. Specifically, we hypothesized that practice optimizes the neural representational geometry of task representations to minimally separate the highest- level task contingencies needed for successful performance. This involves efficiently reaching conjunctive neural states that integrate task-critical features nonlinearly while abstracting over non-critical dimensions. To test this hypothesis, human participants (n = 40) engaged in extensive practice of a simple, context-dependent action selection task over 3 days while recording EEG. During initial rapid improvement in task performance, representations of the highest-level, context-specific conjunctions of task- features were enhanced as a function of the number of successful episodes. Crucially, only enhancement of these conjunctive representations, and not lower-order representations, predicted the power-law improvement in performance. Simultaneously, over sessions, these conjunctive neural states became more stable earlier in time and more aligned, abstracting over redundant task features, which correlated with offline performance gain in reducing switch costs. Thus, practice optimizes the dynamic representational geometry as task-tailored neural states that minimally tesselate the task space, taming their high-dimensionality.

Phase-Dependent Stimulation of the Hippocampus: A Computational Modeling Approach
Phase-amplitude coupling (PAC) between brain oscillations of different frequencies plays a fundamental role in neural processing, and phase-dependent neuromodulation has emerged as a promising strategy to modulate PAC. In the hippocampus, theta-gamma PAC is critically involved in memory-related functions and information propagation. Computational models provide a valuable platform for investigating the neurobiological mechanisms underlying phase-dependent effects, bypassing the limitations of in vivo and in vitro experiments. In this study, we extended a previously published computational model of the hippocampal CA3 region using the NEURON and Python environments. A closed-loop autoregressive (AR) forward prediction model was employed to sample the network's local field potential (LFP) in real time, enabling the precise calculation of phase-locked stimulus time points. Our results demonstrated the successful delivery of phase-locked current injections to all neuronal populations at both the peak and trough of theta oscillations. Phase-specific alterations in the theta band were observed during stimulation, along with enhanced theta-gamma coupling induced by peak-phase stimulation. Single neuron activity analysis highlighted the critical role of oriens lacunosum-moleculare (OLM) cells in modulating phase-dependent network dynamics. These findings underscore the potential of closed-loop stimulation systems to modulate PAC, with significant implications for the treatment of neurological disorders characterized by abnormal oscillatory activity, such as Alzheimer's disease and other memory-related disorders.

A brainstem circuit controls cough-like airway defensive behaviors in mice
The respiratory tract is subject to complex neural control for eupneic breathing and distinct airway defensive reflexes. Growing evidence has revealed a large heterogeneity of airway-innervating vagal sensory neurons in mediating various respiratory functions, but the central neuronal pathways and neural circuits involved in the airway regulation remain less understood. Combining whole-body plethysmography (WBP), audio, and video tracking to access breathing and airway defensive behaviors in conscious animals, we developed a quantitative paradigm implementing the mouse as a suitable model to study cough-like defensive behaviors. Using TRAP2 transgenic mice and in vivo fiber photometry, we found that the neural activity in the caudal spinal trigeminal nucleus (SP5C) is strongly correlated with tussigen-evoked cough-like responses. Impairing synaptic outputs or chemogenetic inhibition of the SP5C effectively abolished cough-like reflexes. Optogenetic stimulation of SP5C excitatory neurons or their projections to the rostral ventral respiratory group (rVRG) triggered robust cough-like behaviors in the absence of tussive stimuli. Remarkably, tonic elevation of SP5C excitability caused spontaneous cough-like activities chronically in mice. Together, our data provide strong evidence for a brainstem circuit controlling cough-like defensive behaviors in mice.

Attentional Information Routing in The Human Brain
Brain-wide communication supports behaviors that require coordination between sensory and associative regions. However, how large-scale brain networks route sensory information at fast timescales to guide upcoming actions remains unclear. Using spiking neural networks and human intracranial electrophysiology during spatial attention tasks, where participants detected a target at cued locations, we show that high-frequency activity bursts (HFAb) serve as information-carrying events, facilitating fast and long-range communications. HFAbs emerged as bouts of neural population spiking and were coordinated brain-wide through low-frequency rhythms. At the network-level, HFAb coordination identified distinct cue- and target-activated subnetworks. HFAbs following the cue onset in cue-subnetworks predicted successful target detection and preceded the information in target-subnetworks following target onset. Our findings suggest HFAbs as a neural mechanism for fast brain-wide information routing that supports attentional performance.

