bioRxiv Subject Collection: Neuroscience's Journal

The effect of task demand on EEG responses to irrelevant sound and speech in simulated surgical environments.
Complex soundscapes in high-stakes environments, such as the operating room (OR), are characterized by a variety of overlapping auditory stimuli and present significant challenges for personnel, particularly during periods of high demand. This study investigates how task demand and an OR soundscape including irrelevant speech, influence perceived workload, surgical performance, and auditory processing in a simulated surgical environment, using mobile electroencephalography (EEG). Participants performed two simulated surgical tasks, namely peg transfer and suturing, representing a low-demand and high-demand task, respectively. The tasks were performed under two sound conditions: An OR soundscape was presented with irrelevant speech or alone. Neural responses to transient and continuous auditory stimuli were analyzed using event-related potentials (ERPs) and temporal response functions (TRFs), respectively. Results showed that irrelevant speech increased self-reported workload and distraction. EEG analyses revealed reduced neural responses to transient sounds and irrelevant speech under high task demand, reflecting early-stage sensory filtering of auditory distractions. Notably, an inverse relationship was observed between neural responses to speech and self-reported workload, indicating that the speech responses may serve as a marker for perceived workload. Overall, this study demonstrates the potential of EEG to assess irrelevant sound processing in realistic work-like settings and highlights the critical role of task demand in modulating neural responses and self-reported workload to soundscapes.

Body movement perception is shaped by both generic and actor-specific models of human bodies
Body movement perception is shaped by knowledge of the human body biomechanics. Apparent motion elicited by rapidly alternating pictures follows the shortest path between two body postures only if it is biomechanically plausible. And although we tend to perceive the location of a moving body part as slightly shifted forward along its trajectory, this perceptual extrapolation is absent or reduced if the movement would have been unlikely to continue along the same trajectory because of the body biomechanical constraints. The received view is that perception is shaped by a model of the observer's own body. Here, we report three lines of evidence suggesting otherwise. In Experiments 1 and 2, we report the typical influence of knowledge of the upper limb biomechanics on apparent movement perception and perceptual extrapolation in two individuals born completely without upper and lower limbs. In Experiment 3, we report that we failed to find evidence that observers' own biomechanics influence perceptual extrapolation of body movements. And in Experiments 4 to 8, we show that participants' perception is influenced by their knowledge of actor specific biomechanics. We conclude that body movement perception is shaped by visually acquired models of both generic and actor-specific body biomechanics.

Parietal alpha frequency shapes own-body perception by modulating the temporal integration of bodily signals
An influential proposal in the field of cognitive neuroscience suggests that alpha-frequency brain oscillations constrain the temporal sampling of external sensory signals, shaping the temporal binding window (TBW), the interval during which sensory signals are integrated. However, whether alpha frequency modulates the integration of self-related sensory signals and the perception of the body as one's own (body ownership) remains unknown. Here, we demonstrate that individual alpha frequency (IAF) from the parietal cortex predicted TBWs and perceptual sensitivities in body ownership and visuotactile simultaneity judgment tasks, with faster frequencies narrowing TBWs and increasing sensitivities, and vice versa. Modulating IAF through brain stimulation altered TBWs and sensitivities, establishing a causal relationship. Computational modeling linked IAF to uncertainty in asynchrony information within the causal inference process, providing a mechanism. These findings demonstrate that parietal alpha frequency shapes the sense of body ownership by modulating the temporal integration of bodily sensory signals.

Therapeutic assessment of a novel mitochondrial complex I inhibitor in in vitro and in vivo models of Alzheimer's disease
Despite recent approval of monoclonal antibodies that reduce amyloid (A{beta}) accumulation, the development of disease-modifying strategies targeting the underlying mechanisms of Alzheimer's disease (AD) is urgently needed. We demonstrate that mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signaling, benefiting AD mouse models with A{beta} and p-Tau pathologies. Rational design and structure-activity relationship studies yielded novel mtCI inhibitors profiled in a drug discovery funnel designed to address their safety, selectivity, and efficacy. The new lead compound C458 is highly protective against A{beta} toxicity, has favorable pharmacokinetics, and has minimal off-target effects. C458 exhibited excellent brain penetrance, activating neuroprotective pathways with a single dose. Preclinical studies in APP/PS1 mice were conducted via functional tests, metabolic assessment, in vivo 31P-NMR spectroscopy, blood cytokine panels, ex vivo electrophysiology, and Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis, antioxidant signaling, and cellular energetics. These studies provide further evidence that the restoration of mitochondrial function and brain energetics in response to mild energetic stress represents a promising disease-modifying strategy for AD.

