Neuron最新文献

Using single-cell technologies on postmortem brains, Handsaker et al.¹ have demonstrated that substantial somatic expansion of the CAG repeat that causes Huntington's disease results in progressive transcriptional dysregulation and drives the loss of spiny projection neurons in the caudate.

Poor understanding of the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies. To address this gap, we analyzed 632,000 single-nucleus RNA sequencing profiles from 156 brain tissue samples of MS and control donors to examine inter- and intra-donor heterogeneity. We found distinct cell type-specific gene expression changes between MS gray and white matter, highlighting clear pathology differences. MS lesion subtypes had different cellular compositions but surprisingly similar cell-type gene expression patterns both within and across patients, suggesting global changes. Most gene expression variability was instead explained by patient effects, allowing us to stratify patients and describe the different pathological processes occurring between patient subgroups. Future mapping of these brain molecular profiles with blood and/or CSF profiles from living MS patients will allow precision medicine approaches anchored in patient-specific pathological processes.

Autoimmune neurology is a rapidly expanding field driven by the discovery of neuroglial autoantibodies and encompassing a myriad of conditions affecting every level of the nervous system. Traditionally, autoantibodies targeting intracellular antigens are considered markers of T cell-mediated cytotoxicity, while those targeting extracellular antigens are viewed as pathogenic drivers of disease. However, recent advances highlight complex interactions between these immune mechanisms, suggesting a continuum of immunopathogenesis. The breakdown of immune tolerance, central to these conditions, is affected by modifiable and non-modifiable risk factors such as genetic predisposition, infections, and malignancy. While significant therapeutic advancements have revolutionized treatment of certain diseases, such as neuromyelitis optica, our understanding of many others, particularly T cell-mediated conditions, remains limited, with fewer treatment options available. Future research should focus on improving effector function modeling and deepening our understanding of the factors influencing immune tolerance, with the goal of providing novel treatment options and improving patient care.

Remembering events is crucial to intelligent behavior. Flexible memory retrieval requires a cognitive map and is supported by two key brain systems: hippocampal episodic memory (EM) and prefrontal working memory (WM). Although an understanding of EM is emerging, little is understood of WM beyond simple memory retrieval. We develop a mathematical theory relating the algorithms and representations of EM and WM by unveiling a duality between storing memories in synapses versus neural activity. This results in a formalism of prefrontal WM as structured, controllable neural subspaces (activity slots) representing dynamic cognitive maps without synaptic plasticity. Using neural networks, we elucidate differences, similarities, and trade-offs between the hippocampal and prefrontal algorithms. Lastly, we show that prefrontal representations in tasks from list learning to cue-dependent recall are unified as controllable activity slots. Our results unify frontal and temporal representations of memory and offer a new understanding for dynamic prefrontal representations of WM.

Internal state-dependent behavioral flexibility, such as the ability to switch between rejecting and accepting sexual advances based on a female's reproductive capacity, is crucial for maintaining meaningful social interactions. While the role of the ventrolateral ventromedial hypothalamus (VMHvl) in sexual acceptance is well established, the neural mechanisms underlying sexual rejection remain unexplored. In this study, we identify progesterone receptor-expressing neurons in the anterior VMHvl (aVMHvl^PR+) as key regulators of cyclical female sexual rejection behavior. In vivo recordings reveal that these neurons are active during sexual rejection but inactive during sexual acceptance. Slice electrophysiology demonstrates that aVMHvl^PR+ neurons receive a reduced excitatory-to-inhibitory synaptic input balance in receptive females. Furthermore, activating and inhibiting aVMHvl^PR+ neurons increases rejection in receptive females and reduces rejection in non-receptive females, respectively. Thus, aVMHvl^PR+ neurons constitute a critical neural substrate controlling female sexual behavior, providing an additional barrier to mating when fertilization is not possible.

