bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, June 5th, 2025
| Time |
Event |
| 8:35a |
A Role for Exaptation in Sculpting Sexually Dimorphic Brains from Shared Neural Lineages.
Sex differences in behaviours arise from variations in female and male nervous systems, yet the cellular and molecular bases of these differences remain poorly defined. Here, we take an unbiased, single-cell transcriptomic approach to uncover how sex shapes the adult Drosophila melanogaster brain. We show that sex differences do not result from large-scale transcriptional reprogramming but through fine-tuning of otherwise shared developmental templates via the sex-differentiating transcription factors Doublesex and Fruitless. We reveal, with unprecedented resolution, the extraordinary genetic diversity within these sexually dimorphic cell types and find birth order represents a novel axis of sexual differentiation. Neuronal identity in the adult reflects spatiotemporal patterning and sex-specific survival, with female-biased neurons arising early and male-biased neurons arising late. This pattern reframes dimorphic neurons as 'paralogous' rather than 'orthologous', suggesting sex leverages distinct developmental windows to build behavioural circuits and highlights a role for exaptation in diversifying the brain. | | 8:35a |
Animate-inanimate object categorization from minimal visual information in the human brain, human behavior, and deep neural networks
The distinction between animate and inanimate things is a main organizing principle of information in perception and cognition. Yet, animacy, as a visual property, has so far eluded operationalization. Which visual features are necessary and sufficient to see animacy? At which level of the visual hierarchy does the animate-inanimate distinction emerge? Here, we show that the animate-inanimate distinction is preserved even among images of objects that are made unrecognizable and only retain low- and mid-level visual features of their natural version. In particular, in three experiments, healthy human adults saw rapid sequences of images (6 Hz) where every five exemplars of a category (i.e., animate), an exemplar of another category (i.e., inanimate) was shown (1.2 Hz). Using frequency-tagging electroencephalography (ftEEG), we found significant neural responses at 1.2 Hz, indicating rapid and automatic detection of the periodic categorical change. Moreover, such effect was found -although increasingly weaker- for 'impoverished' stimulus-sets that retained only certain (high-, mid- or low-level) features of the original colorful images (i.e., grayscale, texform and phase-scrambled images), and even if the images were unrecognizable. Similar effects were found with two Deep Neural networks (DNNs) presented with the same stimulus-sets. In sum, reliable categorization effects for dramatically impoverished and unrecognizable images, in humans' EEG and DNN data, demonstrate that animacy representation emerges early in the visual hierarchy and is remarkably resilient to the loss of visual information. | | 8:35a |
Alterations in auditory midbrain processing is observed in both female andmale mouse model of Fragile X Syndrome
Introduction: Sensory processing deficits presenting as auditory hypersensitivity is a common phenotype associated with Fragile X Syndrome (FXS), a leading monogenic cause of intellectual disability and autism spectrum disorder. Auditory hypersensitivity can also be observed in the FMR1- knockout (KO) mice, a well-established mouse model of autism and FXS. FXS is an X-linked disorder that is more prevalent in males compared to females, as a result most auditory and electrophysiology studies are performed in males. Previous in-vivo electrophysiology studies at the inferior colliculus (IC), an essential component of the auditory pathway, in male FMR1-KO mice at post-natal days 14, 21 and 34 (P14, P21 and P34) demonstrated increased neuronal firing, suggesting that the IC could play a role in auditory hypersensitivity. However, very little is known about the role of the central nucleus of the IC (ICc) and auditory hypersensitivity in females. Methods: Here we investigated auditory processing at P20 and P30, representative of early and late developmental stage of auditory development, respectively, at the central nucleus of the IC (ICc) of both female and male FMR1-KO mice, compared with wildtype (WT) animals. Results: In-vivo electrophysiology recordings from the ICc neurons of the FMR1-KO mice at both developmental ages