DynamoSort: Using machine learning approaches for the automatic classification of seizure dynamotypes
Objective: Epilepsy is characterised by unprovoked and recurring seizures, which can be electrically measured using electroencephalograms (EEG). To better understand the underlying mechanisms of seizures, researchers are exploring their temporal dynamics through the lens of dynamical systems modelling. Seizure initiation and termination patterns of spiking amplitude and frequency can be sorted into "dynamotypes", which may be able to serve as biomarkers for intervention. However, manual classification of these dynamotypes requires trained raters and is prone to variability. To address this, we developed DynamoSort, a machine-learning algorithm for automatic seizure onset and offset classification. Methods: We used approximately 2100 seizures from an intra-amygdala kainic acid (IAK) mouse model of mesial temporal lobe epilepsy, categorized by five trained raters. MATLAB's classification learner application was used to create an ensemble model to score and label dynamotypes of individual seizures based on spiking and frequency features. Results: Dynamotype classification of real EEG data lacks a definitive ground truth, with mean inter-rater agreement at 73.4% for onset and 64.2% for offset types. Despite this, DynamoSort achieved a mean area under the curve (AUC) of 0.81 for onset and a mean AUC of 0.75 for offset types. Machine-human agreement was not significantly different from human-to-human agreement. To address the lack of ground truth in ratings, DynamoSort assigns probabilistic scores (-20 to 20), to indicate similarity to each seizure dynamotype based on spiking features, allowing for a characterization of seizure dynamics on a spectrum rather than the traditional qualitative taxonomy. Significance: Automating the classification of dynamotypes is a critical step for their inclusion as a biomarker in clinical and research applications. DynamoSort is a straightforward, open-access tool that uses automatic labelling and probabilistic scoring to quantify subtle changes in seizure onset and offset dynamics.

Combined Transplantation of Mesenchymal Progenitor and Neural Stem Cells to repair cervical spinal cord injury.
Mesenchymal progenitor cells (MPC) are effective in reducing tissue loss, preserving white matter and improving forelimb function after spinal cord injury (SCI) (White et al., 2016). We proposed that by preconditioning the mouse by intravenous delivery (IV) of MPCs for 24 hours following SCI that this would provide a more favorable tissue milieu for NSC intraspinal bridging transplantation at day 3 and day 7. In com-bination these transplants will provide better anatomical and functional outcomes. The intravenous MSCs would provide cell protection and reduce inflammation. NSCs would provide a tissue bridge for axonal regeneration and myelination and reconnect long tract spinal pathways. Results showed that initial protection of the injury site by IV MPCs transplantation resulted in no increased survival of the NSCs transplanted at Day 7. However, integration of transplanted NSCs was increased at the Day 3 time point indicating MPCs influence very early immune signaling. We show in this study that MPC transplantation resulted in a co-operative NSC cell survival improvement at Day 3 post SCI. In addition to increased NSC survival at day 3 there was an increase in NSC derived mature oligodendrocytes at this early time point. In vitro analysis confirmed MPC driven oligodendrocyte differentiation which was statistically increased when compared to control NSC only cultures. These observations provide important information about the combination, delivery, and timing of two cellular therapies in treating SCI. This study provides important new data on understanding the MPC inflammatory signaling within the host tissue and time points for cellular transplantation survival and oligodendroglia differentiation. These results demonstrate that MPC transplantation can alter the therapeutic window for intraspinal transplantation by controlling both the circulating inflammatory response and local tissue milieu.

