Saturday, August 2nd, 2025

Time	Event
12:32a	A sustained Hox program delineates brainstem neurons essential for breathing Respiratory neurons in the brainstem must diversify and acquire unique properties during development to enable breathing at birth. Dbx1-expressing progenitors give rise to functionally and molecularly distinct excitatory respiratory populations, including rhythm-generating pre-Botzinger complex (preBotC) neurons and phrenic motor neuron (MN)-projecting rostral Ventral Respiratory Group (rVRG) neurons. These neurons are organized rostrocaudally within the ventral respiratory column (VRC) but, despite their critical functions in breathing, the mechanisms that control their organization and diversification are not well understood. Here, we generate a novel genetic tool to label brainstem neurons within the VRC. We find that rVRG neurons selectively express Hox5 genes through postnatal stages. Selective deletion of all Hox5 paralogs from Dbx1-derived neurons leads to respiratory dysfunction, perinatal death, and changes in the pattern and amplitude of phrenic MN firing. We show that Hox5 inactivation leads to a caudal expansion of putative preBotC neurons, likely at the expense of the rVRG. Collectively, our findings indicate that Hox5 proteins are required for the delineation and functional specialization of excitatory brainstem neurons essential for breathing. (Comment on this)
12:32a	GFAP Proteolysis in TBI: Linking Novel Modified Cleavage Products to Astrocyte Pathology and Patient Outcomes Monitoring patients with traumatic brain injury (TBI) is essential for mitigating secondary complications. TBI disrupts proteostasis, leading to increased protein degradation and proteinopathy, which heighten the risk of neurodegeneration and underscore the need for early detection via noninvasive biomarkers. Glial fibrillary acidic protein (GFAP), an astroglial intermediate filament, is a well-established TBI biomarker, yet pathomechanisms and proteoforms of GFAP release are incompletely understood. This translational study defined the GFAP degradome in TBI through mass spectrometry (MS) sequencing of immunopurified GFAP breakdown products (BDPs) from patient biofluids. The TBI-GFAP fragments differed from those of Alzheimers and Alexander Diseases, revealing novel coil1/coil2-harboring cleavage products in TBI CSF, while TBI serum samples had only coil1-products. Trauma-specific citrullinations and acetylations were validated via MS spectra. Epitope mapping identified a novel trauma-specific cleavage site and revealed coil1-BDPs as selectively released into fluid, while coil2 fragments remained intracellular in a human trauma culture model. Citrullinated GFAP-specific antibodies exhibited distinct binding patterns from those of unmodified, native GFAP in TBI patients CSF and detected unique granular aggregates in dystrophic astrocytes without staining filamentous GFAP. TBI-GFAP fragments were produced by stepwise trauma-activated calpain and caspase activities shown by in vitro inhibitor studies. Live cell imaging with fluorescent protease reporters demonstrates coexisting calpain and caspase activities, along with membrane disruption jointly identifying distinct astrocyte injury states. The trajectory of GFAP proteolysis was analyzed in CSF samples from 24 TBI patients over 10PIDs, via calibrated, band-specific scaled immunoblot densitometry. These profiles covaried with patient age and body temperature. Full-length GFAP and 45-49kDa fragments peaked on injury day and declined over time, whereas calpain-generated 37-39kDa BDPs remained elevated. Small BDPs exhibited either delayed rises or remained undetected. Compared to the 20-26kDa BDPs, 15-19kDa products were notably underrepresented, consistent with coil1-BDPs preferred release and coil2-BDPs selective cellular retainment. Fluid levels of calpain-generated GFAP fragment were time and severity-dependent in the trauma culture model. TBI CSF trajectories of GFAP-BDPs differentiated TBI patients with poor versus those with good outcomes on the extended Glasgow Outcome scale (GOSE), whereas uncleaved GFAP trajectories failed in early prediction of patient outcome at six months. These findings define trauma-specific GFAP degradome dynamics and highlight novel longitudinal proteolysis profiles for patient monitoring and stratification. This work is significant as it supports GFAP fragment profiling for potential context of use (COU) in neurocritical care TBI monitoring, and offers preliminary insights into diagnosing astroglial proteinopathy-linked neurodegeneration after TBI. (Comment on this)
