Neuron最新文献

In this issue of Neuron, Park et al.¹ show that striatal activity is necessary for the specification of movement kinematics using a novel reach-to-pull task for mice. Through simultaneous cortical and subcortical recordings and manipulations, they demonstrate that motor cortex and striatum conjointly specify parameters necessary for shaping flexible, goal-directed actions.

Continuous sleep restores the brain and body, whereas fragmented sleep harms cognition and health. Microarousals (MAs), brief (3- to 15-s-long) wake intrusions into sleep, are clinical markers for various sleep disorders. Recent rodent studies show that MAs during healthy non-rapid eye movement (NREM) sleep are driven by infraslow fluctuations of noradrenaline (NA) in coordination with electrophysiological rhythms, vasomotor activity, cerebral blood volume, and glymphatic flow. MAs are hence part of healthy sleep dynamics, raising questions about their biological roles. We propose that MAs bolster NREM sleep's benefits associated with NA fluctuations, according to an inverted U-shaped curve. Weakened noradrenergic fluctuations, as may occur in neurodegenerative diseases or with sleep aids, reduce MAs, whereas exacerbated fluctuations caused by stress fragment NREM sleep and collapse NA signaling. We suggest that MAs are crucial for the restorative and plasticity-promoting functions of sleep and advance our insight into normal and pathological arousal dynamics from sleep.

Integrating analyses of genetically defined cell types with population-level approaches remains poorly explored. We investigated this question by focusing on hippocampal spatial maps and the contribution of two genetically defined pyramidal cell types in the deep and superficial CA1 sublayers. Using single- and dual-color miniscope imaging in mice running along a linear track, we found that population activity from these cells exhibited three-dimensional ring manifolds that encoded the animal position and running direction. Despite shared topology, sublayer-specific manifolds displayed distinct geometric features. Manipulating track orientation revealed rotational and translational changes in manifolds from deep cells, contrasting with more stable representations by superficial cells. These transformations were not observed in manifolds derived from the entire CA1 population. Instead, cell-type-specific chemogenetic silencing of either sublayer revealed independent geometric codes. Our results show how genetically specified subpopulations may underpin parallel spatial maps that can be manipulated independently.

The brain's primary immune cells, microglia, are a leading causal cell type in Alzheimer's disease (AD). Yet, the mechanisms by which microglia can drive neurodegeneration remain unresolved. Here, we discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a microglia subset with neurodegenerative outcomes. Autonomous activation of ISR in microglia is sufficient to induce early features of the ultrastructurally distinct "dark microglia" linked to pathological synapse loss. In AD models, microglial ISR activation exacerbates neurodegenerative pathologies and synapse loss while its inhibition ameliorates them. Mechanistically, we present evidence that ISR activation promotes the secretion of toxic lipids by microglia, impairing neuron homeostasis and survival in vitro. Accordingly, pharmacological inhibition of ISR or lipid synthesis mitigates synapse loss in AD models. Our results demonstrate that microglial ISR activation represents a neurodegenerative phenotype, which may be sustained, at least in part, by the secretion of toxic lipids.

The choroid plexus (CP) serves as the primary source of cerebrospinal fluid (CSF). The blood-CSF barrier, composed of tight junctions among the epithelial cells in the CP, safeguards CSF from unrestricted exposure to bloodborne factors. This barrier is thus indispensable to brain homeostasis and is associated with age-related neural disorders. Nevertheless, its aging is poorly understood. Here, we report that cathepsin S (CTSS), a protease secreted from the CP macrophages, is upregulated in aged CP due to increased cell senescence. CTSS cleaves the essential tight junction component, claudin 1 (CLDN1), and, in turn, impairs the blood-CSF barrier. Notably, inhibiting CTSS or upregulating CLDN1 in aged CP rejuvenates the blood-CSF barrier and brain functions. Our findings uncover a vital interplay between immune and barrier cells that accelerates CP and brain aging, identify CTSS as a potential target to improve brain homeostasis in aged animals, and underscore the critical role of circulating proteinases in aging.