Tuning of Task-Relevant Stiffness in Multiple Directions
The dynamics of any mechanical system can be described in terms of forces and motions. The interaction of these terms is often captured in the metric of mechanical impedance - a generalization of stiffness - used to describe how a mechanical system resists the application of force. The ability to adaptively change impedance is advantageous when encountering variable environmental conditions. Changing impedance in robotic systems is limited, whereas humans can rapidly and elegantly adapt the impedance of their limbs, especially during initial contact with objects. This is especially true for movements of our arms and hands. Multiple studies have examined the arm's response to perturbation with the idea of impedance as a reactive component. In this study, we investigate the ability of humans to predictively set their arm impedance in a contact breaking task to perform fast movements to target positions in different directions. Our findings show that subjects (n=20) predictively co-activate antagonist muscles to primarily adjust one component of the arm's impedance - stiffness - to match different task constraints before the movement begins irrespective of movement direction. Interestingly, the subjects' performance was limited by the task-dependent stiffness rather than the required force and they tended to generate minimal stiffness to perform the task. With this robust strategy, task success is optimized at the expense of energy efficiency. This type of control is essential for the uniquely human ability to interact with objects.

Synaptotoxic forms of amyloid-b and a-synuclein act through a common pathway.
It has been suggested that a-synuclein (aSyn), a major player in Parkinson's disease (PD), plays a role in Alzheimer's disease (AD). Several reports have also concluded that aSyn and amyloid-beta (Ab) are mechanistically linked, although how is unclear. Synapse loss is an early feature in both PD and AD and held to be the driver of both diseases. We have previously uncovered a signalling pathway required for Ab-driven dendritic spine loss - a non-canonical branch of Wnt signalling known as the Wnt/Planar Cell Polarity (Wnt/PCP) pathway. We asked if a synaptotoxic form of aSyn known to impact dendritic spines, the A53T autosomal dominant PD mutant form of aSyn (A53T-aSyn), might act on synapses through the same pathway. Here, by blocking all Wnt activity with the porcupine inhibitor IWP2, we show that A53T-aSyn driven spine loss is Wnt-dependent. By silencing Daam1, which is unique to Wnt/PCP, we show that A53T-aSyn spine loss is Daam1-dependent. Finally, using the pan-ROCK inhibitor fasudil indicates the mechanism also involves ROCK1/2, which Daam1 signals to via RhoA to modulate actin cytoskeletal dynamics within dendritic spines. Together, these observations indicate that A53T-aSyn-driven spine loss involves the Wnt/PCP pathway, the same pathway that mediates Ab synaptotoxicity. This indicates that Ab and aSyn are mechanistically connected and that a common pathway is responsible for synapse loss in AD and PD. It also begins to explain why this group of neurodegenerative diseases have many features in common and suggests that drugs which target Wnt/PCP could be of benefit for both AD and PD.

Delayed transplantation of neural stem cells improves initial graft survival following stroke
Neural stem cell therapies hold great promise for improving stroke recovery, but the hostile stroke microenvironment can hinder the initial graft survival. It has long been well documented that the microenvironment evolves over time, making it crucial to identify the optimal transplantation window to maximize therapeutic efficacy. However, it remains uncertain whether acute or delayed local cell transplantations better supports graft viability after stroke. Here, we show that delayed intracerebral transplantation of neural progenitor cells (NPCs) derived from human induced pluripotent cells (iPSCs) at 7 days post stroke significantly enhances graft proliferation and survival, compared to acute transplantation at 1 day post stroke, in a mouse model of large cortical stroke. Using in vivo bioluminescence imaging over a 6-week period post-transplantation, we observe a more than 5-fold increase in bioluminescence signal in mice that received delayed NPC therapy, compared to those that underwent acute NPC transplantation. The increased number of cell grafts in mice receiving delayed NPC transplantation was driven by increased proliferation rates early after transplantation, which subsequently declined to similarly low levels in both groups. Notably, we found that the majority of transplanted NPCs differentiated into neurons after 6 weeks, with no significant differences in the neuron-to-glia ratio between acute and delayed transplantation groups. These findings suggest that delayed NPC transplantation improves early graft survival and proliferation, which could help identify the optimal therapeutic window for maximizing the effectiveness of NPC-based therapies in stroke.

