Neuron最新文献

Much effort has been spent clustering neurons into transcriptomic or functional cell types and characterizing the differences between them. Beyond subdividing neurons into categories, we must recognize that no two neurons are identical and that graded physiological or transcriptomic properties exist within cells of a given type. This often overlooked "within-type" heterogeneity is a specific neuronal implementation of what statistical physics refers to as "disorder" and exhibits rich computational properties, the identification of which may shed crucial insights into theories of brain function. In this perspective article, we address this gap by highlighting theoretical frameworks for the study of neural tissue heterogeneity and discussing the benefits and implications of within-type heterogeneity for neural network dynamics, computation, and self-organization.

Genetic variations in MS4A4A and MS4A6A Triggering receptor expressed on myeloid cells 2 (TREM2) are linked to the regulation of cerebrospinal-fluid-soluble TREM2 levels and are associated with Alzheimer's disease (AD) risk and progression. By modulating MS4A4A using knockout, overexpression, and degrading antibodies in macrophages, microglia, non-human primates (NHPs), and a mouse model of amyloid pathology, we provide evidence that MS4A4A and MS4A6A are negative regulators of both the transmembrane and soluble TREM2 proteins. Additionally, MS4A4A limits microglia viability, phagocytosis, and lysosomal function, processes that contribute to disease pathology. Mechanistically, we find that MS4A4A restrains TREM2 by an indirect mechanism: MS4A4A interacts with MS4A6A and protects it from degradation. MS4A6A, in turn, forms a complex with and blocks the co-receptor DNAX-activating protein of 12 kDa (DAP12), which modulates the levels of TREM2 and other receptors. Taken together, the data indicate that MS4A4A and MS4A6A are cooperative post-transcriptional negative regulators of TREM2 and microglial function as well as potential drug targets for AD.

Breast cancer patients often exhibit disrupted diurnal rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality; however, the exact cause of this phenomenon remains unclear. Here, we demonstrate that breast tumor-bearing mice exhibit blunted GC rhythms and a loss of diurnal rhythms in the activity of paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (PVN^CRH). This change in neuronal activity is mediated by disinhibition from upstream GABAergic neurons. Using chemogenetics to stimulate PVN^CRH neurons at different times of day, we show that stimulation just before the light-to-dark transition restores normal GC rhythms, reduces tumor progression, and increases intra-tumor effector T cells (CD8+). Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control the output of the hypothalamic-pituitary-adrenal (HPA) axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression via enhancing anti-tumor immunity.

Value-guided decisions are a cornerstone of cognition, yet the underlying circuit-level mechanisms remain elusive. We used reinforcement learning to train recurrent neural network models endowed with Dale's law on a battery of economic choice tasks, which revealed a two-stage computational framework. First, value estimation occurs at the input level, where learned weights store subjective preferences and approximate the non-linear multiplication of reward magnitude and probability to yield expected values. This feedforward mechanism enables generalization to novel choice options. Second, option values are compared within the recurrent network, where specific connectivity patterns mediate robust winner-take-all decisions, with both excitatory and inhibitory neurons exhibiting value and choice selectivity. By training a single network on multiple tasks, we show compositional representations combining a shared computational schema with specialized neural modules. Reproducing key neurophysiological findings from the primate orbitofrontal cortex, our model unifies value computation, comparison, and generalization into a coherent framework with testable predictions.

Defective nucleocytoplasmic transport (NCT) has emerged as a contributing factor in the pathogenesis of neurodegenerative diseases and aging. Valosin-containing protein (VCP) is an AAA+ATPase required for disassembly of protein complexes, and mutations in VCP cause neurodegenerative and neuromuscular diseases. We find that VCP is required for quality control of nuclear pore complexes (NPCs) by extracting selected nucleoporins from NPCs for proteasome-mediated degradation. Pathogenic VCP variants cause a reduction in nucleoporins in Drosophila, induced pluripotent stem cell (iPSC)-derived motor neurons, and muscle biopsies from patients, indicating a dominant gain-of-function mechanism. Mechanistically, disease-associated mutations in VCP result in increased recruitment to NPCs through interactions with Ufd1-Npl4, leading to the removal of a subset of nucleoporins from NPCs and disrupting NCT. These findings show that the VCP-Ufd1-Npl4 pathway regulates NPC quality control and that disease-associated variants aberrantly activate the VCP-Ufd1-Npl4 complex to degrade NPCs and disrupt NCT.