demonstrated increased response magnitude measured by spike number to pure tones of varying frequency and amplitude, compared with age- and sex-matched WT animals. In addition, within the FMR1-KO group we also observed significant developmental and sex difference wherein higher response magnitudes were displayed at P20 and in the female mice. Minimum threshold of ICc neuron in the KO mice was significantly decreased at both P20 and P30. The ICc neurons in the KO mice also displayed increased response duration compared to WT animals at both P20 and P30, but significant sex difference was only observed at P30. Our data also indicated that the ICc neurons of both groups displayed weak negative relationship between latency and response magnitude at P20, and at P30 the WT mice showed a stronger relationship only in the female group. In terms of developmental changes, we observed decreasing neuronal firing only in the KO mice between 20- and 30-day old female and male mice. Reduced response duration was observed in 30-day old mice of both sexes of both genotypes. Regarding minimum threshold, we observed a decline between early and late auditory development only in the male mice. Finally, our results also indicated that in the WT mice the reverse relationship between latency and response magnitude became more pronounced and consistent with age, a developmental trend that was absent in both the female and male FMR1-KO mice. Discussion: Overall, our findings demonstrate that auditory processing deficits can also be observed in the female FMR1-KO mice using in-vivo electrophysiology studies, highlighting the importance of including female subjects in future studies. These results also indicate that auditory hypersensitivity can be observed robustly in younger mice, suggesting that the early development stage could be an ideal target for interventions. | | 8:35a |
Dendrite-targeting inhibitory interneurons form biased circuits with deep and superficial pyramidal cells in hippocampal CA1
In CA1 hippocampus, pyramidal cells (PCs) can be classified as deep or superficial based on their radial position within the stratum pyramidale. Deep and superficial PCs form biased circuits with perisomatic-targeting PV+ basket cells, but it is unknown if such cell-type-specific circuit motifs extend to dendrite-targeting interneurons. Using male and female mice, we investigated synaptic connectivity and physiology in brain slices from four transgenic lines thought to capture distinct subsets of interneurons: SST-IRES-Cre, Nkx2.1-Cre, Chrna2-Cre, and Htr3a-GFP. First, we found that oriens-lacunosum moleculare (OLM) cells captured by the Chrna2-Cre line are a subset of Htr3a-GFP+ cells in the hippocampus. This novel finding is consistent with previous work showing Nkx2.1-Cre OLM cells are distinct from both Chrna2-Cre and Htr3a-GFP+ cells. Indeed, in paired whole-cell recordings, Nkx2.1-Cre+ interneurons in the stratum oriens, but not Chrna2-Cre+ or Htr3a-GFP+ cells, received more excitatory synaptic connections from superficial PCs relative to deep PCs. Next, we used optogenetic-assisted circuit mapping to investigate inhibition along the proximal and distal dendrites of PCs. We found that superficial PCs received stronger inhibition along their proximal dendrites than deep PCs from SST+ interneurons. Furthermore, this circuit motif was dependent on layer but not PC projection class. Finally, Chrna2-Cre OLM cells provided stronger inhibition to the distal dendrites of deep PCs relative to superficial PCs. Our data reveal that superficial and deep PCs engage in cell-type-specific circuits with dendrite-targeting interneurons. Furthermore, they support that Nkx2.1-Cre OLM cells and Chrna2-Cre/Htr3a-GFP OLM cells are distinct subtypes that form unique circuits in CA1. | | 8:35a |
Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation
Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABAB receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders including autism. Using chemogenetics to activate this midbrain-striatal circuit, we observed increased calcium signaling in microglia involving GABAB receptors. Leveraging this model, we examined microglial responses within neural circuits harboring an SCN2A nonsense (C959X) mutation associated with profound autism. Remarkably, microglia displayed heightened calcium responses to SCN2A mutation-mediated neuronal hyperactivity, and engaged in excessive synaptic pruning. These pathological effects were reversed by pharmacological inhibition of microglial GABAB receptors. Collectively, our findings establish an advanced platform to dissect human neuroimmune interactions in sub-cortical regions, highlighting the important role of microglia in shaping critical circuitry related to neuropsychiatric disorders. | | 12:46p |