The 5-HT1F Receptor Agonist Lasmiditan improves Cognition and Ameliorates Associated Cortico-Hippocampal Pathology in Aging Parkinsonian Mice
While the etiopathology of Parkinsons disease (PD) is complex, mitochondrial dysfunction is established to have a central role. Thus, mitochondria have emerged as targets of therapeutic interventions aiming to slow or modify PD progression. We have previously identified serotonergic 5-HT1F receptors as novel mediators of mitochondrial biogenesis (MB) - the process of producing new mitochondria. Given this, here, we assessed the therapeutic potential of the FDA-approved 5-HT1F receptor agonist, lasmiditan, in a chronic progressive PD model (Thy1-aSyn line 61 mice). It was observed that systemic lasmiditan exhibited robust brain penetration and reversed cognitive deficits in young (4-5.5 months old) Thy1-aSyn mice (1mg/kg, every other day). Anxiety-like behavior was also improved while motor function remained unaffected. These behavioral changes were associated with enhanced MB and mitochondrial function, paired with reduced alpha-synuclein aggregation particularly in cortico-hippocampal regions. Furthermore, in older (10-11.5 months old) mice, although the effects were milder, daily lasmiditan administration increased MB and bettered cognitive abilities. In essence, these findings indicate that repurposing lasmiditan could be a potent strategy to address PD-related cognitive decline.

Reversable Acute Sedation Response of Phosphorothioate Antisense Oligonucleotides Following Local Delivery to the Central Nervous System
Antisense oligonucleotides (ASOs) locally delivered to the central nervous system (CNS) are being approved as therapies for neurological diseases. After intrathecal injection of some ASOs, transient toxicities have been reported, but considerable inconsistencies remain in classifying them and their underlying mechanisms. Here, we characterize an acute sedation response that can include loss of lower spinal reflexes, hypoactivity, paresis, sedation and ataxia, peaking ~3 hours post-intrathecal injection of some phosphorothioate ASOs and reversing by 24 hours with no sequelae. Acute sedation is distinct from acute activation, which is hyperactivity and muscle cramping that occurs immediately after administering oligonucleotides. Acute sedation translates across species from rodents to non-human primates and is sequence-, dose-, and chemistry dependent. Acute sedation can be mitigated by strategic placement of phosphorothioate backbone linkages in ASOs and by avoiding G-rich sequences. The acute sedation response can be modeled in primary neural cultures, with good predictability of in vivo response. Mechanistically, we demonstrate that acute sedation is caused by high extracellular ASO concentrations inhibiting synaptic transmission, which reverses as ASO is cleared from the extracellular space and taken up into cells. Our results provide a comprehensive framework for quantifying and mitigating acute sedation caused by some phosphorothioate ASOs.

AAV-mediated peripheral single chain variable fragments administration to reduce cerebral tau in adult P301S transgenic mice: mono- vs combination therapy
Tau is a primary target for immunotherapy in Alzheimers disease. Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels in vitro and in vivo. Here, we compared the effects of single-chain variable fragments (scFv) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used adeno-associated virus 1 (AAV1) to deliver scFvs to skeletal muscle cells in eight-week-old P301S tau transgenic mice. We evaluated motor and behavioral functions at 16 and 23 weeks of age and measured misfolded, soluble, oligomeric and insoluble brain tau species. Monotherapy with scFv-MC1 improved motor and behavioral functions more effectively than scFv-PHF1 or combination therapy. Brain glucose metabolism also benefited from scFv-MC1 treatment. Surprisingly, combining scFvs targeting early (MC1) and late (PHF1) tau modifications did not produce additive or synergistic effects. These results confirm that intramuscular AAV1-mediated scFv-MC1 gene therapy holds promise as a potential treatment for Alzheimers disease. Our findings also suggest that combining scFvs targeting different tau epitopes may not necessarily enhance efficacy if administered together in a prevention paradigm. Further research is needed to explore whether other antibodies combinations and/or administration schedules could improve the efficacy of scFv-MC1 alone.

