bioRxiv Subject Collection: Neuroscience's Journal

Neuronal signatures of successful one-shot memory in mid-level visual cortex
High-capacity, one-shot visual recognition memory challenges theories of learning and neural coding because it requires rapid, robust, and durable representations. Most studies have focused on the hippocampus and other higher areas. However, behavioral evidence demonstrating links between image properties and memorability and revealing image specificity of visual memory suggests an important role for mid-level visual cortex. We tested the hypothesis that area V4 contains signals that could support recognition memory. Our task increased difficulty, allowing comparisons of neuronal population responses on correct and error trials. We observed signatures of several proposed memory mechanisms including magnitude coding, repetition suppression, sparse coding, and population response consistency, but only sparse coding and population response consistency predicted behavior. Familiar images also evoked faster dynamics, consistent with pattern completion. These findings demonstrate that the building blocks of fast, high-capacity memory are present in mid-level sensory cortex, highlighting its role in distributed memory networks.

BET protein inhibitor JQ1 reduces inflammation and hippocampal amyloid-β level without altering Tau phosphorylation in LPS-challenged adult wild-type mice
Introduction A growing body of evidence highlights the role of infection and inflammation in the progression of Alzheimer's disease (AD). In this study, we aimed to analyze the impact of JQ1, an inhibitor of bromodomain and extraterminal domain (BET) proteins, which are key readers of the epigenetic acetylation code, on AD-related gene expression changes and biochemical alterations in the hippocampus during a lipopolysaccharide (LPS)-induced systemic inflammatory response in mice. Methods JQ1 and LPS were administered intraperitoneally to adult male wild-type C57BL/6J mice. Changes in selected general and brain-specific parameters were measured for up to 12 h. Results Our results demonstrated that inhibition of BET proteins reduced LPS-induced sickness behavior and time-dependent elevation of proinflammatory signaling. LPS did not significantly alter amyloid-{beta} (A{beta}) levels; however, a significant reduction in A{beta} load was observed in JQ1-treated animals overall, suggesting that BET proteins play a crucial role in regulating A{beta} levels in the brain. At the same time, JQ1 treatment did not affect LPS-induced increases in phospho-Tau levels. Discussion Our results suggest that inhibiting BET proteins, in addition to their anti-inflammatory action, may be an effective strategy for reducing A{beta} levels in the brain. However, a mechanistic explanation of this phenomenon requires further investigation.

Molecular deconstruction of the pre-Bötzinger Complex/Nucleus Ambiguus (preBötC/NA) region: cellular constituencies and transcriptional responses to repeated seizures in the rat hindbrain
Epilepsy affects millions worldwide, but a significant portion suffers from uncontrollable epilepsy. Repeated seizures have many consequences, including a high risk of post-ictal cardiorespiratory failure and Sudden Unexpected Death in Epilepsy (SUDEP). Major risk factors for SUDEP include biological sex in addition to the occurrence of generalized tonic-clonic seizures (GTCSs). How repeated seizures lead to cardiorespiratory dysfunction remains unknown. A key factor in many neurological diseases is neuroinflammation, predominantly mediated by microglia and astrocytes that become dysfunctional. Mechanistically, questions remain how they affect neuronal function in epilepsy and contribute to cardiorespiratory dysfunction and increased SUDEP risk. Previously, we have shown that repeated seizures in our novel rat model with genetic mutations in kcnj16, an inwardly rectifying K+ channel, in the Dahl salt sensitive rat (SSkcnj16-/-) led to increased neuroinflammation in key ventilatory regions at 3 and 5 days of seizures. Specifically, there was increased recruitment of various inflammatory mediators, increased recruitment of activated microglia, with improvement in post-ictal respiratory dysfunction and mortality with usage of anti-inflammatory agents. Here we tested the hypothesis that repeated seizures lead to differential neuroinflammatory activation after repeated seizures in CNS regions of ventilatory control. Male SSkcnj16-/- rats were subjected to 0 (Naive), 3, 7 or 10 days of seizure, and subsequently, the pre-Bötzinger Complex/Nucleus Ambiguus (preBötC/NA) was isolated and sent for nuclei isolation and sequencing. Seurat was utilized to filter and process the data, integrate across conditions and allow for differential gene expression (DEG) analysis. Afterwards, pathways enrichment analysis was performed allowing for determination of unique pathways recruited across cell types for each seizure condition. Overall, we were able to identify 18 unique cell types based on transcriptomic signatures, with 8 different neuronal populations, grouped based on Type 1, Type 2 or a mixed Type 1 & Type 2 genetic expression, indicating rhythm generation or pattern generation, respectively. We found that majority of the neuronal clusters were Type 1 or mixed type, indicating predominantly rhythmogenic neuronal populations. Importantly, these critical neuronal populations showed significant upregulation in various metabolic and neurological disease pathways at the 3 and 7 Day timepoints. Furthermore, we identified various glial cells, including microglia and astrocytes and saw increased recruitment in various Inflammatory pathways, Metabolic pathways and Chemokine related pathways after 3 and 7Days of seizures, confirming our previous results. Consequently, our results show for the first time, transcriptomic characterization of crucial rhythmogenic neuronal populations after repeated seizures and the changes that may underlie their dysfunction in SUDEP, mediated in part through the network change in upregulated inflammatory pathways in surrounding glial cells.