Receptor-enriched analysis of functional connectivity (REACT) for understanding cannabinoid neuropsychopharmacology
Background: Cannabis is one of the most widely used psychoactive substances in the world and is increasingly investigated as a treatment for neuropsychiatric conditions. Cannabis contains delta-9-tetrahydrocannabinol (THC), which is thought to underlie its main psychoactive effects, and cannabidiol (CBD), which has been proposed to modulate the effects of THC on the brain. Both have activity at CB1 receptors, whilst THC also binds to CB2 receptors. However, it is unclear how THC's effects on brain function are related to cannabinoid receptors, or how CBD co-administration affects this. We aimed to investigate the effects of vaporised THC and the moderating effects of CBD on CB1 and CB2 receptor-enriched functional connectivity. Methods: Forty-eight participants (24 adolescents and 24 adults) who used cannabis 0.5-3 days/week (mean=1.5 days/week) participated in a randomised, crossover, placebo-controlled, double-blind experiment where they inhaled vaporised cannabis containing either THC-only (8mg/75kg person), THC+CBD (8 mg THC + 24mg CBD/75kg person) or no psychoactive compounds (placebo). Resting-state functional MRI data were collected approximately 50 minutes post-administration. Receptor distribution maps were derived from positron emission tomography (PET) imaging for CB1 receptors and the Allen Human Brain Atlas (AHBA) for CB2 receptors. Receptor-Enriched Analysis of Connectivity by Targets (REACT) analytical methodology was used to investigate changes in functional connectivity related to specific receptor targets. Results: Inhalation of both THC-only and THC+CBD cannabis induced significant decreases in CB1 and CB2 receptor-enriched functional connectivity compared to placebo. The THC+CBD condition showed more extensive reductions than THC-only cannabis for both CB1- and CB2-enriched functional connectivity, affecting regions including the dorsolateral prefrontal cortex, cingulate cortex, insula, hippocampus, amygdala, and putamen. Higher THC plasma levels were associated with greater decreases in functional connectivity in the THC+CBD condition. Exploratory analyses identified significant positive and negative relationships between subjective drug effects and receptor-enriched functional connectivity in a region-dependent manner. Conclusions: Cannabis with and without CBD decreased resting-state functional connectivity in networks associated with CB1 and CB2 receptor distribution. Co-administration of CBD with THC appears to enhance these effects. The REACT analytical methodology identified changes in CB1- and CB2-enriched functional connectivity are related to THC and CBD plasma levels as well as subjective drug effects across a range of regions. | | 2:48p |
A High-Resolution Atlas of the Brain Predicts Lineage and Birth Order Underly Neuronal Identity.
Gene expression shapes the nervous system at every biological level, from molecular and cellular processes defining neuronal identity and function to systems-level wiring and circuit dynamics underlying behaviour. Here, we generate the first high-resolution, single-cell transcriptomic atlas of the adult Drosophila melanogaster central brain by integrating multiple datasets, achieving an unprecedented tenfold coverage of every neuron in this complex tissue. We show that a neuron's genetic identity overwhelmingly reflects its developmental origin, preserving a genetic address based on both lineage and birth order. We reveal foundational rules linking neurogenesis to transcriptional identity and provide a framework for systematically defining neuronal types. This atlas provides a powerful resource for mapping the cellular substrates of behaviour by integrating annotations of hemilineage, cell types/subtypes and molecular signatures of underlying physiological properties. It lays the groundwork for a long-sought bridge between developmental processes and the functional circuits that give rise to behaviour. | | 4:45p |
Prediction, Syntax and Semantic Grounding in the Brain and Large Language Models