Graphical abstract/eTOC synopsisKatel and colleagues show that peripheral vectorized scFvMC1 (in monotherapy) reduces pathological tau species in tau transgenic mice more efficiently than in combination with scFv-PHF1. The authors observed improved motor and behavioral functions together with increased brain glucose metabolism in scFv-MC1-treated mice.

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Shared brain basis of aggression in clinical, forensic, and healthy samples: A meta-analysis
BackgroundAggression, violence, and antisocial behaviour constitute a large-scale societal problem. Aggression is common in incarcerated offenders and psychiatric conditions, but also healthy and noninstitutionalized populations vary in violent and aggressive behaviour. The brain basis of aggression has been studied extensively in the past, but the similarities between criminal, pathological and everyday aggression in the brain remain elusive.

MethodsWe conducted an activation likelihood estimation (ALE) meta-analysis of 406 neuroimaging studies with 28 968 subjects using structural magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and single photon emission tomography (SPECT). The included studies had either i) measured haemodynamic responses during aggression-related functional tasks, ii) compared the brain structure, molecular organization, or function between aggressive forensic and psychiatric populations and control groups, or iii) addressed the effects of trait aggression on brain structure or function.

ResultsAggression was consistently associated with altered function and structure in the amygdala, hippocampus, basal ganglia, anterior cingulate cortex, and the dorsolateral and orbitofrontal cortices. Functional coactivation analysis suggested that these regions are most consistently associated with emotional and reward function as well as their regulation. The results were comparable in healthy subjects as well as forensic and psychiatric populations.

ConclusionsAggression is linked with alterations in multiple neurocognitive systems forming a common network for aggressiveness. Particularly the neural systems implicated in reward, emotions and regulation were commonly associated with aggression. The established network is involved in the whole continuum of aggression from benign variations in healthy volunteers to forensic subjects and violent clinical populations, suggesting a common aggression network whose severe perturbations may be linked with criminal behaviour or pathological aggression.

Timing matters: modeling the effects of gestational cannabis exposure on social behavior and microglia in the developing amygdala
Cannabis is the most frequently used illicit drug during pregnancy, with use steadily increasing in the United States as legalization and decriminalization expand to more states. Many pregnant individuals use cannabis to reduce adverse symptoms of pregnancy, considering it to be less harmful than other pharmaceuticals or alcohol. The primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), acts on the endocannabinoid (eCB) system, yet whether it perturbs neural development of the fetus is poorly understood. Previously we have shown that androgen mediated eCB tone in the developing amygdala promotes microglial phagocytosis of newborn astrocytes which has enduring consequences on the neural circuits regulating sex differences in social behavior. Microglia are the resident immune cells of the brain and express both receptors of the eCB system, CB1R and CB2R, making them likely targets of modulation by THC. It is also plausible that exposure to THC at differing gestational timepoints can result in distinct outcomes, as is the case with alcohol exposure. To model human cannabis use during either late or early pregnancy, we exposed rodents to THC either directly during the early postnatal period via intraperitoneal (IP) injection or in utero during the prenatal period via dam IP injection respectively. Here we show that postnatal THC exposure results in sex specific changes in microglial phagocytosis during development as well as social behavior during the juvenile period. Interestingly prenatal exposure to THC resulted in inverse changes to phagocytosis and social behavior. These findings highlight the differential effects of THC exposure across gestation.

Comparative molecular landscapes of immature neurons in the mammalian dentate gyrus across species reveal special features in humans
Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity, learning and memory, but their evolutionary changes across species and specialized features in humans remain poorly understood. Here we performed machine learning-augmented analysis of published single-cell RNA-sequencing datasets and identified macaque imGCs with transcriptome-wide immature neuronal characteristics. Our cross-species comparisons among humans, monkeys, pigs, and mice showed few shared (such as DPYSL5), but mostly species-specific gene expression in imGCs that converged onto common biological processes regulating neuronal development. We further identified human-specific transcriptomic features of imGCs and demonstrated functional roles of human imGC-enriched expression of a family of proton-transporting vacuolar-type ATPase subtypes in development of imGCs derived from human pluripotent stem cells. Our study reveals divergent gene expression patterns but convergent biological processes in the molecular characteristics of imGCs across species, highlighting the importance of conducting independent molecular and functional analyses for adult neurogenesis in different species.

