Sunday, October 5th, 2025

Time	Event
4:45a	Spatiotemporal Gray Matter Plasticity During Chronification of Preclinical Neuropathic Pain Chronic neuropathic pain is increasingly recognized as a brain disease characterized by time-dependent structural and functional reorganization of key neural circuits. While human imaging studies implicate widespread changes in network connectivity and gray matter density (GMD), animal models enable direct longitudinal mapping of such plasticity. Here, we applied high-resolution structural MRI in a rat model of chronic pain (spared nerve injury, SNI) and quantified GMD changes across 134 brain regions. Dynamic weight bearing analysis confirmed persistent pain in SNI rats, validating the chronic pain phenotype in our experimental cohort. Longitudinal MRI revealed significant GMD alterations in 31 regions, predominantly within limbic, prefrontal, and cingulate circuits, representing 21% of total brain volume. Among this affected volume, over 17% of brain volume demonstrated GMD increases while only ~3% showed GMD decreases, indicating a heterogeneous neuroplastic response. Specifically, the Frontal Association Cortex exhibited an approximate 10% increase in GMD, the Primary Cingular Cortex showed a modest increase of about 2%, and the Amygdalohyppocampic Area demonstrated a ~10% decrease in GMD over 28 days. Primary sensory, parietal, visual, retrosplenial, and temporal cortices remained largely unaffected. No significant changes were observed in healthy animals over the same period, highlighting the specificity of brain reorganization to persistent neuropathic pain. These findings reaffirm the ability of MRI to robustly quantify pain-induced neuroanatomical remodeling but leave open critical questions about the underlying cellular and molecular mechanisms. Future studies integrating histological and molecular approaches are needed to determine the precise substrate and reversibility of these structural changes, with the goal of identifying therapeutic targets to prevent or reverse maladaptive neuroplasticity in chronic. (Comment on this)
10:48a	Developmental Dysregulation of Synaptic and Myelin-Related Genes in Frontal Cortex and Serum Infrared Spectroscopy Signature in the Valproic Acid Model of Autism Neural circuits emerge during development through dynamic interactions between genetic instructions and environmental cues that shape cell fate, connectivity, and the timing of myelination. In developmental disorders such as autism, abnormalities in sensory processing, social cognition, and motor behavior are thought to arise from disruptions in these processes. Here, we investigated early-life molecular changes following prenatal exposure to valproic acid (VPA), an environmentally induced model of autism. We integrated cortical gene expression analysis using RNA sequencing/qPCR, alternative splicing profiling, in situ myelin quantification, plasma serotonin determination, and machine learning-assisted classification of blood serum molecular profiles using infrared spectroscopic (FTIR) data. Our findings revealed downregulation of myelin-associated genes and upregulation of synapse-related genes in the frontal cortex of young VPA-exposed rats. qPCR confirmed reduced cortical expression of Mobp and PLP1 along with increased Penk and C1ql3 expression. Alternative splicing analysis identified numerous novel transcript variants, enriched in synaptic-related genes, indicating widespread post-transcriptional remodeling in VPA animals. These molecular alterations were accompanied by a significant reduction in myelin content within the cingulate and motor cortex of adult animals. Peripheral molecular profiling showed elevated plasma serotonin in VPA-treated animals and demonstrated that a support vector machine trained on serum FTIR spectra classified VPA-exposed animals with 85% accuracy. Collectively, our findings suggest that prenatal VPA exposure induces early dysregulation of myelin organization, synaptic gene networks, and RNA splicing programs, potentially leading to long-term impairments in neuronal communication and processing efficiency. Furthermore, our results highlight serum spectroscopic signatures as promising peripheral biomarkers for autism, warranting further investigation. (Comment on this)
10:48a	TMS-EEG reveals causal dynamics of the premotor cortex during musical improvisation Musical improvisation illustrates the brain's capacity for flexible, creative motor control, yet the causal mechanisms underlying this complex behaviour remain poorly understood. We employed transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) to probe state-dependent cortical dynamics in the left dorsal premotor cortex (PMd) of professional jazz pianists (n = 3) during improvisation, sight-reading, and rest. This proof-of-concept study demonstrates the feasibility of combining perturbational neuroscience with ecologically valid musical performance. Multiple convergent analyses revealed distinct cortical signatures during improvisation: reduced local mean field power, decreased phase-locking of evoked responses, and preserved but gain-modulated early components as revealed by Correlated Components Analysis. These findings suggest that improvisation is characterized by attenuated PMd excitability and more variable response timings, while preserving the fundamental architecture of cortical responses. This perturbational signature supports a neural efficiency model of expertise whereby expert musicians achieve creative flexibility through training-induced streamlined, optimized cortical processing. Our results establish TMS-EEG as a powerful approach for investigating the causal dynamics of creative cognition and demonstrate how the brain reconfigures its response properties to support internally driven motor performance. (Comment on this)