Language comprehension involves continuous prediction of upcoming words, with syntactic structure and semantic meaning intertwined in the human brain. To date, few studies have used combined magnetoencephalography (MEG) and electroencephalography (EEG) measurements to investigate how syntactic processing, predictive coding, and semantic grounding interact in real time. Here we present the first combined MEG-EEG investigation of syntactic processing and semantic grounding under naturalistic conditions. Twenty-nine healthy participants listened to a German audio book while their neural responses were recorded. Event-related fields and event-related potentials for four word classes - nouns, verbs, adjectives, and proper nouns - showed highly reproducible, characteristic spatio-temporal signatures, including significant pre-onset activity for nouns, suggesting enhanced predictability of this word class. Source-space analyses revealed pronounced activation in the pre- and post-central gyri for nouns, suggesting a deeper semantic grounding of nouns in e.g. sensory experiences than verbs. To further investigate predictive mechanisms, we analyzed the hidden representations of the large language model Llama. By comparing the transformer-based representations to neural responses, we explored the relationship between computational language models and human brain activity, offering new insights into syntactic and semantic prediction. These findings highlight the power of simultaneous MEG-EEG recordings in unraveling the predictive, syntactic, and semantic mechanisms that underlie the comprehension of natural language. | | 4:45p |
Kv2/Kv6.4 heteromeric potassium channels are expressed in spinal motor neurons and localized at C-bouton synapses
Voltage-gated K+ channels of the Kv2 family co-assemble with electrically silent KvS subunits in specific subpopulations of brain neurons, forming heteromeric Kv2/KvS channels with distinct functional properties. Little is known about the composition and function of Kv2 channels in spinal cord neurons, however. Here, we show that while Kv2.1 is broadly expressed in multiple classes of spinal cord neurons, the Kv6.4 electrically-silent subunit is specifically expressed in motor neurons. In motor neurons, we find that Kv6.4 protein is co-clustered with Kv2.1 and Kv2.2 subunits at endoplasmic reticulum-plasma membrane (ER-PM) junctions beneath C-bouton synapses. In Kv2.1 S590A mutant mice, in which Kv2.1 is unable to bind ER VAP proteins, Kv2.1 and Kv6.4 clustering at ER-PM junctions is severely reduced suggesting Kv2 channels are localized at ER-PM junctions by the same molecular mechanism in motor neurons and brain neurons. Moreover, clustering of Kv6.4, as well as the AMIGO-1 auxiliary subunit, are severely reduced in Kv2.1 knockout mice and moderately reduced in Kv2.2 knockout mice. Thus, expression and localization of Kv6.4 subunits is dependent on Kv2 subunits, likely through their co-assembly into heteromeric channels. Finally, we find that presynaptic C-boutons and postsynaptic clusters of the ER-resident sigma1-receptor are preserved in motor neurons of Kv2 knockout mice. Together, these findings identify a specific Kv2/KvS channel subtype expressed in motor neurons that localizes to C-bouton junctions where it could regulate neuronal excitability and signaling at ER-PM junctions. | | 4:45p |
The Cerebellum and Striatum in Reward Processing: Caring About Being Right vs. Caring About Reward
Emerging evidence indicates the cerebellum contributes to cognitive functions including social reward processing, yet its specific role relative to established reward regions like the ventral striatum remains undefined. We hypothesized the cerebellum would respond equivalently to both positive and negative social rewards. This prediction is grounded in classical findings that the cerebellum operates via supervised learning mechanisms that rely on error signals rather than traditional reward-based reinforcement. Using fMRI, we examined adolescents and young adults during a social prediction task where participants forecasted others' opinions of them and received accuracy feedback. Findings reveal that both the ventral striatum and a subregion of the posterior cerebellum (Crus I and II) were sensitive to social rewards. However, unlike the ventral striatum, the cerebellum exhibited a more uniform response to feedback, treating correct predictions about being liked and disliked in a similar manner. No age-related differences were observed. These findings suggest the cerebellum processes social rewards distinctly from the ventral striatum, likely reflecting its computational emphasis on prediction errors rather than reward valence. This functional distinction advances our understanding of cerebellar contributions to social cognition and learning mechanisms. | | 4:45p |