Evidence for abstract codes in parietal cortex guiding prospective working memory
The recent past helps us predict and prepare for the near future. Such preparation relies on working memory (WM) which actively maintains and manipulates information providing a temporal bridge. Numerous studies have shown that recently presented visual stimuli can be decoded from fMRI signals in visual cortex (VC) and the intra-parietal sulcus (IPS) suggesting that these areas sustain the recent past. Yet, decoding concrete, sensory signals leaves open how past information is transformed into the abstract codes critical for guiding future cognition. Here, human participants used WM to maintain a separate spatial location in each hemifield wherein locations were embedded in a star-shaped sequence. On each trial, participants made a sequence-match decision to a spatial probe and then updated their WM with the probe. The same abstract star-shaped sequence guided judgments in each hemifield allowing us to separately track concrete spatial locations (hemifield-specific) and abstract sequence positions (hemifield-general), while also tracking representation of the past (last location/position) and future (next location/position). Consistent with previous reports, concrete past locations could be decoded from VC and IPS. Moreover, in anticipation of the probe, representations shifted from past to future locations in both areas. Critically, we observed abstract coding of future sequence positions in the IPS whose magnitude related to speeded performance. These data suggest that the IPS sustains abstract codes to facilitate future preparation and reveal the transformation of the sensory past into the abstract future.

Disentangling Rhythmic and Aperiodic Neural Activity: Investigating the Role of GABA Modulation in Sensorimotor Beta Oscillations
Beta oscillations (13-30 Hz) in the sensorimotor cortex are fundamental to motor control and are disrupted in motor disorders such as Parkinsons disease and stroke. Animal studies and pharmacological research in humans have implicated GABAergic mechanisms in modulating these oscillations. Here, we explored the impact of GABAergic modulation on sensorimotor beta oscillations using magnetoencephalography (MEG) during a finger abduction task, with participants administered gaboxadol and zolpidem, two GABA-A positive allosteric modulators. We combined traditional oscillatory analyses with spectral parametrisation methods to separate periodic and aperiodic neural components. Time-frequency representations (TFRs) showed that gaboxadol induced a stronger modulation of beta dynamics than zolpidem, leading to deeper beta desynchronisation during movement and a more pronounced post-movement beta rebound. When accounting for aperiodic activity, gaboxadol showed modest effects limited to movement initiation, with increased beta power during movement onset but no significant impact during post-movement rebound. In contrast, zolpidem significantly enhanced beta power and altered aperiodic components, suggesting differential influences on GABAergic modulation and excitation-inhibition balance. These results underscore the necessity of distinguishing between periodic and aperiodic signals in spectral measures to improve the interpretation of neural oscillatory data.

Single-cell multiomics of neuronal activation reveals context-dependent genetic control of brain disorders
Despite hundreds of genetic risk loci identified for neuropsychiatric disorders (NPD), most causal variants/genes remain unknown. A major hurdle is that disease risk variants may act in specific biological contexts, e.g., during neuronal activation, which is difficult to study in vivo at the population level. Here, we conducted a single-cell multiomics study of neuronal activation (stimulation) in human iPSC-induced excitatory and inhibitory neurons from 100 donors, and uncovered abundant neuronal stimulation-specific causal variants/genes for NPD. We surveyed NPD-relevant transcriptomic and epigenomic landscape of neuronal activation and identified thousands of genetic variants associated with activity-dependent gene expression (i.e., eQTL) and chromatin accessibility (i.e., caQTL). These caQTL explained considerably larger proportions of NPD heritability than the eQTL. Integrating the multiomic data with GWAS further revealed NPD risk variants/genes whose effects were only detected upon stimulation. Interestingly, multiple lines of evidence support a role of activity-dependent cholesterol metabolism in NPD. Our work highlights the power of cell stimulation to reveal context-dependent "hidden" genetic effects.

