N Nature Neuroscience · Dec 05, 2025 The striatal indirect pathway mediates hesitation Hesitation—that is, pausing an action in the face of uncertainty—is ubiquitous in daily life, yet little is known about its underlying neural circuitry. We present a new experimental paradigm that reliably evokes hesitation in mice and find that hesitation is mediated by indirect, but not direct, pathway neurons in the dorsomedial striatum. These data establish a new role for the indirect pathway in suppressing action under uncertainty. Neural circuits Sensorimotor processing biology mouse experiments
N Nature Neuroscience · Dec 04, 2025 In vivo CRISPR screen reveals regulation of macrophage states in neuroinflammation Here we established an in vivo CRISPR screening pipeline using genetically editable progenitor cells to dissect macrophage regulation in mouse models of multiple sclerosis (MS). Screening over 100 cytokine receptors and signaling molecules identified interferon-γ, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor and transforming growth factor-β as essential regulators of macrophage polarization in vivo. Single-cell transcriptomics confirmed that transferred progenitor cells generate all blood-derived CNS myeloid cell populations, enabling Perturb-seq analysis of cytokine actions in neuroinflammation. Combined with biosensor expression, our approach allows monitoring cytokine effects on myeloid cell migration, debris phagocytosis and oxidative activity in vivo. Comparative transcriptomic analyses revealed conserved neuroinflammatory cytokine signatures across myeloid populations, CNS compartments and species, elucidating cytokine cues shaping myeloid function in the cerebrospinal fluid and parenchyma of individuals with MS. This versatile pipeline thus provides a scalable framework for high-resolution analysis of macrophage states and uncovers the cytokine signals that underlie their regulation in MS and MS models. Autoimmunity Monocytes and macrophages Multiple sclerosis Neuroimmunology biology mouse experiments
N Nature Neuroscience · Dec 04, 2025 Rapid motor skill adjustment is associated with population-level modulation of cerebellar error signals A core principle of cerebellar learning theories is that climbing fibers from the inferior olive convey error signals about movement execution to Purkinje cells in the cerebellar cortex. These inputs trigger synaptic changes, which are purported to drive progressive adjustment of future movements. Individually, binary complex spike signals lack information about the sign and magnitude of errors which presents a problem for cerebellar learning paradigms exhibiting fast adaptation. Here, using a newly developed behavioral paradigm in mice, we introduced sensorimotor perturbations into a simple joystick-pulling behavior and found parasagittal bands of Purkinje cells with reciprocal modulation of complex spike activity, along with rapid adaptation of the behavior. Whereas complex spiking showed little modulation in the unperturbed condition, alternating bands were activated or inhibited when the perturbation was introduced and this modulation encoded the sign and magnitude of the resulting sensorimotor mismatch. These findings provide important insight about how the cerebellum uses supervised learning to quickly adapt motor behavior in response to perturbations. Cellular neuroscience Neural circuits biology mouse experiments
N Nature Neuroscience · Dec 02, 2025 The regulatory code of injury-responsive enhancers enables precision cell-state targeting in the CNS Enhancer elements direct cell-type-specific gene expression programs. After injury, cells change their transcriptional state to adapt to stress and initiate repair. Here we investigate how injury-induced transcriptional programs are encoded within enhancers in the mammalian CNS. Leveraging single-nucleus transcriptomics and chromatin accessibility profiling, we identify thousands of injury-induced, cell-type-specific enhancers in the mouse spinal cord after a contusion injury. These are abundant in glial cells and retain cell-type specificity, even when regulating shared wound response genes. By modeling glial injury-responsive enhancers using deep learning, we reveal that their architecture encodes cell-type specificity by integrating generic stimulus response elements with cell identity programs. Finally, through in vivo enhancer screening, we demonstrate that injury-responsive enhancers can selectively target reactive astrocytes across the CNS using therapeutically relevant gene delivery vectors. Our decoding of the principles of injury-responsive enhancers enables the design of sequences that can be programmed to target disease-associated cell states. Astrocyte Epigenetics and plasticity Molecular neuroscience Spinal cord injury biology mouse experiments
N Nature Neuroscience · Dec 02, 2025 High-frequency bursts facilitate fast communication for human spatial attention Brain-wide communication supporting flexible behavior requires coordination between sensory and associative regions but how brain networks route sensory information at fast timescales to guide action remains unclear. Using human intracranial electrophysiology and spiking neural networks during spatial attention tasks, where participants detected targets at cued locations, we show that high-frequency activity bursts (HFAbs) mark temporal windows of elevated population firing that enable fast, long-range communications. HFAbs were evoked by sensory cues and targets, dynamically coupled to low-frequency rhythms. Notably, both the strength of cue-evoked HFAbs and their decoupling from slow rhythms predicted behavioral accuracy. HFAbs synchronized across the brain, revealing distinct cue- and target-activated subnetworks. These subnetworks exhibited lead–lag dynamics following target onset, with cue-activated subnetworks preceding target-activated subnetworks when cues were informative. Computational modeling suggested that HFAbs reflect transitions to population spiking, denoting temporal windows for network communications supporting attentional performance. These findings establish HFAbs as signatures of population state transitions, supporting information routing across distributed brain networks. Attention Biophysical models Cognitive control Perception Sensory processing biology
N Nature Neuroscience · Dec 01, 2025 Oxidized phosphatidylcholines deposition drives chronic neurodegeneration in a mouse model of progressive multiple sclerosis via IL-1β signaling Oxidized phosphatidylcholines (OxPCs) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPCs contribute to the pathophysiology of P-MS is unclear. Here we show that stereotactic OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this model, we found that although microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte-derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology inCasp1/Casp4-deficient mice and by blockade of IL-1R1 indicate that IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPCs and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization could be effective for treating P-MS. Multiple sclerosis Neuroimmunology biology mouse experiments