Brain-Penetrating Peptide and Antibody Radioligands for Proof-of-Concept PET Imaging of Fibrin in Alzheimer's Disease
Background: Alzheimer's disease (AD) is increasingly recognized as a multifactorial disorder with vascular contributions, including a pro-coagulant state marked by fibrin deposition in the brain. Fibrin accumulation may exacerbate cerebral hypoperfusion, leading to neurodegeneration. Identifying patients with this pathology could enable targeted anticoagulant therapy. However, current imaging tools lack the specificity and sensitivity to detect fibrin in the brain. This study aimed to develop and evaluate brain-penetrating peptide- and antibody-based PET radioligands targeting fibrin to enable individualized treatment strategies in AD. Results: A fibrin-binding peptide (FBP) was conjugated to the antibody fragment scFv8D3, which targets the transferrin receptor (TfR), to facilitate transcytosis across the blood-brain barrier. FBP-scFv8D3 bound TfR and with modest affinity to fibrin, though with limited selectivity over fibrinogen. In vivo studies in Tg-ArcSwe mice, that exhibit fibrin along with brain amyloid-{beta} pathology, and wild-type mice showed that [125I]FBP-scFv8D3 retained brain-penetrating properties but did not demonstrate significant fibrin-specific retention. In contrast, the monoclonal antibody 1101 and its bispecific, brain penetrant variant 1101-scFv8D3 exhibited high fibrin selectivity and TfR binding. Both antibodies showed a trend towards higher brain retention in Tg-ArcSwe mice and [125I]1101-scFv8D3 showed a higher brain-to-blood ratio compared to [124I]1101. PET imaging with [124I]1101 and [124I]1101-scFv8D3 revealed low brain uptake but ex vivo autoradiography suggested specific cortical retention in Tg-ArcSwe mice. Conclusion: This study demonstrates the feasibility of using bispecific antibody-based PET radioligands to target fibrin in the AD brain. While the FBP-scFv8D3 conjugate showed limited specificity, the bispecific antibody 1101-scFv8D3 exhibited promising brain penetration and fibrin selectivity. These findings support further development of antibody-based imaging tools toward the goal to stratify AD patients who may benefit from anticoagulant therapy. | | 4:45p |
Neural Tracking of Audiovisual Effects in Noise Using Deep Neural Network-Generated Virtual Humans
This study investigates the effectiveness of Deep Neural Network (DNN)-generated virtual humans in enhancing audiovisual speech perception in noisy environments, with a focus on using neural measures to quantify these effects. Lip movements are essential for speech comprehension, especially when auditory cues are degraded by noise. Traditional recording methods produce high-quality audiovisual materials but are resource intensive. This research explores the use of DNN avatars as a promising alternative, utilizing a commercially available tool to create realistic virtual humans. The study included both simple sentences and a short story to improve ecological validity. Eleven young, normal-hearing participants proficient in Flemish-Dutch listened to semantically meaningful sentences and a short story with various speaker types: a female FACS avatar, male and female DNN avatars, and a video of a human male speaker. The study included behavioral measures which consisted of an adaptive recall procedure and an adaptive rate procedure and electrophysiological measures consisting of neural tracking. Findings in the adaptive recall procedure showed consistent audiovisual benefits, with the human speaker offering the greatest benefit (-4.75 dB SNR), followed by the DNN avatar (-4.00 dB SNR) and the FACS avatar (-1.55 dB SNR). Additionally in the adaptive rate procedure, the DNN avatar improved speech intelligibility, with average SRTs enhancing from -7.17 dB SNR (audio-only) to -9.02 dB SNR (audiovisual). The results from the neural tracking procedure indicated that most participants experienced audiovisual benefits, particularly in the -9 dB SNR range, revealing that audiovisual cues provided by DNN avatars can enhance speech perception, validating these avatars as effective tools for studying audiovisual effects when using both behavioral measures and electrophysiological measures. | | 5:15p |
LOSS OF ARGINASE 2 DISRUPTS STRIATUM-SPECIFIC POLYAMINE HOMEOSTASIS