The Human Cerebello-Hippocampal Circuit Across Adulthood
Direct communication between the hippocampus and cerebellum has been shown via coactivation and synchronized neuronal oscillations in animal models. Further, this novel cerebello-hippocampal circuit may be impacted by sex steroid hormones. The cerebellum and hippocampus are dense with estradiol and progesterone receptors relative to other brain regions. Females experience up to a 90% decrease in ovarian estradiol production after the menopausal transition. Postmenopausal women show lower cerebello-cortical and intracerebellar FC compared to reproductive aged females. Sex hormones are established modulators of both memory function and synaptic organization in the hippocampus in non-human animal studies. However, investigation of the cerebello-hippocampal (CB-HP) circuit has been limited to animal studies and small homogeneous samples of young adults as it relates to spatial navigation. Here, we investigate the CB-HP circuit in 138 adult humans (53% female) from 35-86 years of age, to define its FC patterns, and investigate its associations with behavior, hormone levels, and sex differences therein. We established robust FC patterns between the CB and HP in this sample. We predicted and found negative relationships between age and CB-HP FC. As expected, estradiol levels exhibited positive relationships with CB-HP. We found lower CB-HP FC with higher levels of progesterone. We provide the first characterization of the CB-HP circuit across middle and older adulthood and demonstrate that connectivity is sensitive to sex steroid hormone levels. This work provides the first clear CB-HP circuit mapping in the human brain and serves as a foundation for future work in neurological and psychiatric diseases.

Astrocytic contribution to sensory hypersensitivity in a mouse model of fragile X syndrome
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a leading cause of autism spectrum disorder (ASD). FXS is caused by mutations in the fragile X messenger ribonucleoprotein gene 1 (FMR1), which result in complete or partial loss of expression of its protein product, fragile X messenger ribonucleoprotein (FMRP). Neuronal impairments in the absence of FMRP have been extensively characterized. However, much less is known about the impact that loss of FMRP has on the physiology and function of astrocytes and the implications for behavior. A common behavior exhibited by both FXS and ASD patients is hypersensitivity to sensory stimuli, but how astrocytes contribute to hypersensitivity in the context of FXS remains unknown. Using mice with astrocyte-specific reduction of Fmr1 (Fmr1 conditional KO (cKO)) and mice with astrocyte-specific expression of Fmr1 (Fmr1 cON), we demonstrated that reduction in astrocytic FMRP is sufficient but not necessary to confer susceptibility to audiogenic seizures, an indication of auditory hypersensitivity. In addition, reduction of astrocytic FMRP impacts neuronal activity, resulting in spontaneous seizures. Using a whisker stimulation assay, we found that reduction in astrocytic FMRP does not contribute to tactile hypersensitivity. Our results reveal that astrocytes lacking FMRP contribute to auditory hypersensitivity and spontaneous seizures.

Long-term offspring loss in lactating rats: Neurobiological and emotional consequences in a novel animal model
The maternal bond is a vital social connection that supports the survival and well-being of both the caregiver and offspring. Disruption of this bond, particularly following offspring loss, can result in profound trauma with long-lasting consequences. While considerable research has focused on the impact of maternal separation on offspring development, the biological effects of offspring loss on the mother remain largely unexplored. In this study, we examined the long-term effects of offspring loss on neuroplasticity, the oxytocin (OXT) and corticotropin-releasing factor (CRF) systems, and stress-coping behaviors in Sprague-Dawley rat mothers. We compared mothers that experienced one day of motherhood followed by 19 days of offspring loss, mothers that were with their pups throughout the 20 days, and naive virgin rats. Our results reveal that mothers who lost their pups expressed increased oxytocin receptor binding and decreased dendritic spine density in limbic brain regions, with no changes in estrogen receptor or calbindin cells. Additionally, separated mothers showed increased passive stress-coping behaviors in the forced swim test and elevated plasma corticosterone levels. Remarkably, the passive stress-coping behavior was rescued by central CRF receptor blockade but not by oxytocin treatment, suggesting that the CRF system plays a key role in the grieving process following offspring loss, and highlights the suitability of the rat model for studying maternal grief. This research provides insights into the complex neurobiology of grief, and suggests potential directions for future studies.

