Neuron最新文献

Genetic variations in MS4A4A and MS4A6ATriggering 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.

In a constantly changing world, effective intelligence means anticipating future changes. We argue that organisms adapt prospectively, modeling how environments and capabilities of the organism evolve, thus optimizing decisions for tomorrow's unpredictable world.

In this issue of Neuron, Choi et al.¹ demonstrate that stroke disrupts cortical state transitions underlying reach-to-grasp control. Recovery depends on restoring separability between beta bursts and execution-related co-firing, a process enhanced by low-frequency stimulation that promotes motor recovery.

Ripples support memory consolidation via neuronal replay. Castelli et al.¹ identify two ripple types with distinct inputs and dynamics. This Preview discusses their findings in the context of current views on ripple diversity and hypothesizes that such diversity reflects a replay grammar.

Cortical neurons are characterized by their variable spiking patterns. Here, we examine the specific hypothesis that cortical synchrony drives spiking variability in vivo. Using dynamic clamps, we demonstrate that intrinsic neuronal properties do not contribute substantially to spiking variability, but rather spiking variability emerges from weakly synchronous network drive. With large-scale electrophysiology, we quantify the degree of synchrony and its timescale in cortical networks in vivo. The timescale of synchrony shifts in a range from 25 to 200 ms, depending on the presence of external sensory input. In particular, when the network moves from spontaneous to driven modes, the synchrony timescales shift from slow to fast, leading to a natural reduction in response variability across cortical areas. Finally, while an individual neuron exhibits reliable responses to physiological drive, different neurons respond in a distinct fashion according to their intrinsic properties, contributing to stable synchrony across the neural network.

Stroke is a major cause of disability. Astrocytes respond to stroke in a gradated manner, but details of that response and its consequences for tissue repair are poorly understood, particularly across brain regions and stroke subtypes. We identified phenotypically and morphologically distinct zones of reactive astrocytes in mouse models of cortical and white matter stroke. Zone-specific transcriptomic analyses revealed that cortical, but not white matter, astrocytes upregulated transcriptional programs promoting the formation of new blood vessels, a key repair mechanism. Viral gain- and loss-of-function strategies showed that astrocytic Lamc1, in particular, is an endogenous mechanism by which cortical, but not white matter, astrocytes drive remodeling of larger-caliber brain microvessels. Exogenous induction of Lamc1 in white matter astrocytes improved vessel remodeling and repair and triggered differential T cell infiltration post stroke. Astrocyte subpopulations show region-specific responses to ischemia that can be leveraged to promote repair, including astrocyte-induced vascular remodeling.

The vasculature is increasingly recognized as an active regulator of homeostasis and repair, beyond conventional roles in nutrient delivery. In the central nervous system, vascular cells adopt region-specific traits tailored to the distinct demands of the brain, retina, and spinal cord. Despite long-standing interest in the spinal cord as a model for neural development and injury, its vascular organization and properties remain understudied. The assumption that spinal cord and brain neurovascular systems are built and function in the same way has limited progress. Here, we challenge this view by examining specific properties underlying spinal cord vascular development, physiology, and pathology. We highlight unique angioarchitecture and homeostatic mechanisms, and discuss how neurovascular disruption contributes to spinal disorders and regenerative failure after injury. Identifying critical knowledge gaps, we aim to stimulate new research in spinal cord neurovascular biology, redefining its importance for health and disease.

Stroke disrupts movement control by damaging descending motor pathways, yet the cortical dynamics underlying recovery remain poorly defined. Using a non-human primate model of primary motor cortex injury with impaired reach-to-grasp control, we examined how dorsal premotor cortex (PMd) activity supports recovery. Specifically, we studied the interaction between beta activity (12-30 Hz), often linked to "idle" states, and execution-related ensemble co-firing quantified with dimensionality reduction. Stroke impaired the temporal separability between beta bursts and movement-related co-firing, leading to slower reaction times and reduced performance. Recovery was associated with increased separability, and during grasping, beta activity progressively declined with recovery. These results indicate that reliable transitions between high-beta idle and high co-firing execution states are important for movement control, whereas pathological beta intrusions during execution degrade performance. Importantly, low-frequency alternating current stimulation (ACS) via a ringtrode interface enhanced temporal separability and improved reach-to-grasp performance, highlighting a potential therapeutic strategy.

Economic decision-making requires evaluating information about available options, such as their expected value and economic risk. Previous studies have shown that frontal cortical neurons encode these variables, but how this encoding is structured across different frontal regions and projection pathways remains unclear. We developed a decision-making task for head-fixed mice in which we varied the expected value and risk associated with reward-predicting stimuli. Using large-scale electrophysiology, two-photon imaging, and projection-specific optotagging, we identified distinct spatial gradients for these variables, with stronger expected value coding in dorsal frontal regions and stronger risk coding in medial regions. We then demonstrated that this encoding further depends on the neuronal projections: frontal neurons projecting to the dorsomedial striatum and claustrum differentially encoded economic variables. Our findings illustrate that frontal cortical representation of economic variables is jointly determined by spatial organization and downstream connectivity of neurons, revealing a structured, multi-scale code for economic variables.

Over the past decade, the PsychENCODE Consortium has transformed psychiatric genomics-from static maps of genetic risk to dynamic, cell-resolved models of the human brain-linking DNA sequence to neural circuitry and behavior and laying the foundation for precision approaches to mental illness.