Oligodendrocyte progenitor cell responses to inflammatory demyelination with aging
Oligodendrocyte progenitor cells (OPCs) have the capacity to self-renew, differentiate into mature myelinating cells, and remyelinate the central nervous system in response to demyelination. Normal aging is associated with a reduction in the functional capacity of OPCs and induces distinct transcriptional signatures even in the absence of an autoimmune inflammatory demyelination insult. To determine how aging impacts the OPC response to an acute inflammatory insult comparable to a demyelinating event in multiple sclerosis (MS), we performed adoptive transfer of young myelin-reactive Th17 T cells into young and aged mice. Spinal cord OPC responses were quantified using lineage tracing and myelin sheath thickness was quantified using transmission electron microscopy. In the subacute phase 9-10 days after adoptive transfer, the density of both young and aged OPCs is enriched in spinal cord lesions compared to non-lesion white matter. After adoptive transfer, the density of aged OPCs is significantly higher than naive/non-adoptive transfer aged spinal cord. Differentiated oligodendrocytes (OLs) are relatively preserved within lesions of aged and young animals despite an overall reduction in OL density after adoptive transfer. While lineage tracing identified newly formed oligodendrocytes after adoptive transfer in both young and aged lesions, less oligodendrocyte differentiation was observed in aged animals. Despite the reduction of OPC differentiation in aged animals, there was no significant difference in the extent of remyelination observed for young and aged lesions. Aged OPCs rise to the challenge in response to a strong auto-immune attack, suggesting that compensatory strategies allow both young and aged OPCs to survive and remyelinate in the inflammatory environment. Identifying pathways that promote resilience of young and aged OPCs in the face of an inflammatory challenge will facilitate the development of remyelinating therapies for the treatment of people with MS across the full spectrum of human aging.

Functional organization of the human visual system at birth and across late gestation
Understanding how the brain's functional architecture emerges prior to substantial postnatal visual experience is crucial for determining what initial capabilities infants possess and how they learn from their environment. Using resting-state fMRI from 584 neonates in the Developing Human Connectome Project, we provide the first comprehensive systems-level characterization of human visual cortex within hours of birth and across the third trimester of gestation. We discover that newborns possess a sophisticated visual architecture already functionally organized into three distinct pathways (ventral, lateral, and dorsal), each exhibiting posterior-to-anterior hierarchical structure and adult-like topographic organization. This tripartite visual organization differs from the bipartite organization observed in macaques, suggesting this architecture emerges through intrinsic developmental mechanisms rather than being a product of extensive postnatal experience and environmental adaptation. Moreover, pathway segregation, hierarchical ordering, and connectivity maturity all strengthen progressively with gestational age, revealing that visual cortical organization emerges through an active developmental program that unfolds across late gestation. Yet, despite this large-scale structure, individual pathways follow strikingly different maturation trajectories: dorsal areas exhibit a near-adult-like functional organization, even at the earliest gestational timepoints tested, whereas ventral areas remain immature and poised for experience-dependent refinement. These findings reframe our understanding of early visual development by revealing that complex functional networks emerge before substantial visual experience, yet are differentially prepared for plasticity, providing crucial insights into how evolution has optimized the brain for rapid learning while maintaining the flexibility needed for adaptation to diverse environments.

