We report a role for activity in the development of the primary sensory neurons that detect touch. Genetic deletion of Piezo2, the principal mechanosensitive ion channel in somatosensory neurons, caused profound changes in the formation of mechanosensory end-organ structures. Peripheral-nervous-system-specific deletion of the voltage-gated sodium channel Nav1.6 (Scn8a), which resulted in altered electrophysiological

Hereditary hearing loss accounts for about 60% of congenital deafness. Although adeno-associated virus (AAV)-mediated gene therapy shows substantial potential for treating genetic hearing impairments, there remain significant concerns regarding the specificity and safety of AAV vectors. The sophisticated nature of the cochlea further complicates the challenge of precisely targeting gene delivery. Here

Natural vision requires circuit mechanisms which process complex spatiotemporal stimulus features in parallel. In the mammalian forebrain, one signature of circuit activation is fast oscillatory dynamics, reflected in the local field potential (LFP). Using data from the Allen Neuropixels Visual Coding project, we show that local visual features in naturalistic stimuli induce in mouse primary visual

Sensory-motor integration is crucial in the processing of chronic pain. The primary motor cortex (M1) is emerging as a promising target for chronic pain treatment. However, it remains elusive how nociceptive sensory inputs influence M1 activity and how rectifying M1 defects, in turn, regulates pain processing at cellular and network levels. We show that injury/inflammation leads to hypoactivity of

Preterm birth remains a significant global health concern despite advancements in neonatal care. While survival rates have increased, the long-term neurodevelopmental consequences of preterm birth persist. Notably, the profile of the preterm infant has shifted, with infants at earlier gestational ages surviving and decreased rates of gross structural injury secondary to intracranial hemorrhage. However

The endogenous opioid peptide dynorphin and its receptor κ-opioid receptor (KOR) have been implicated in divergent behaviors, but the underlying mechanisms remain elusive. Here, we show that dynorphin released from nucleus accumbens dynorphinergic neurons exerts powerful modulation over a ventral pallidum (VP) disinhibitory circuit, thereby controlling cholinergic transmission to the amygdala and reward-seeking

Stroke affects approximately 1 in 6 individuals globally and is the leading cause of adult disability, which is attributed to neuronal damage and neurological impairments. The mechanisms by which the brain tissue microenvironment supports neurogenesis and neurorepair post-stroke remain to be fully elucidated. In this study, we report that group 2 innate lymphoid cells (ILC2s) accumulate within the

Neurotechnologies and genetic tools for dissecting neural circuit functions have advanced rapidly over the past decade although the development of complementary pharmacological methodologies has comparatively lagged. Understanding the precise pharmacological mechanisms of neuroactive compounds is critical for advancing basic neurobiology and neuropharmacology, as well as for developing more effective

α-synuclein transmission and propagation are hallmarks of synucleinopathies, yet the molecular mechanisms remain elusive. Using α-synuclein preformed fibrils as pathological seeds, we observed a gradual decline in neuronal transmission activity during serial propagation. Fibril polymorphisms were identified from the initial generation: mini-P, with higher neuronal seeding activity, and mini-S, which

Food intake serves to maintain energy homeostasis; however, overeating can result in obesity, which is associated with serious health complications. In this review, we explore the intricate relationship between overeating, obesity, and the underlying neurobiological mechanisms. We review the homeostatic and hedonic feeding systems, highlighting the role of the hypothalamus and reward systems in controlling

MicroRNAs (miRNAs) are critical for brain development; however, if, when, and how miRNAs drive neuronal subtype specification remains poorly understood. To address this, we engineered technologies with vastly improved spatiotemporal resolution that allow the dissection of cell-type-specific miRNA-target networks. Fast and reversible miRNA loss of function showed that miRNAs are necessary for Purkinje

Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) are hallmarks of several neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been challenging. Here, we produced amyloid-like fibrils from recombinant TDP-43 low-complexity domain and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cells, including induced pluripotent

Neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade

Spontaneous pain, characterized by episodic shooting or stabbing sensations, is a major complaint among neuropathic pain patients, yet its mechanisms remain poorly understood. Recent research indicates a connection between this pain condition and “clustered firing,” wherein adjacent sensory neurons fire simultaneously. This study presents evidence that the triggers of spontaneous pain and clustered

Within adult rodent hippocampus (HPC), opioids suppress inhibitory parvalbumin-expressing interneurons (PV-INs), disinhibiting local microcircuits. However, it is unknown whether this disinhibitory motif is conserved across cortical regions, species, or development. We observed that PV-IN-mediated inhibition is robustly suppressed by opioids in HPC proper but not primary neocortex in mice and non-human