Sleep-wake states are encoded across emotion-regulation regions of the mouse brain
Emotional dysregulation is highly comorbid with sleep disturbances. Sleep is comprised of unique physiological states that are reflected by conserved brain oscillations. Though the role of these state-dependent oscillations in cognitive function has been well established, less is known regarding the nature of state-dependent oscillations across brain regions that strongly contribute to emotional function. To characterize these dynamics, we recorded local field potentials simultaneously from multiple cortical and subcortical regions implicated in sleep and emotion-regulation and characterize widespread patterns of spectral power and synchrony between brain regions during sleep/wake states. First, we showed that these brain regions encode sleep state, albeit to various degrees of accuracy. We then identified network-based classifiers of sleep based on the combination of features from all recorded brain regions. Spectral power and synchrony from brain networks allowed for automatic, accurate and rapid discrimination of wake, non-REM sleep (NREM) and rapid eye movement (REM) sleep. When we examined the impact of commonly prescribed sleep promoting medications on neural dynamics across these regions, we found disparate alterations to both cortical and subcortical activity across all three states. Finally, a we found that a stress manipulation that disrupts circadian rhythm produced increased sleep fragmentation without altering the underlying average brain dynamics across sleep-wake states. Thus, we characterized state dependent brain dynamics across regions canonically associated with emotions.

Evaluating and Comparing Measures of Aperiodic Neural Activity
Neuro-electrophysiological recordings contain prominent aperiodic activity - meaning irregular activity, with no characteristic frequency - which has variously been referred to as 1/f (or 1/f-like activity), fractal, or 'scale-free' activity. Previous work has established that aperiodic features of neural activity is dynamic and variable, relating (between subjects) to healthy aging and to clinical diagnoses, and also (within subjects) tracking conscious states and behavioral performance. There are, however, a wide variety of conceptual frameworks and associated methods for the analyses and interpretation of aperiodic activity - for example, time domain measures such as the autocorrelation, fractal measures, and/or various complexity and entropy measures, as well as measures of the aperiodic exponent in the frequency domain. There is a lack of clear understanding of how these different measures relate to each other and to what extent they reflect the same or different properties of the data, which makes it difficult to synthesize results across approaches and complicates our overall understanding of the properties, biological significance, and demographic, clinical, and behavioral correlates of aperiodic neural activity. To address this problem, in this project we systematically survey the different approaches for measuring aperiodic neural activity, starting with an automated literature analysis to curate a collection of the most common methods. We then evaluate and compare these methods, using statistically representative time series simulations. In doing so, we establish consistent relationships between the measures, showing that much of what they capture reflects shared variance - though with some notable idiosyncrasies. Broadly, frequency domain methods are more specific to aperiodic features of the data, whereas time domain measures are more impacted by oscillatory activity. We extend this analysis by applying the measures to a series of empirical EEG and iEEG datasets, replicating the simulation results. We conclude by summarizing the relationships between the multiple methods, emphasizing opportunities for re-examining previous findings and for future work.

Exploiting correlations across trials and behavioral sessions to improve neural decoding
Traditional neural decoders model the relationship between neural activity and behavior within individual trials of a single experimental session, neglecting correlations across trials and sessions. However, animals exhibit similar neural activities when performing the same behavioral task, and their behaviors are influenced by past experiences from previous trials. To exploit these informative correlations in large datasets, we introduce two complementary models: a multi-session reduced-rank model that shares similar behaviorally-relevant statistical structure in neural activity across sessions to improve decoding, and a multi-session state-space model that shares similar behavioral statistical structure across trials and sessions. Applied across 433 sessions spanning 270 brain regions in the International Brain Laboratory public mouse Neuropixels dataset, our decoders demonstrate improved decoding accuracy for four distinct behaviors compared to traditional approaches. Unlike existing deep learning approaches, our models are interpretable and efficient, uncovering latent behavioral dynamics that govern animal decision-making, quantifying single-neuron contributions to decoding behaviors, and identifying different activation timescales of neural activity across the brain.