Comparative Connectomics Highlights Conserved Architectural Synaptic Motifs in the Drosophila Mushroom Body
While the influence of synaptic plasticity on learning and memory has been extensively studied, the detailed patterns of synaptic connectivity remain incompletely mapped. Convergent synaptic motifs -- a tight grouping of at least two axons whose active zones are within 300nm and which are presynaptic to the same target -- are a common feature of neural circuits in the insect brain and are believed to serve as an important computational primitive in many brain areas. The Mushroom Body (MB) of Drosophila, for instance, is the center of associative learning and memory, where sensory information is conducted by Kenyon cells (KCs), the intrinsic neurons of the MB, and integrated by MB output neurons (MBONs). Indeed, the majority of KC-to-MBON synapses occur in a convergent motif. Nonetheless, the functional role of this convergent motif is not well studied. To gain insight into their potential role in the MB, we combine big-data network neuroscience tools with existing electron microscopy connectome datasets to detect and map the distribution of convergent synaptic motifs. We find that convergent motifs consistently occur across the MB in different individuals, including the lobe where they were first quantified, and we report on both the variance and consistency in the formation of these motifs across different MB regions and individuals. Our discovery of multiply-convergent motifs -- where two KCs target multiple postsynaptic targets simultaneously -- reveals a previously unrecognized synaptic economy that may optimize information transfer while conserving neural resources. These stereotyped arrangements likely represent fundamental organizational principles underlying associative learning across species. Lastly, to our knowledge, this study offers the first and most extensive comparative analysis of synaptic motifs across Drosophila connectomes, establishing a framework for enabling systematic motif analysis of synapses across species.

Resolving Competition in Auditory Cortex: Effects of Emotional Content and Misophonia Sensitivity
How the human auditory cortex prioritizes relevant information amid concurrent sounds has been a long-standing question in auditory cognitive neuroscience. The present study used auditory steady-state responses (ASSR) to tag the electrocortical response to a tone embedded in concurrent naturalistic sounds, addressing methodological challenges with overlapping auditory streams. Participants endorsing low (LMS) or high in misophonia symptoms (HMS) - a condition with decreased tolerance to specific, typically orofacial, sounds - were recruited. Sounds varied in their emotional valence (pleasant, neutral, unpleasant, and orofacial) to investigate how emotional content modulates attentional competition and how competition is resolved in listeners with misophonia traits. Affective ratings, alpha-band changes, and pupil dilation in response to the sounds were also assessed. Hypothetical models of competition were tested, revealing a facilitation trend in the ASSR amplitude when accompanied by pleasant and unpleasant, compared to neutral sounds, regardless of misophonia symptoms. However, ASSR was selectively reduced in the HMS but not the LMS group when accompanied by orofacial sounds. Analyses of alpha-band, pupil, and rating data showed that the groups differed primarily in their response to pleasant sounds and orofacial sounds, with the HMS group exhibiting a stronger response to orofacial sounds than the LMS group.

Morphine regulates astrocyte transcriptional dynamics in the ventral tegmental area by stimulation of glucocorticoid signaling
Opioids are potent analgesics often prescribed for the treatment of chronic pain, a condition affecting millions worldwide. Although pain states increase vulnerability to opioid use disorders, the neural mechanisms underlying this interaction remain incompletely understood. The ventral tegmental area (VTA) is a key site for opioid actions, and emerging evidence suggests that pain states and opioid experience both induce transcriptional, molecular, and circuit adaptations in the VTA that contribute to motivated behaviors. However, the transcriptional responses of distinct VTA cell types to each of these factors (alone or in combination) have not been identified. Here, we employed single-nucleus RNA sequencing to comprehensively define transcriptional alterations in the rat VTA to acute morphine administration in a chronic inflammatory pain model. We report that morphine induces gene expression changes primarily in glial cells and dopamine neurons, with minimal effects in other neuronal cell types. Surprisingly, VTA astrocytes and oligodendrocytes exhibited the most robust transcriptional responses to opioid exposure, despite lacking detectable opioid receptor expression. Among the most highly regulated glial genes was Fkbp5, which encodes a co-chaperone protein that acts in concert with heat shock proteins to modulate stress responses. Using pharmacological and CRISPR-based approaches in rat glial cells and human astrocytes, we demonstrate that regulation of Fkbp5 is mediated indirectly through glucocorticoid signaling rather than direct opioid receptor activation. These findings reveal that glial cells within reward circuits undergo profound transcriptional reprogramming in response to opioids through indirect, stress-hormone mediated mechanisms, highlighting a previously unappreciated non-neuronal contribution to opioid-induced neural adaptations.