Arginase converts arginine (Arg) to ornithine (Orn), regulating their availability for the metabolic pathways that utilize these amino acids. The roles of arginase isoenzymes, Arg1 and Arg2, vary by cell type, tissue, and physiological state. In the brain, Arg2 is the predominant isoenzyme, particularly enriched in the striatum, where it localizes to a striatum-specific neuronal population - medium spiny neurons (MSNs). While the precise role of Arg2 in MSNs remains unclear, its loss alters the striatal metabolomic profile, highlighting its metabolic significance. Here, to investigate the basis of these complex metabolic changes, we examined Arg metabolism in Arg2 knockout (Arg2-/-) mice. Targeted analysis of Arg-related metabolites and selected proteins regulating Arg metabolic pathways revealed that Arg2 loss significantly increased Arg levels but did not affect Orn, likely due to compensatory synthesis of Orn from Arg (via arginine:glycine amidinotransferase) and/or proline (via ornithine aminotransferase). Additionally, markers of nitric oxide (NO) production remained unchanged, suggesting that striatal Arg2 is not involved in the regulation of this pathway, a role commonly attributed to arginase. Most notably, Arg2 loss disrupted polyamine homeostasis, shifting the balance toward higher polyamines at the expense of lower ones and altering the expression of polyamine-regulating proteins. These findings highlight Arg2 crucial role in striatal metabolism and its potential relevance to striatum-related disorders. Given that striatal Arg2 impairment has been reported in Huntington's disease, a neurodegenerative disorder specifically affecting MSNs, understanding its function may provide insights into the pathology. | | 5:15p |
Increased circulating TREM2+ microglia extracellular vesicles in aged APP/PS1 Alzheimer's disease rats
Introduction: TREM2 is a microglial marker important in Alzheimer's disease (AD) pathogenesis, but current methods to detect microglial TREM2 expression in vivo are limited. Circulating microglia-derived extracellular vesicles (EVs) show promise as potential biomarkers for AD and may offer insight into TREM2 activity. Methods: TMEM119+/TREM2+ EVs were assessed using nanoscale flow cytometry in plasma from wildtype and APP/PS1 rats aged to 3-. 9-, and 15-months-old. Molecular and histological assays were used to assess microglia markers in rat brain tissue and a radial arm water maze task was employed to evaluate spatial working and reference memory. Results: Circulating TMEM119+/TREM2+ EVs were increased in 15-month APP/PS1 rats and associated with severity of cognitive impairment. TREM2 brain expression varied by anatomical region, age, transgene, and assay. Discussion: Collectively, this study provides the first assessment of TMEM119+?Tremem2+ EVs as a biomarker of brain microglia expression and cognition in an AD rat model. | | 6:00p |
Dissecting surveying behavior of reactive microglia under chronic neurodegeneration
In the healthy brain, microglia maintain homeostasis by continuously surveying neuronal health through highly dynamic processes that form purinergic junctions with neuronal somas. These mechanisms are finely tuned for the rapid detection of acute injuries. However, during the transition to a chronically reactive state in neurodegenerative diseases, microglial ramification decreases even as the need for neuronal monitoring escalates. How reactive microglia adapt their surveillance strategies under these conditions remains poorly understood. Using time-lapse imaging of acute brain slices from prion-infected mice, we identified a previously unrecognized mode of neuronal surveillance employed by reactive microglia. Unlike homeostatic microglia, which exhibit low somatic mobility and high process motility, enabling broad, simultaneous monitoring, reactive microglia display high somatic mobility. These cells actively migrate through the brain parenchyma, pausing to form direct and extensive body-to-body contacts with individual neurons. Contact durations ranged from minutes to several hours, often involving partial or full somatic envelopment, with transitions between these states being both frequent and reversible. Notably, reactive microglia exhibited sustained intracellular calcium bursts correlated with their increased mobility. Pharmacological inhibition of the P2Y6 receptor partially reduced microglial migration without disrupting their ability to form neuronal contacts. Furthermore, this highly mobile behavior persisted in acutely isolated reactive microglia in vitro, even in the absence of external stimuli, indicating that dynamic mobility is an intrinsic feature of the reactive phenotype. These findings reveal a fundamental shift in microglial surveillance architecture during chronic neurodegeneration - transforming from static, multi-neuron monitoring to dynamic, neuron-by-neuron engagement. This work uncovers a novel, adaptive strategy of microglial behavior with critical implications for understanding microglia-neuron interaction under chronic neurodegeneration. | | 6:00p |