Spinal and cortical premotor control of primate dexterous hand movements
Skilled hand movements are an evolutionary advance in primates. Phylogenetically distinct corticospinal pathways are involved in hand control: "newer" direct corticomotoneuronal (CM) pathways and "older" indirect corticospinal pathways mediated by spinal premotor interneurons (PreM-INs). However, the functional differences of these pathways remain unclear. Here we show that CM cells and PreM-INs have distinct physiological properties for the activation of hand muscles and provide different types of movement control signals while monkeys perform a precision grip task. Spike-triggered averaging of electromyographic activity indicated that PreM-INs coactivate a larger number of muscles, whereas CM cells more selectively control fewer muscles. The firing activity of PreM-INs was tightly correlated with their target muscle activity and had a greater contribution to generating hand muscle activity. In contrast, CM cell activity diverged temporally from the target muscle activity and had a smaller contribution to its generation. On the basis of these results, we hypothesize that PreM-INs produce gross muscle activity by activating synergistic muscles, whereas CM cells fine-tune target muscle activity. This idea was supported by dimensional reduction analyses of hand muscle activity, as PreM-IN activity was specifically correlated with lower dimensional control of muscle activity, and CM cell activity was correlated with higher dimensional control. These results indicate that the two pathways have distinct functions, synergistic control and fine tuning of hand muscle activity, both of which are essential for the development of dexterous hand movement in primates.

Spike Count Analysis for MultiPlexing Inference (SCAMPI)
Understanding how neurons encode multiple simultaneous stimuli is a fundamental question in neuroscience. We have previously introduced a novel theory of stochastic encoding patterns wherein a neuron's spiking activity dynamically switches among its constituent single-stimulus activity patterns when presented with multiple stimuli (Groh et al., 2024). Here, we present an enhanced, comprehensive statistical testing framework for such "multiplexing" or "code juggling". Our new approach evaluates whether dual-stimulus responses can be accounted for as mixtures of Poissons either anchored to or bounded by single-stimulus benchmarks. Our enhanced framework improves upon previous methods in two key ways. First, it introduces a stronger set of foils for multiplexing, including an "overreaching" category that captures overdispersed activity patterns unrelated to the single-stimulus benchmarks, reducing false detection of multiplexing/code-juggling. Second, it detects faster fluctuations - i.e. at sub-trial timescales - that would have been overlooked before. We utilize a Bayesian inference framework, considering the hypothesis with the highest posterior probability as the winner, and employ predictive recursion marginal likelihood method for the involving nonparametric density estimation. Reanalysis of previous findings confirms the general observation of "code juggling" and indicates that such juggling may well occur on faster timescales than previously suggested. We further confirm that juggling is more prevalent in (a) the inferotemporal face patch system for combinations of face stimuli than for faces and non-face objects; and (b) the primary visual cortex for distinct vs fused objects.

Connectomic analysis of taste circuits in Drosophila
Our sense of taste is critical for regulating food consumption. The fruit fly Drosophila represents a highly tractable model to investigate mechanisms of taste processing, but taste circuits beyond sensory neurons are largely unidentified. Here, we use a whole-brain connectome to investigate the organization of Drosophila taste circuits. We trace pathways from four populations of sensory neurons that detect different taste modalities and project to the subesophageal zone (SEZ). We find that second-order taste neurons are primarily located within the SEZ and largely segregated by taste modality, whereas third-order neurons have more projections outside the SEZ and more overlap between modalities. Taste projections out of the SEZ innervate regions implicated in feeding, olfactory processing, and learning. We characterize interconnections between taste pathways, identify modality-dependent differences in taste neuron properties, and use computational simulations to relate connectivity to predicted activity. These studies provide insight into the architecture of Drosophila taste circuits.

Comparative study on the effects of different types of acute exercise on cortisol levels and cognitive functions
This study examines the different effects of dual-task and single-task exercises on cortisol levels and cognitive performance. Seventeen male college students participated, performing each exercise on separate days. Salivary samples were taken before and after exercise to assess cortisol levels. Cognitive functions were measured using the 2-Back Test, Bells Test, and Mental Rotation Test. Results showed that both exercises significantly improved reaction times across cognitive tests. However, dual-task exercise caused a more notable increase in cortisol levels (p=0.002) than the single-task. A negative correlation between post-exercise cortisol levels and reaction times suggests that higher cortisol levels might enhance cognitive processing speed. Cognitive performance ac-curacy remained unchanged across both exercises. These findings indicate that while both exercise types enhance cognitive speed, dual-task exercise triggers a greater cortisol response, potentially offering more benefits for cognitive processing speed without affecting accuracy. This research highlights the complex interaction between acute exercise, stress hormones, and cognitive function, providing insights into how different exercise types influence cognitive performance through hormonal pathways.