Distinct cellular processes drive motor skill learning in the human brain
Despite decades of research, the biological mechanisms by which motor skills consolidate in the human brain remain poorly understood. Diffusion MRI provides a unique opportunity to probe biological processes non-invasively, as water displacements occur on the micrometer scale. Using diffusion tensor imaging (DTI), our team showed that motor sequence learning (MSL) induces microstructural changes in the hippocampus and key motor regions, suggesting that declarative and procedural systems may operate as part of the same network. Yet DTI cannot identify the cellular source of these changes, leaving open whether they reflect structural plasticity, remodeling of dendritic and astrocytic processes described in rodents, or transient homeostatic responses that accompany learning, neuronal and astrocytic swelling. Here, we combined ultra-high-gradient diffusion MRI with the compartment-based Soma and Neurite Density Imaging (SANDI) model to disentangle the cellular basis of motor skill memory consolidation. DTI showed that MSL induced rapid microstructural changes in the hippocampus, precuneus, and motor regions, but only those in the precuneus and posterior parietal cortex (PPC) persisted overnight. SANDI revealed that DTI changes were driven by two distinct cellular processes: a transient enlargement of the cell soma across all regions consistent with a short-lived homeostatic response, and a sustained rise in cell-process density restricted to the precuneus and PPC, compatible with structural plasticity. By decomposing diffusion signals into their cellular sources, our work disambiguates transient and enduring processes, providing the first non-invasive evidence for the cellular basis of human motor memory consolidation and a framework for studying neuroplasticity in vivo.

Modular inhibitory coding in binary networks
We developed and characterized properties of new class of binary models where, as observed in biological networks, excitatory neurons are functionally separated from inhibitory units. New patterns, represented as activation and inactivation of binary units in excitatory layer, are stored in the network through recruitment and training of inhibitory units that are group into individual modules and interact with excitatory layer. We investigate the roles the two populations play in memory storage and show that inhibitory layer plays a critical role in memory storage and management and that capacity of this new type of network scales with number of inhibitory neurons. Further, we show that performance of the network is only gradually diminished when excitatory to excitatory connections are removed, but critically depends on inhibitory to excitatory connections. These results are in line with new experimental work showing that inhibitory interneurons are playing critical role in memory storage and recall in the brain networks and may also address why generally excitatory networks exhibit sparser reciprocal connectivity as compared to connections to/from inhibitory units. We further show advantages of so designed coding shame in terms of memory capacity, its expansion with progressive storage of new memories as well as network behavior for large memory loading.

Impact of Task Similarity and Training Regimes on Cognitive Transfer and Interference
Learning depends not only on the content of what we learn, but also on how we learn and on how experiences are structured over time. To investigate how task similarity and training regime interact during learning, we trained participants on spatial and conceptual learning tasks that shared either similar or distinct underlying structures, using either interleaved or blocked regimes. Interleaving the two tasks hindered performance when their structures were similar, compared to when they were different. In contrast, blocked training produced the opposite effect: it improved performance and facilitated transfer across similar tasks. This effect, however, emerged only when participants first learned the conceptual task, followed by the spatial task, suggesting an asymmetric interaction between task order and structural similarity. We also replicated our results using a neural network model, providing converging evidence for the computational principles governing the interplay between training regime and structural similarity in multi-task learning.