Oxytocin release modulates acute neuroinflammation and improves brain development after pediatric traumatic brain injury
Pediatric traumatic brain injury (TBI) is a leading cause of death and disability early in life in infants, and its neurodevelopmental consequences cannot currently be effectively treated. Since TBI is associated with neuroinflammation, modulation of the post-injury neuroinflammatory response is a promising strategy. Oxytocin is thought to have anti-inflammatory properties and appears to play a role in clinical interventions that improve brain development in neonates. However, the underlying mechanisms remain unclear, as does its applicability in acute brain injury. Here we investigate the effects of chemogenetic modulation of endogenous oxytocin on acute neuroinflammation and on long-term brain development after TBI in postnatal day 7 (P7) male mice. We show that oxytocin release attenuates the acute neuroinflammatory response to TBI 24 hours after injury, by reducing the expression of immune- and inflammation-related genes in astrocytes and promoting gene pathways for brain repair and development in microglia. In the long term, oxytocin exposure ameliorates subcortical and cortical white matter damage after TBI, prevents hyperactivity and loss of social behavior, and restores TBI-induced alterations in resting-state functional connectivity of the isocortex. These findings enhance our understanding of the modulation of neuroinflammation and its long-term effects and support intervention related to endogenous oxytocin release as a promising neuroprotective strategy in pediatric TBI. | | 6:32p |
Chronic benzodiazepine treatment triggers gephyrin scaffold destabilization and GABAAR subsynaptic reorganization
Benzodiazepines (BZDs) are important clinical drugs with anxiolytic, anticonvulsant, and sedative effects mediated by potentiation of inhibitory GABA type A receptors (GABAARs). Tolerance limits the clinical utility of BZDs, yet the mechanisms underlying tolerance after chronic exposure have not been thoroughly investigated. Here, we assessed the impact of chronic (7-day) treatment with the BZD diazepam (DZP) on the dynamic plasticity and subsynaptic organization of the gephyrin scaffold and {gamma} subunit-containing GABAARs in primary neurons. After functional confirmation of diminished BZD sensitivity, we provide the first super-resolution analysis of inhibitory nanoscale plasticity induced by chronic BZD exposure: gephyrin subsynaptic domains were smaller and the inhibitory postsynaptic area was overall diminished by DZP treatment, resulting in a condensation of synaptic {gamma}2-GABAARs into smaller subsynaptic areas. Using a novel fluorescence-based in situ proximity ligation assay and biochemical fractionation analysis, the mechanism for gephyrin downregulation was revealed to be dependent on phosphorylation and protease cleavage. Accordingly, DZP treatment impaired gephyrin synaptic stability, demonstrated by live-imaging photobleaching experiments. Despite the loss of BZD sensitivity and stable synaptic gephyrin, 7-day DZP treatment did not reduce the surface or total protein levels of BZD-sensitive {gamma}2-GABAARs, as shown in prior short-term BZD treatment studies. Instead, chronic DZP treatment induced an accumulation of {gamma}2-GABAARs in the extrasynaptic membrane. Surprisingly, {gamma}2-GABAAR interactions with gephyrin were also enriched extrasynaptically. An identified rise in extrasynaptically-localized gephyrin cleavage fragments may function to confine receptors away from the synapse, as supported by a decrease in extrasynaptic {gamma}2-GABAAR mobility. Altogether, we find that chronic BZD treatment triggers several subtle converging plasticity events at inhibitory synapses which effectively restrict the synaptic renewal of BZD-sensitive GABAARs via mechanisms distinct from those observed with short-term treatment. |
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