12:32a	Noninvasive detection of bacterial biofilms using an insect olfactory brain-based gas sensor Bacteria emit volatile organic compounds (VOCs) that can be targeted for disease detection. Biological olfactory systems have keen senses of smell, can detect VOCs at low concentrations, and are naturally adapted to classifying mixtures of VOCs as odors. Here, we employed locust (Schistocerca americana) olfactory neural circuitry to differentiate biofilm and planktonic cultures of Pseudomonas aeruginosa and Staphylococcus aureus using their odors. In vivo extracellular neural recordings were taken from the second-order olfactory processing center (antennal lobe) of locusts. The VOCs from biofilm cultures evoked distinct spiking responses compared to the planktonic cultures for both bacterial species. By analyzing the population neuronal responses, we classified individual bacterial biofilm vs. planktonic odors with up to 96% accuracy. The neural responses were highly discriminatory within the first couple of seconds of odor presentation and our analysis was conducted on less than five seconds of data, highlighting the potential of our biological sensor for real-time biofilm detection. (Comment on this)
12:32a	Transdiagnostic electrophysiological subtypes reveal brain-behavior dimensions in youth psychiatry Conventional psychiatric diagnoses often fail to reflect the underlying neurobiological and behavioral complexity of mental health conditions. Here, we propose a transdiagnostic, data-driven framework for stratifying youth based on large-scale multisite electroencephalography (EEG) data from 1,707 individuals aged 5-18 years, including healthy controls and individuals diagnosed with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety disorders (ANX), and learning disabilities (LD), along with their common comorbidities. By applying normative modeling to quantify individual deviations from typical brain functional maturation, and integrating multidimensional EEG features across spectral, temporal, complexity, and dynamical domains via similarity network fusion clustering, we identified three robust neurophysiological biotypes. These biotypes showed distinct electrophysiological and behavioral profiles, and captured meaningful brain-behavior relationships. Our findings suggest that biologically informed subtypes capture meaningful neuropsychiatric heterogeneity in youth, challenging conventional diagnostic boundaries in psychiatric nosology. (Comment on this)
12:32a	Corrective sub-movements link feedback to feedforward control in the cerebellum The ability to execute accurate movements is thought to rely on both anticipatory feedforward commands and rapid feedback corrections, yet how these control systems are integrated within cerebellar circuits remains unclear. Here, we show that corrective sub-movements (CSMs) -- structured, feedback-driven adjustments occurring spontaneously during naturalistic mouse reaching -- are not only encoded in anterior interposed (IntA) output neurons, but also act as instructive signals for feedforward learning. Closed-loop perturbations that trigger CSMs lead to learned shifts in the timing of future corrections, even in the absence of further perturbation. Strikingly, this learning depends on the timing of corrective responses, rather than the timing of the error itself, and is accompanied by physiological adaptation in cerebellar output neuronal firing rates. These findings reveal a cerebellar mechanism by which feedback responses train future anticipatory control signals, bridging the gap between reactive and anticipatory motor control in the cerebellum. (Comment on this)
12:32a	CaNetiCs - An Open-Source Toolbox for Standardized Dimensionality Reduction of Neuronal Calcium Activity The widespread use of calcium imaging has produced large-scale datasets capturing neuronal population activity across diverse experimental contexts, posing challenges for analyzing complex, high-dimensional data. Dimensionality reduction (DR) methods have been pivotal in addressing these challenges by simplifying data into interpretable, low-dimensional structures, while capturing essential network dynamics. Among DR methods, Nonnegative Matrix Factorization (NMF) can produce biologically meaningful representations through its nonnegativity constraint and parts-based decomposition, making it especially suited for analyzing neuronal calcium signals. To enhance accessibility and standardization in the analysis of state-dependent neuronal dynamics, we introduce Calcium Network dynamiCs (CaNetiCs), an open-source toolbox centered on NMF, integrating standardized DR methods (PCA, ICA, UMAP), geometric low-dimensional component space analyses, and neuronal network simulation modules. We validate our toolbox by applying it to two diverse