Familial Risk for Dementia, Cognitive Performance, and the Human Cerebello-Hippocampal Circuit: A Study in the European Prevention of Alzheimers Disease cohort
The cerebellohippocampal (CBHP) circuit is increasingly implicated in episodic and spatial memory, yet its role in normal aging, dementia risk, and sex differences remains unclear. Structure and function in both the hippocampus and cerebellum have been linked to mild cognitive impairment, Alzheimers Disease, and cognitive decline in healthy older adults. Literature on the CBHP circuit is largely limited to animal studies and small samples of young adults in the context of visuospatial abilities, underscoring the need for large, diverse aging cohorts to establish CB-HP connectivity as an early, translatable marker of neurodegeneration. Here, we investigate the CBHP circuit in the context of aging, dementia risk, behavior, and sex differences in healthy older adults to advance understanding of cognitive decline in the aging population. We explored this relationship in 857 healthy adults with and without a family history of dementia (aged 50-88, 59% female, 71% family history positive) using resting-state functional connectivity MRI (rsMRI) and behavioral assessments. We hypothesized that CB-HP functional connectivity (FC) would be lower with increased age, relate positively to cognitive performance, be lower in females positive for family history of dementia, and be lower in mild cognitive impairment (MCI)-risk than cognitively normal (CN) participants with sex differences therein. We observed selective links between CBHP FC, cognition, and sex. MCI risk participants performed worse on spatial memory performances than CN, whereas CBHP FC showed opposite performance slopes by risk status, suggesting the CBHP circuit may function as a compensatory network for short-term recall. Sex differences were seen on cognitive tasks (delayed episodic memory and spatial tasks) and in CBHP a better visuospatial index was linked to greater FC in females, while males displayed an inverse relationship. Behavioral differences by familial dementia history were shown, although CBHP FC did not show effects here. Overall, CB-HP networks appear behaviorally silent in the aggregate but reveal risk and sex dependent relationships when memory demands and circuit nodes are considered.

Differential functional connectivity between hippocampus and prefrontal cortex is associated with heterogeneity in open field exploration
A common paradigm in behavioral neuroscience involves recording neural activity from freely moving rodents as they forage in an open field. This procedure is often used in studies investigating spatial navigation, where recording is conducted in regions such as the hippocampus and entorhinal cortex. It is usually assumed that there is no systematic variation in behavior in this paradigm, thereby allowing spatial representations to be examined without the confounding effects of behavior change. Here we show that the behavior of rats in this paradigm can be algorithmically divided into at least two distinct modes, and that the transitions between these modes is marked by distinct differences in theta and gamma band power in the hippocampus, as well as transition-associated communication between hippocampus and prefrontal cortex, with information strongly flowing from hippocampus to prefrontal cortex during the transition period. Moreover, we show that following a maternal immune activation intervention, intra-regional changes in power are preserved, but communication between hippocampus and prefrontal cortex is impaired. These findings demonstrate that animals in the open field perform distinct behaviors that are accompanied by marked changes in brain activity and regional communication.

Establishing a continuum of cell types in the visual cortex
The mammalian cerebral cortex is composed of neurons whose properties vary in a continuous fashion rather than falling into discrete cell types. In the mouse visual cortex, excitatory neurons in layer 2 and 3 (L2/3) form such a continuum along cortical depth, patterned by the graded expression of hundreds of genes. Here we sought to understand how this continuum develops and contributes to cortical wiring. Using single-nucleus multiomics (RNA- and ATAC-Seq) and spatial transcriptomics, we show that the L2/3 continuum is established in two phases. During the first postnatal week, a genetically hardwired program establishes a primitive continuum of cell identities spanning the depth of L2/3. The second program, promoted by visual experience, is later superimposed upon the preexisting continuum. This second phase is driven by activity-regulated transcription factors that drive the L2/3 depth-dependent expression of genes linked to synaptic function and plasticity. We show that neurons at different positions along the L2/3 continuum project preferentially to distinct higher visual areas and that visual deprivation disrupts targeting to some higher visual areas while sparing others. Thus, cortical continua emerge through a stepwise process in which genetic programs and sensory experience specify neuronal identity and sculpt intracortical wiring specificity.

Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons
We have investigated changes in chromosome conformation, nuclear organization, and transcription during differentiation and maturation of control and mutant motor neurons harboring hexanucleotide expansions in the C9orf72 gene that cause amyotrophic lateral sclerosis (ALS). Using an in vitro reprogramming, differentiation and neural maturation protocol, we obtained highly purified populations of post-mitotic motor neurons for both normal and diseased cells. As expected, as fibroblasts are reprogrammed into iPSCs, and as iPSCs differentiate into motor neurons, chromatin accessibility, chromosome conformation, and nuclear organization change along with large-scale alterations in transcriptional profiles. We find that the transcriptome changes extensively during the first three weeks of post-mitotic neuronal maturation, with thousands of genes changing expression, but then is relatively stable for the next three weeks. In contrast, chromosome conformation and nuclear organization continue to change over the entire 6-week maturation period: chromosome territoriality increases, long-range interactions along chromosomes decrease, compartmentalization strength increases, and centromeres and telomeres increasingly cluster. In motor neurons derived from ALS patients such changes in chromosome conformation were much reduced. Chromatin accessibility changes also showed delayed maturation. The transcriptome in these cells matured relatively normally but with notable changes in expression of genes involved in lipid, sterol and mitochondrial function. We conclude that neural maturation is associated with large scale post-mitotic changes in gene expression, chromosome conformation and nuclear organization, and that these processes are defective in motor neurons derived from ALS patients carrying C9orf72 hexanucleotide repeat expansions.

Beyond Alzheimer's story: how an engineered molecule gained an endogenous essence
A hallmark of Alzheimer's disease (AD) is extra-neuronal protein aggregates formed mainly by the amyloid-{beta} peptide (A{beta}), that are deposited inside the brain as amyloid plaques. The engineered peptide Ac-His-Ala-Glu-Glu-NH2 (HAEE) suppresses the formation of amyloid plaques in vivo and is being tested as an anti-amyloid drug candidate. Here, by using a quantitative mass-spectrometry method we discover that HAEE peptide represents a normal endogenous component of human blood plasma. Moreover, the HAEE level has been significantly reduced in patients with a clinical diagnosis of AD (n=200) as compared with the control participants with no clinical diagnosis of cognitive impairment (n=150). Thus, endogenous HAEE may be considered as a potential blood-based biomarker in the diagnosis of Alzheimer's disease, while exogenous HAEE may serve as a drug in AD-modifying therapy.

Transcriptomic Signatures of Hippocampal Subregions and Neuronal Nuclei in Active Place Avoidance Memory Maintenance
The gene expression changes associated with memory acquisition, consolidation and reconsolidation, all active epochs in memory formation, have been well characterized in the rodent hippocampus. Less is known, however, of the changes in gene expression supporting the maintenance of memory, particularly when it remains undisturbed or offline days after the memory experience. In this study, we used a combination of spatial transcriptomic and single nuclear RNA sequencing (snRNA-seq) to measure the gene expression changes in the dorsal hippocampus during an early phase of offline memory maintenance, 3 days after the post-training retention test of an active place avoidance memory. Through spatial transcriptomics we identified spatially regionalized differential gene expression and biological process enrichment, with CA1, CA3, and DG exhibiting differential expression of genes involved in post-synaptic function, synaptic vesicle transport, and neuronal differentiation, respectively. Notably, through snRNA-seq, differentially expressed genes detected in clusters of hippocampal neurons from the trained animal were largely defined by their down regulation of genes involved in ATP synthesis and cytoplasmic translation. With both techniques we also examined the gene expression changes in a putative subset of memory-associated neurons through the detection of eYFP mRNA in the Arc-Cre/flox-eYFP double transgenic mouse line. Amongst this population of cells, we detected a limited number of differentially expressed genes unique to each subregional population and associated with synaptic plasticity and post-synaptic signaling. Our results suggest that two overarching transcriptomic patters contribute to the functional changes in hippocampal cells during offline memory maintenance: a regional distribution of pathways linked to synaptic functions, and a reduction of metabolic activity across hippocampal sub-regions and memory-associated neuronal ensembles.

