Neuron最新文献

The basolateral amygdala (BLA) has been implicated in threat detection and the generation of anxiety states. While previous experiments have demonstrated the important role of BLA principal neurons in driving anxiety-related behaviors, population-level recordings suggest that principal neurons encode exploratory states rather than anxiety per se. This discrepancy raises the question of whether anxiety is indeed represented within the BLA. Here, using simultaneous in vivo calcium recordings in BLA astrocytes and principal neurons, we find that, in contrast to neurons, astrocyte activity provides a stable and scalable representation of anxiety states across an array of behavioral tasks. We show that driving BLA astrocyte activity increases anxiety-related behaviors and identify noradrenaline acting on α1 adrenoreceptors as responsible for endogenous astrocyte activation and subsequent modulation of anxiety. Our results shed light on a specialized encoding property of BLA astrocytes and establish these cells as key computational elements of anxiety circuits.

Excitation-inhibition (E/I) balance depends on dynamic communication between neuronal subtypes, potentially beyond classical neurotransmission. While membrane-bound ion channels are essential for neuronal function, their potential roles as extracellular regulators of network dynamics remain largely unexplored. Here, we identify a soluble form of the voltage-gated Ca²⁺ channel subunit α2δ-1 in human cerebrospinal fluid (CSF) and show that it acts as an activity-regulated intercellular modulator of network homeostasis. Soluble α2δ-1 is reduced in the CSF of individuals with schizophrenia (SZ). Its synthetic analog, synthetic ectodomain of Alpha2Delta-1 (SEAD1), modulates cortical activity by enhancing the function of parvalbumin-positive (PV+) interneurons and restoring E/I balance. A single SEAD1 injection into the prefrontal cortex of a genetic mouse model of SZ reversed synaptic and behavioral deficits, including memory and social impairments. These findings reveal soluble synaptic ectodomains as a previously underappreciated class of extracellular signaling molecules with therapeutic potential in neuropsychiatric disorders.

The brain has the remarkable ability to guide the performance of complex tasks. Distinct prefrontal cortical areas make specific contributions to this ability, with the orbitofrontal cortex (OFC) critical for processing information related to trial outcomes and the dorsomedial prefrontal cortex (dmPFC) critical for sustained effort and selecting the right action at the right time. Yet, in both areas, neural activity represents both outcome- and action-related quantities. How similar neural representations support different functions remains unclear. Here, we compared OFC and dmPFC activity in rats performing a spatial alternation task. We show that, in contrast to other task-related variables, task progression is represented in both areas, but with distinct patterns of across-trial reliability that match each area's previously documented functional specialization. Our results indicate that the engagement of reliable, task-phase-specific activity patterns differs across prefrontal regions in a manner well suited to engage different computations at different times.

The sympathetic nervous system has emerged as a critical regulator of cancer progression, yet the underlying mechanisms remain unclear. Here, we compare genetic, pharmacological (6-hydroxydopamine [6-OHDA]), and surgical denervation in mouse breast cancer models. While all methods deplete sympathetic nerves, only 6-OHDA suppresses tumor growth, revealing a disconnect between sympathetic ablation and antitumor effect. Mechanistic investigations reveal that 6-OHDA suppresses tumor growth through immune activation rather than sympathetic ablation. 6-OHDA induces cancer cell interferon (IFN)-β production, which promotes monocyte differentiation into pro-inflammatory macrophages characterized by interferon-stimulated gene (ISG) expression. These ISG⁺ macrophages are essential for the expansion of type 1 T helper (T_H1) cells, which mediate prolonged tumor suppression. By contrast, sympathetic ablation alone does not affect macrophage differentiation or tumor growth. Our findings uncover an immunomodulatory function of 6-OHDA beyond its established neurotoxic activity and suggest the therapeutic potential of harnessing the macrophage-T_H1 axis for breast cancer.

In this issue of Neuron, Fenstermacher et al.¹ reveal that subregions of the descending serotonin system innervate separate structures in the spinal cord and are differentially active during locomotion. The results suggest fine-grained neuromodulatory control of sensation and movement.

Enteric glia are key components of the nervous system, contributing to many aspects of gastrointestinal function. In this issue of Neuron, Muppirala and colleagues reveal that anatomical niches dictate enteric glial transcriptional identity, identifying Tacr3 as a specific marker for intraganglionic glia.

In this Neuron issue, Liu et al.¹ show that the C9orf72 expanded G4C2 repeat RNA forms hybrid G-quadruplexes with CG-rich promoter regions, which impedes RNA polymerase II. This process causes global transcriptional dysregulation in C9orf72 amyotrophic lateral sclerosis patient-derived cells.

Partial cellular reprogramming can modulate aging-associated decline across multiple tissues. However, whether targeting memory-encoding ensembles within specific brain regions is sufficient to restore cognitive function has remained unknown. In this issue of Neuron, Berdugo-Vega et al. show that engram rejuvenation rescues memory deficits and restores epigenetic-transcriptional features and intrinsic excitability.

One of the largest glial populations outside the brain is in the gut. These enteric glia are involved in many functions, from intestinal peristalsis to immunity, yet it is unclear whether subtypes exist with distinct roles in homeostasis. Comparing glia from divergent microenvironments in the mouse intestine, we found that mucosal glia most resembled microglia, while muscularis glia resembled satellite glia. Tacr3, encoding the receptor for neuropeptide neurokinin B (NKB), was enriched within muscularis glia associated with neuronal soma and was undetectable in extraintestinal glia. Genetic or pharmacological manipulation of NKB-TACR3 signaling disrupted the establishment of enteric glial populations during postnatal development and dynamically modulated intestinal motor behaviors in adult mice. Collectively, we delineate spatially, transcriptionally, and functionally distinct populations of enteric glia; identify one as an unanticipated target of TACR3 antagonists in clinical use; and establish this pathway as necessary for enteric glial diversification and function.

Synaptic responses adapt on millisecond-to-second timescales through short-term plasticity (STP), a key process that filters and transforms neuronal information. While STP is classically ascribed to presynaptic release mechanisms, postsynaptic receptor properties-particularly desensitization and surface diffusion-also shape synaptic responses. Here, we dissect pre- and postsynaptic contributions to synaptic adaptation using molecular tools to visualize glutamate release and manipulate AMPA receptor (AMPAR) diffusion in intact circuits. We find that synaptic gain during STP is tuned by synapse-specific regulation of AMPAR biophysics and diffusion-trapping. These features are determined constitutively by auxiliary subunit profiles and dynamically by activity-dependent signaling engaged during long-term plasticity. With modeling, we quantified how short-term synaptic dynamics are impacted by postsynaptic regulation of filtering properties, which broadened heterogeneity of filtering timescales to refine temporal selectivity in synaptic networks. By augmenting desensitization-mediated synaptic depression, AMPAR diffusion-trapping emerges as a fundamental regulatory mechanism of postsynaptic integration and circuit-level information processing.