Motor output results from the coordinated activity of neural circuits distributed across multiple brain regions that convey information to the spinal cord via descending motor pathways. Yet the organizational logic through which supraspinal systems target discrete components of spinal motor circuits remains unclear. Here, using viral transsynaptic tracing along with serial two-photon tomography, we have generated a whole-brain map of monosynaptic inputs to spinal V1 interneurons, a major inhibitory population involved in motor control. We identified 26 distinct brain structures that directly innervate V1 interneurons, spanning medullary and pontine regions in the hindbrain as well as cortical, midbrain, cerebellar, and neuromodulatory systems. Moreover, we identified broad but biased input from supraspinal systems onto V1^Foxp2 and V1^Pou6f2 neuronal subsets. Collectively, these studies reveal elements of biased connectivity and convergence in descending inputs to molecularly distinct interneuron subsets and provide an anatomical foundation for understanding how supraspinal systems influence spinal motor circuits.

Attention deficit hyperactivity disorder (ADHD), affecting 4% of the population, is characterized by inattention, hyperactivity, and impulsivity; however, its neurophysiological mechanisms remain unclear. Here, we discovered that deficiency of histamine H₂ receptor (H₂R) in parvalbumin-positive neurons in substantia nigra pars recticulata (PV^SNr) attenuates PV⁺ neuronal activity and induces hyperactivity, impulsivity, and inattention in mice. Moreover, decreased H₂R expression was observed in PV^SNr in patients with ADHD symptoms and dopamine-transporter-deficient mice, whose behavioral phenotypes were alleviated by H₂R agonist treatment. Dysfunction of PV^SNr efferents to the substantia nigra pars compacta dopaminergic neurons and superior colliculus differently contributes to H₂R-deficiency-induced behavioral disorders. Collectively, our results demonstrate that H₂R deficiency in PV⁺ neurons contributes to hyperactivity, impulsivity, and inattention by dampening PV^SNr activity and involving different efferents in mice. It may enhance understanding of the molecular and circuit-level basis of ADHD and afford new potential therapeutic targets for ADHD-like psychiatric diseases.

Magnesium (Mg²⁺) is a key regulatory ion of N-methyl-ᴅ-aspartate (NMDA) receptors, including conferring them to function as coincidence detectors for excitatory synaptic transmission. However, the structural basis underlying the Mg²⁺ action on NMDA receptors remains unclear. Here, we report the cryo-EM structures of GluN1-N2B receptors and identify three distinct Mg²⁺-binding pockets. Specifically, site Ⅰ is located at the selectivity filter where an asparagine ring forms coordination bonds with Mg²⁺ and is responsible for the voltage-dependent block. Sites Ⅱ and Ⅲ are located at the N-terminal domain (NTD) of the GluN2B subunit and involved in the allosteric potentiation and inhibition, respectively. Site Ⅱ consists of three acidic residues, and the combination of three mutations abolishes the GluN2B-specific Mg²⁺ potentiation, while site Ⅲ overlaps with the Zn²⁺ pocket, and mutations here significantly reduce the inhibition. Our study enhances the understanding of multifaceted roles of Mg²⁺ in NMDA receptors and synaptic plasticity.

The enteric nervous system (ENS) controls digestion autonomously via a complex neural network within the gut wall. Enteric neurons expressing glutamate have been identified by transcriptomic studies as a distinct subpopulation, and glutamate can affect intestinal motility by modulating enteric neuron activity. However, the nature of glutamatergic neurons, their position within the ENS circuit, and their function in regulating gut motility are unknown. We identify glutamatergic neurons as longitudinally projecting descending interneurons in the small intestine and colon and as a novel class of circumferential neurons only in the colon. Both populations make synaptic contact with diverse neuronal subtypes and signal with multiple neurotransmitters and neuropeptides in addition to glutamate, including acetylcholine and enkephalin. Knocking out the glutamate transporter VGLUT2 from enkephalin neurons disrupts gastrointestinal transit, while ex vivo optogenetic stimulation of glutamatergic neurons initiates colonic propulsive motility. Our results posit glutamatergic neurons as key interneurons that regulate intestinal motility.