Hippocampal functional connectivity changes associated with active and lecture-based physics learning
Introductory university physics courses often face the dual challenge of introducing students to new physics concepts while also addressing their preconceived notions that conflict with scientific principles. Active learning pedagogical approaches, which employ constructivist principles and emphasize active participation in the learning process, have been shown to be effective in teaching complex physics concepts. However, while the behavioral effects of constructivist methodologies are largely understood, the neurobiological underpinnings that facilitate this process remain unclear. Using functional magnetic resonance imaging (fMRI), we assessed students enrolled in either an active learning or lecture-based physics course before and after a 15-week semester of learning and examined changes in hippocampal whole-brain connectivity. We focused on the hippocampus given its critical role in learning and memory. Our findings revealed that hippocampal connectivity with brain regions in the frontal and parietal lobes decreased over time, regardless of instructional approach. Results also indicated that active learning students exhibited increased hippocampal connectivity with parietal, cerebellar, and frontal regions, reflecting experiential learning based on constructivist principles, whereas lecture-based students exhibited increased hippocampal connectivity with the fusiform gyrus, suggesting learning through passive observation. Our findings demonstrate that while some aspects of hippocampal functional connectivity may decrease over time, active vs. passive learning may preferentially enhance hippocampal connectivity during physics learning.

Neuroanatomical Correlates of Negative Symptoms in Schizophrenia
Background: Schizophrenia is characterized by widespread structural brain abnormalities, but associations between structural abnormalities and negative symptom severity are not well understood. Negative symptoms have been conceptualized in a hierarchical structure of two second-order dimensions -motivation and pleasure (MAP) and expression (EXP)- and five first-order domains: anhedonia, avolition, and asociality (MAP), and blunted affect and alogia (EXP). A better understanding of the neural circuitry underlying negative symptom dimensions and domains is important given their reported association with poor functional outcome and lack of available treatments. Study Design: The meta-analysis included 1,591 individuals with schizophrenia across 16 samples with structural imaging and Scale for Assessment of Negative Symptoms data. The study generated correlations of cortical thickness and subcortical volumes with the negative symptom dimensions and domains. Study results: Negative symptoms showed mainly negative associations with cortical thickness and subcortical volumes. The effect sizes were small but there was a pattern of associations in predominantly frontal lobe cortical thickness and limbic subcortical volumes. The regional correlation patterns of cortical thickness and subcortical volumes with symptom domains support the conceptualized hierarchical structure of negative symptoms: correlations of MAP domains were stronger with the MAP than EXP dimension, and vice versa. Exploratory analyses with receptor densities further supported the hierarchy. Conclusion: Our findings reveal small but consistent associations between negative symptom dimensions and predominantly prefrontal region cortical thickness, and limbic region volumes. These findings advance our understanding of the network of anatomical regions that may contribute to the severity of negative symptoms in schizophrenia.

Spinal dI3 neurons are involved in sustained motor adaptation elicited by low-threshold cutaneous afferents
Adaptation of muscle activity to meet a certain target or intention is traditionally attributed to supraspinal structures. However, evidence is mounting that this process can occur within the spinal cord through intrinsic plasticity and circuit reorganization. Here, we investigate the role of a class of excitatory spinal interneurons, called dorsal interneuron 3 (dI3), in the acquisition of novel motor behaviors independent of supraspinal input. Using a real-time closed-loop stimulation paradigm in spinalized mice, we promoted a persistent adaptation in the hindlimb position to be higher than its resting level by delivering saphenous nerve stimulation contingent on toe elevation. The stimulation intensities were calibrated to selectively recruit low-threshold mechanoreceptors (LTMRs). To test the contribution of dI3s in this motor adaptation, inhibitory DREADD (hM4Di) receptors were expressed in Isl1/Vglut2 cells, achieving reversible, cell-type-specific silencing of dI3s. Our results demonstrate that stimulation of cutaneous inputs to the spinal cord contingent on a certain positional goal can generate sustained changes in motor activity, in this case, in the form of elevation of toe position above a preset vertical threshold. Chemogenetic silencing of dI3s abolished this motor adaptation induced by activation of LTMRs. These findings indicate that dI3 activity is essential for a particular type of motor adaptation driven primarily by LTMR input.

NEW & NOTEWORTHYWe developed a real-time, closed-loop stimulation paradigm in spinalized mice using kinematic video tracking to trigger electrical stimulation of the saphenous nerve. We discovered that low-threshold stimulations targeting non-nociceptive cutaneous afferents can elicit sustained motor adaptations independently from supraspinal input. Furthermore, using two chemogenetic techniques to transiently inhibit a population of spinal neurons, called dI3s, we found that these neurons are crucial for integrating these low-threshold stimuli to elicit sustained changes in motor behaviour.