No Disconnection Syndrome after Near-Complete Callosotomy
Much of the sensory-motor processing in the human brain is lateralized to either hemisphere, with the corpus callosum integrating these distinct processes into a seemingly unified conscious experience. The corpus callosum is thought to be topographically organized, with different subregions along its anterior-to-posterior axis involved in integrating information across different sensory modalities and cognitive domains. In complete callosotomy patients, where the corpus callosum is fully severed, this integration is typically disrupted across these domains. But which types of inter-hemispheric integration can still be preserved with small posterior callosal remnants? We studied four callosotomy patients-three complete and one partial with approximately 1 cm of preserved splenium-using an array of lateralized visual, tactile, visuospatial, and language tasks. While complete callosotomy patients showed the expected behavioral disconnection effects-performing poorly on tasks requiring inter-hemispheric integration but well on intra-hemispheric ones-the partial callosotomy patient with a preserved portion of the splenium showed no disconnection effects across all tasks. The splenium is traditionally implicated in visual transfer, yet our findings show that minimal splenial preservation maintains functional integration across multiple perceptual and cognitive domains. This is at odds with the presumed topographical organization of the corpus callosum, suggesting a broader inter-hemispheric integrative capacity of the posterior callosal fibers. Structure-function relationships in brain networks are known to be complex and nonlinear-these findings provide novel insights into flexible structural mechanisms for inter-hemispheric communication enabling a variety of integrated behaviors.

Evidence of functional connectivity disruptions between auditory and non-auditory regions in adolescents living with HIV
Children with perinatally acquired HIV (CPHIV) exhibit hearing impairments and language delays despite combination antiretroviral therapy (cART). Efficient sound processing depends on the peripheral and central auditory systems (PAS, CAS), yet studies of HIV's effects have mainly focused on the PAS. Language processing also relies on interactions between CAS and non-auditory brain regions. This study used resting-state fMRI to map functional connectivity (FC) in 11-year-old CPHIV, focusing on CAS and its links to non-auditory regions, within a Bayesian framework. Graph theory analyzed regional network properties, and relationships between FC and neurocognitive outcomes were examined. We hypothesized that CPHIV would show disrupted FC within the CAS and between CAS and non-auditory regions, altered network properties, and links between these changes and neurocognitive outcomes. Findings revealed lower FC in the primary auditory cortex (PAC) of CPHIV, with disrupted connections between CAS regions (including the PAC) and non-auditory regions such as the hippocampus, lingual gyrus, and basal ganglia. Network analysis showed reduced nodal degree and efficiency in CAS regions like the cochlear nucleus/superior olivary complex and inferior colliculus. In CPHIV, associations between middle temporal and superior frontal nodal efficiency and working memory (delayed recall) were absent. These findings highlight CAS FC alterations and network disruptions in CPHIV, linking them to hearing and language impairments. They offer insights into how HIV affects auditory and broader brain function in this population.

Path integration impairments reveal early cognitive changes in Subjective Cognitive Decline
Path integration, the ability to track one's position using self-motion cues, is critically dependent on the grid cell network in the entorhinal cortex, a region vulnerable to early Alzheimer's disease pathology. In this study, we examined path integration performance in individuals with subjective cognitive decline (SCD), a group at increased risk for Alzheimer's disease, and healthy controls using an immersive virtual reality task. We developed a Bayesian computational model to decompose path integration errors into distinct components. SCD participants exhibited significantly higher path integration error, primarily driven by increased memory leak, while other modelling-derived error sources, such as velocity gain, sensory and reporting noise, remained comparable across groups. Our findings suggest that path integration deficits, specifically memory leak, may serve as an early marker of neurodegeneration in SCD and highlight the potential of self-motion-based navigation tasks for detecting pre-symptomatic Alzheimer's disease-related cognitive changes.