Neuron最新文献

High-throughput methods are revolutionizing our ability to classify neurons based on their transcriptome. In this issue of Neuron, Hozhabri and colleagues¹ first categorize songbird GABAergic neurons by functional role and then link these functional subtypes to molecular identity.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we profiled genome-wide histone modifications and found that a decrease in histone H3 acetylation (ac) at downregulated genes is among the earliest molecular changes occurring well before any measurable deficiencies in electrophysiology and neurological function. These data reveal a molecular cascade that drives disease independent of any developmental contributions or secondary pathogenesis.

Transient exposure to ketamine can trigger lasting changes in behavior and mood. We found that brief ketamine exposure causes long-term suppression of futility-induced passivity in larval zebrafish, reversing the "giving-up" response that normally occurs when swimming fails to cause forward movement. Whole-brain imaging revealed that ketamine hyperactivates the norepinephrine-astroglia circuit responsible for passivity. After ketamine washout, this circuit exhibits hyposensitivity to futility, leading to long-term increased perseverance. Pharmacological, chemogenetic, and optogenetic manipulations show that norepinephrine and astrocytes are necessary and sufficient for ketamine's long-term perseverance-enhancing aftereffects. In vivo calcium imaging revealed that astrocytes in adult mouse cortex are similarly activated during futility in the tail suspension test and that acute ketamine exposure also induces astrocyte hyperactivation. The cross-species conservation of ketamine's modulation of noradrenergic-astroglial circuits and evidence that plasticity in this pathway can alter the behavioral response to futility hold promise for identifying new strategies to treat affective disorders.

The cortex amplifies responses to novel stimuli while suppressing redundant ones. Novelty detection is necessary to efficiently process sensory information and build predictive models of the environment, and it is also altered in schizophrenia. To investigate the circuit mechanisms underlying novelty detection, we used an auditory "oddball" paradigm and two-photon calcium imaging to measure responses to simple and complex stimuli across mouse auditory cortex. Stimulus statistics and complexity generated specific responses across auditory areas. Neuronal ensembles reliably encoded auditory features and temporal context. Interestingly, stimulus-evoked population responses were particularly long lasting, reflecting stimulus history and affecting future responses. These slow cortical dynamics encoded stimulus temporal context and generated stronger responses to novel stimuli. Recurrent neural network models trained on the oddball task also exhibited slow network dynamics and recapitulated the biological data. We conclude that the slow dynamics of recurrent cortical networks underlie processing and novelty detection.

Social competition determines hierarchical social status, which profoundly influences animals' behavior and health. The dorsomedial prefrontal cortex (dmPFC) plays a fundamental role in regulating social competitions, but it was unclear how the dmPFC orchestrates win- and lose-related behaviors through its downstream neural circuits. Here, through whole-brain c-Fos mapping, fiber photometry, and optogenetics- or chemogenetics-based manipulations, we identified anatomically segregated win- and lose-related neural pathways downstream of the dmPFC in mice. Specifically, layer 5 neurons projecting to the dorsal raphe nucleus (DRN) and periaqueductal gray (PAG) promote social competition, whereas layer 2/3 neurons projecting to the anterior basolateral amygdala (aBLA) suppress competition. These two neuronal populations show opposite changes in activity during effortful pushes in competition. In vivo and in vitro electrophysiology recordings revealed inhibition from the lose-related pathway to the win-related pathway. Such antagonistic interplay may represent a central principle in how the mPFC orchestrates complex behaviors through top-down control.

Using single-cell technologies on postmortem brains, Handsaker et al.¹ have demonstrated that substantial somatic expansion of the CAG repeat that causes Huntington's disease results in progressive transcriptional dysregulation and drives the loss of spiny projection neurons in the caudate.

Poor understanding of the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies. To address this gap, we analyzed 632,000 single-nucleus RNA sequencing profiles from 156 brain tissue samples of MS and control donors to examine inter- and intra-donor heterogeneity. We found distinct cell type-specific gene expression changes between MS gray and white matter, highlighting clear pathology differences. MS lesion subtypes had different cellular compositions but surprisingly similar cell-type gene expression patterns both within and across patients, suggesting global changes. Most gene expression variability was instead explained by patient effects, allowing us to stratify patients and describe the different pathological processes occurring between patient subgroups. Future mapping of these brain molecular profiles with blood and/or CSF profiles from living MS patients will allow precision medicine approaches anchored in patient-specific pathological processes.

Autoimmune neurology is a rapidly expanding field driven by the discovery of neuroglial autoantibodies and encompassing a myriad of conditions affecting every level of the nervous system. Traditionally, autoantibodies targeting intracellular antigens are considered markers of T cell-mediated cytotoxicity, while those targeting extracellular antigens are viewed as pathogenic drivers of disease. However, recent advances highlight complex interactions between these immune mechanisms, suggesting a continuum of immunopathogenesis. The breakdown of immune tolerance, central to these conditions, is affected by modifiable and non-modifiable risk factors such as genetic predisposition, infections, and malignancy. While significant therapeutic advancements have revolutionized treatment of certain diseases, such as neuromyelitis optica, our understanding of many others, particularly T cell-mediated conditions, remains limited, with fewer treatment options available. Future research should focus on improving effector function modeling and deepening our understanding of the factors influencing immune tolerance, with the goal of providing novel treatment options and improving patient care.

Chronic pain is a leading cause of disability, affecting more women than men. Different immune cells contribute to this sexual divergence, but the mechanisms, especially in females, are not well defined. We show that pannexin-1 (Panx1) channels on microglia and T cells differentially cause mechanical allodynia, a debilitating symptom of neuropathic pain. In male rodents, Panx1 drives vascular endothelial growth factor-A (VEGF-A) release from microglia. Cell-specific knockdown of microglial Panx1 or pharmacological blockade of the VEGF receptor attenuated allodynia in nerve-injured males. In females, nerve injury increased spinal CD8⁺ T cells and leptin levels. Leptin release from female-derived CD8⁺ T cells was Panx1 dependent, and intrathecal leptin-neutralizing antibody injection sex-specifically reversed allodynia. Adoptive transfer of female-derived CD8⁺ T cells caused robust allodynia, which was prevented by a leptin-neutralizing antibody or leptin small interfering RNA (siRNA) knockdown. Panx1-targeted approaches may alleviate neuropathic pain in both sexes, while T cell- and leptin-directed treatments could have sex-dependent benefits for women.

Polymorphisms in CD2-associated protein (CD2AP) predispose to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. Here, we show that loss of CD2AP in cerebral blood vessels is associated with cognitive decline in AD subjects and that genetic downregulation of CD2AP in brain vascular endothelial cells impairs memory function in male mice. Animals with reduced brain endothelial CD2AP display altered blood flow regulation at rest and during neurovascular coupling, defects in mural cell activity, and an abnormal vascular sex-dependent response to Aβ. Antagonizing endothelin-1 receptor A signaling partly rescues the vascular impairments, but only in male mice. Treatment of CD2AP mutant mice with reelin glycoprotein that mitigates the effects of CD2AP loss function via ApoER2 increases resting cerebral blood flow and even protects male mice against the noxious effect of Aβ. Thus, endothelial CD2AP plays critical roles in cerebrovascular functions and represents a novel target for sex-specific treatment in AD.