Decades of theoretical and empirical work have suggested the hippocampus instantiates some form of a cognitive map. Yet, tests of competing theories have been limited in scope and largely qualitative in nature. Here, we develop a novel framework to benchmark model predictions against observed neuronal population dynamics as animals navigate a series of geometrically distinct environments. In this task space, we show a representational structure in the dynamics of hippocampal remapping that generalizes across brains, discriminates between competing theoretical models, and effectively constrains biologically viable model parameters. With this approach, we find that accurate models capture the correspondence in spatial coding of a changing environment. The present dataset and framework thus serve to empirically evaluate and advance theories of cognitive mapping in the brain.

This article is about the neural conundrum behind the slowness of human behavior. The information throughput of a human being is about 10 bits/s. In comparison, our sensory systems gather data at ∼10⁹ bits/s. The stark contrast between these numbers remains unexplained and touches on fundamental aspects of brain function: what neural substrate sets this speed limit on the pace of our existence? Why does the brain need billions of neurons to process 10 bits/s? Why can we only think about one thing at a time? The brain seems to operate in two distinct modes: the "outer" brain handles fast high-dimensional sensory and motor signals, whereas the "inner" brain processes the reduced few bits needed to control behavior. Plausible explanations exist for the large neuron numbers in the outer brain, but not for the inner brain, and we propose new research directions to remedy this.

Understanding how neuronal circuits stabilize their activity is a fundamental yet poorly understood aspect of neuroscience. Here, we show that hippocampal network properties, such as firing rate distribution and dimensionality, are actively regulated, despite perturbations and single-cell drift. Continuous inhibition of N-methyl-D-aspartate receptors (NMDARs) ex vivo lowers the excitation/inhibition ratio and network firing rates while preserving resilience to perturbations. This establishes a new network firing rate set point via NMDAR-eEF2K signaling pathway. NMDARs' capacity to modulate and stabilize network firing is mediated by excitatory synapses and the intrinsic excitability of parvalbumin-positive neurons, respectively. In behaving mice, continuous NMDAR blockade in CA1 reduces network firing without altering single-neuron drift or triggering a compensatory response. These findings expand NMDAR function beyond their canonical role in synaptic plasticity and raise the possibility that some NMDAR-dependent behavioral effects are mediated by their unique regulation of population activity set points.

The central nervous system (CNS) is increasingly recognized as a critical modulator in the oncogenesis of glioblastoma multiforme (GBM), with interactions between cancer and local neuronal circuits frequently leading to epilepsy; however, the relative contributions of these factors remain unclear. Here, we report a coordinated intratumor shift among distinct cancer subtypes within progenitor-like families of epileptic GBM patients, revealing an accumulation of oligodendrocyte progenitor (OPC)-like subpopulations at the cancer-neuron interface along with heightened electrical signaling activity in the surrounding neuronal networks. The OPC-like cells associated with epilepsy express KCND2, which encodes the voltage-gated K⁺ channel K_V4.2, enhancing neuronal excitability via accumulation of extracellular K⁺, as demonstrated in patient-derived ex vivo slices, xenografting models, and engineering organoids. Together, we uncovered the essential local circuitry, cellular components, and molecular mechanisms facilitating cancer-neuron interaction at peritumor borders. KCND2 plays a crucial role in mediating nervous system-cancer electrical communication, suggesting potential targets for intervention.

Merging information across sensory modalities is key to forming robust percepts, yet how the brain achieves this feat remains unclear. Recent studies report cross-modal influences in the primary sensory cortex, suggesting possible multisensory integration in the early stages of cortical processing. We test several hypotheses about the function of auditory influences on mouse primary somatosensory cortex (S1) using in vivo two-photon calcium imaging. We found sound-evoked spiking activity in an extremely small fraction of cells, and this sparse activity did not encode auditory stimulus identity. Moreover, S1 did not encode information about specific audio-tactile feature conjunctions. Auditory and audio-tactile stimulus encoding remained unchanged after both passive experience and reinforcement. These results suggest that while primary sensory cortex is plastic within its own modality, the influence of other modalities is remarkably stable and stimulus nonspecific.