experimental datasets that describe responses to graded anesthesia: whole-ganglion cellular calcium imaging of C. elegans, and two-photon imaging of murine somatosensory cortex. Our analyses recapitulate previously observed trends, such as network suppression and decorrelation with anesthesia, while uncovering novel insights into neuronal activity under differing contexts. CaNetiCs provides an accessible, modular, and interpretable framework, facilitating broader adoption of standardized dimensionality reduction methodologies for deeper exploration of neuronal network dynamics across experimental paradigms. The open-source code, along with documentation, is available at https://github.com/dannycarbonero/CaNetiCs. (Comment on this)
9:22a	Shank3 establishes AMPA receptor subunit composition at cerebellar mossy fiber-granule cell synapses and shapes regional microglia activation. Mutations in Shank3 are the primary genetic cause of Phelan-McDermid Syndrome (PMS), a neurodevelopmental disorder frequently comorbid with autism spectrum disorder (ASD). As a key scaffolding protein in the postsynaptic site, SHANK3 is critical for excitatory glutamatergic synapse function by interacting with AMPARs, NMDARs, and mGluRs. While Shank3 deficiency has been extensively studied in forebrain regions, its role in the cerebellum, a brain area increasingly implicated in ASD pathobiology, remains comparatively underexplored. Cerebellar granule cells (CGCs) exhibit high Shank3 expression. However, its role in cerebellar glutamatergic synapses is poorly understood. This study aims to investigate how Shank3 loss affects mossy fiber-CGC glutamatergic synaptic function. Whole-cell patch clamp electrophysiological recordings from CGCs in ex vivo cerebellar brain slices from adult (4-6 months old) wild type (WT) and homozygous Shank3{triangleup}ex4-22 KO were performed to record miniature, evoked, and glutamate uncaged responses. Similarly, the current-voltage (I-V) relationship was analyzed with intracellular spermine and pharmacological validation of calcium-permeable AMPARs (CP-AMPARs) was done by IEM-1460. Immunofluorescence staining was performed for microglia using IBA1 labeling. We found a significant increase in mEPSC amplitude and AMPAR-mediated response to glutamate uncaging, which indicates that the loss of Shank3 enhances postsynaptic AMPAR function. Furthermore, the KO group showed faster AMPAR decay kinetics, inward rectification, and increased sensitivity to IEM-1460, suggesting that a high proportion of CP-AMPARs with distinct biophysical properties are present at the MF-CGC synapse. Furthermore, KO mice showed less ramified microglia suggesting the possible presence of activated microglia in the cerebellar cortex. Together, these findings highlight a critical role of Shank3 in maintaining the balance between CP- and CI-AMPARs at the MF-CGC synapse, which is essential for synapse maturation and proper cerebellar circuitry function. Dysregulation of this balance, with possible presence of activated microglia in the cerebellum, may underscore cerebellar-related behavioral deficits in Shank3 KO mice and may suggest a potential mechanism contributing to ASD pathophysiology. (Comment on this)
8:17p	Digestive Dimensions of Autism: A Multiscale Exploration of Gut-Brain Interactions Social communication difficulties characterize autism spectrum disorders (ASD). Gastrointestinal (GI) symptoms are more common in ASD than in the general population. The identification of GI problems in individuals with ASD is challenging due to their altered pain perception and irregular behaviors. Importantly, GI symptoms and ASD can potentially aggravate each other. However, it is unclear if GI problems cause ASD symptoms or vice versa. A crosstalk between the digestive system, gut microbiota, and the central and enteric nervous systems has been repeatedly reported. The enteric nervous system (ENS) regulates the GI tract with the central nervous system (CNS) and the autonomic nervous system (ANS), as well as independently through specific neural circuits. Several mechanisms contribute to GI problems in ASD, including genetic mutations that affect the enteric nervous system (ENS), dysregulation of the ANS, alterations in gut microbiota, unhealthy dietary preferences, and changes in metabolomic profiles. Furthermore, studies have shown molecular and cellular differences in the GI biopsy of children with and without ASD. These findings highlight the unique nature of GI issues in ASD, underscoring the importance of further investigating the changes that occur in the digestive system and enteric nervous system (ENS) in ASD models. (Comment on this)

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