10:48a	Neuroinflammatory Stress Preferentially Impacts Synaptic MAPK Signaling and Mitochondria in Excitatory Neurons Background: Understanding synapse-specific effects of neuroinflammation can provide mechanistic and therapeutically relevant insights across the spectrum of neurological diseases. Methods: We applied neuron-specific proteomic biotinylation in vivo, differential centrifugation of brain for crude synaptosome enrichment (P2 fraction) and mass spectrometry (MS) analysis of biotinylated proteins to derive native-state proteomes of Camk2a-positive neurons and their corresponding P2 synaptic compartments. Next, in an in vivo model of systemic lipopolysaccharide (LPS) dosing, we examined the effects of neuroinflammation on whole neuron and synaptic compartments using a combination of MS, network analysis, confirmatory biochemical and ultrastructural assays and integrative approaches across our mouse-derived and existing human datasets. Results: Ultrastructural and biochemical analyses of P2 fractions verified enrichment in synaptic elements, including synaptic vesicles and mitochondria. MS of biotinylated proteins from Camk2a-specific bulk brain homogenates (whole neuron) and P2 fractions (synaptosome) showed enrichment of >1000 proteins, consistent with neuron-specific biotinylation, also confirmed by immunofluorescence microscopy. Camk2a-specific synaptic proteome revealed molecular signatures related to mitochondrial function, synaptic transmission, protein translation. LPS-treated mice displayed body weight loss and neuroinflammation, characterized by glial activation, increased pro-inflammatory cytokine levels and upregulated expression of Alzheimer's disease (AD)-related microglial genes. LPS-induced neuroinflammation exerted distinct effects on the synaptic proteome, including increased mitochondrial and reduced cytoskeletal-synaptic proteins, while suppressed synaptic MAPK signaling. Importantly, these changes were not observed at the whole neuron level, indicating unique vulnerability of the synapse to neuroinflammation. In line with synapse proteomic and signaling changes, LPS altered the ultrastructure of asymmetric synapses, suggesting dysregulation of excitatory neurotransmission. Co-expression network analysis of Camk2a neuronal proteins further resolved mitochondria- and synapse-specific protein modules, some of which were neuroinflammation-dependent. Neuroinflammation increased levels of a mitochondria-enriched module, and decreased levels of a pre-synaptic vesicle module, without impacting a post-synaptic membrane module. LPS-dependent mitochondrial and LPS-independent post-synaptic modules in mouse neurons mapped to post-mortem human AD brain proteomic modules which were decreased in cases with AD dementia and positively correlated to cognitive function, including pro-resilience markers for AD. Conclusion: Our findings using native-state proteomics of Camk2a neurons combined with synaptosome enrichment identify proteome-level mechanisms of early synaptic vulnerability to neuroinflammation relevant to AD. (Comment on this)
10:48a	Multi-stable oscillations in cortical networks with two classes of inhibition In the classic view of cortical rhythms, the interaction between excitatory pyramidal neurons (E) and inhibitory parvalbumin neurons (I) has been shown to be sufficient to generate gamma and beta band rhythms. However, it is now clear that there are multiple inhibitory interneuron subtypes and that they play important roles in the generation of these rhythms. In this paper we develop a spiking network that consists of populations of E, I and an additional interneuron type, the somatostatin (S) internerons that receive excitation from the E cells and inhibit both the E cells and the I cells. These S cells are modulated by a third inhibitory subtype, VIP neurons that receive inputs from other cortical areas. We reduce the spiking network to a system of nine differential equations that characterize the mean voltage, firing rate, and synaptic conductance for each population and using this we find many instances of multiple rhythms within the network. Using tools from nonlinear dynamics, we explore the roles of each of the two classes of inhibition as well as the role of the VIP modulation on the properties of these rhythms. (Comment on this)
10:48a	Comparative transcriptomics reveals shifts in cortical architecture at themetatherian/eutherian transition The neocortex, a layered structure unique to mammals, supports higher-order functions such as perception, learning, and decision-making. While its overall organization is broadly conserved, it remains unclear whether changes to the cell type-specific organization of the cortical column--the basic unit of cortical processing--occurred at the metatherian/eutherian split. To address this, we used single-nucleus RNA sequencing and spatial transcriptomics to compare gene expression, cell types, and laminar architecture in the primary visual cortex of a metatherian (Monodelphis domestica) and a eutherian mammal (Mus musculus). We find distinctions between supragranular (layer 2/3) and infragranular (layers 5 and 6) intratelencephalic (IT) neurons to be more pronounced in mice, with layer 2/3 neurons enriched for transcripts involved in synaptic transmission, adhesion, and dendritic development. Mouse cortex also exhibits expanded populations of disinhibitory interneurons, redistribution of perineuronal nets, and reduced oligodendrocyte density--features known to enhance cortical plasticity. These findings suggest the metatherian/eutherian split was accompanied by remodeling of the cortical column, highlighting potential substrates of neocortical evolution in early mammals. (Comment on this)
11:17p	Age-related microbiome metabolites modulate splicing and chromatin accessibility in the brain The gut microbiome generates diverse metabolites that can enter the bloodstream and alter host biology, including brain function. Hundreds of physiologically relevant, gut-brain signaling molecules likely exist; however, there has been no systematic, high-throughput effort to identify and validate them. Here, we integrate computational, in vitro, and in vivo approaches to pinpoint microbiome-derived metabolites whose blood levels change during aging, and that induce corresponding changes in the mouse brain. First, we mine large-scale metabolomics datasets from human cohorts (each n [≥] 1200) to identify 30 microbiome-associated metabolites whose blood levels change with age. We then screen this panel in an in vitro transcriptomic assay to identify metabolites that perturb genes linked to age-related neurodegeneration. We then test four metabolites in an acute-exposure mouse model, and use multi-omic approaches to evaluate their impact on cellular functions in the brain. We confirm the known neurodegeneration-promoting effects of trimethylamine N-oxide (TMAO), including mitochondrial dysfunction, and further discover its disruptive impact on the pathways of glycolysis, GABAergic signaling, and RNA splicing. Additionally, we identify glycodeoxycholic acid (GDCA), a microbiome-derived secondary bile acid, as a potent regulator of chromatin accessibility and suppressor of genes that protect the brain from age-related, neurodegeneration-promoting insults. GDCA also acutely reduces mobility. Taken together, this work identifies microbiome-derived signals relevant to age-related neurodegeneration, and defines a scalable framework for linking microbiome metabolites to host pathologies. (Comment on this)

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