Classical models of memory in psychology and neuroscience rely on similarity-based retrieval of stored patterns, where similarity is a function of retrieval cues and the stored patterns. Although parsimonious, these models do not allow distinct representations for storage and retrieval, despite their distinct computational demands. Key-value memory systems, in contrast, distinguish representations

Metabolism is vital for brain function. However, a systematic investigation to understand the metabolic exchange between the human brain and circulatory system has been lacking. Here, we compared metabolomes and lipidomes of blood samples from the cerebral venous sinus and femoral artery to profile the brain’s uptake and release of metabolites and lipids (1,365 metabolites and 140 lipids). We observed

Hippocampal reactivation of waking neuronal assemblies in sleep is a key initial step of systems consolidation. Nevertheless, it is unclear whether reactivated assemblies are static or whether they reorganize gradually over prolonged sleep. We tracked reactivated CA1 assembly patterns over ∼20 h of sleep/rest periods and related them to assemblies seen before or after in a spatial learning paradigm

Pain sensation changes according to expectation, context, and mood, illustrating how top-down circuits affect somatosensory processing. Here, we used an intersectional strategy to identify anatomical and molecular-spatial features of supraspinal descending neurons activated by distinct noxious stimulation. This approach captured known descending pain pathways as well as spinal projecting neurons that

Neurons exhibit selectivity for specific features: a property essential for extracting and encoding relevant information in the environment. This feature selectivity is thought to be modifiable by experience at the level of the cortex. Here, we demonstrate that selective exposure to a feature during development can alter the population representation of that feature in the primary visual thalamus.

Ketamine is recognized as a rapid and sustained antidepressant, particularly for major depression unresponsive to conventional treatments. Anhedonia is a common symptom of depression for which ketamine is highly efficacious, but the underlying circuits and synaptic changes are not well understood. Here, we show that the nucleus accumbens (NAc) is essential for ketamine’s effect in rescuing anhedonia

The neural mechanisms underlying the sequential transitions of male sexual behaviors, including mounting, intromission, and ejaculation, remain largely unexplored. Here, we report that acetylcholine (ACh)-dopamine (DA) dynamics in the ventral shell of the nucleus accumbens (vsNAc) regulate these sexual transitions in male mice. During intromission, the vsNAc displays a unique pattern of dual ACh-DA

The apolipoprotein E (APOE) gene is the strongest genetic risk modifier for Alzheimer’s disease (AD), with the APOE4 allele increasing risk and APOE2 decreasing it compared with the common APOE3 allele. Using single-nucleus RNA sequencing of the temporal cortex from APOE2 carriers, APOE3 homozygotes, and APOE4 carriers, we found that AD-associated transcriptomic changes were highly APOE genotype dependent

How the human brain develops and what goes awry in neurological disorders represent two long-lasting questions in neuroscience. Owing to the limited access to primary human brain tissue, insights into these questions have been largely gained through animal models. However, there are fundamental differences between developing mouse and human brain, and neural organoids derived from human pluripotent

Thirst drives animals to reinstate water homeostasis by fluid intake. An increase in blood osmolality is thought to induce thirst by activating a hyperosmolar sensor expressed in the subfornical organ (SFO), but the molecular identity of this sensor remains elusive. Here, we provide behavioral and functional evidence to show that TMEM63B functions as a mammalian hyperosmolar sensor for thirst in SFO

Enteric infections often cause long-term sequelae, including persistent gastrointestinal symptoms, such as pain, discomfort, or irritable bowel syndrome. The plethora of sensory symptoms indicates that gut-innervating neurons might be directly affected by inflammation. However, sequencing studies of neurons in the gastrointestinal tract are hampered by difficulties in purifying neurons, especially

Emerging research suggests the brain operates as a “prediction machine,” continuously anticipating sensory, motor, and cognitive outcomes. Central to this capability is the brain's spontaneous activity—ongoing internal processes independent of external stimuli. Neuroimaging and computational studies support that this activity is integral to maintaining and refining mental models of our environment

Because early-life stress is common and constitutes a strong risk factor for cognitive and mental health disorders, it has been the focus of a multitude of studies in humans and experimental models. Yet, we have an incomplete understanding of what is perceived as stressful by the developing brain, what aspects of stress influence brain maturation, what developmental ages are particularly vulnerable

Changes in β-amyloid (Aβ) and hyperphosphorylated tau (T) in brain and cerebrospinal fluid (CSF) precede Alzheimer’s disease (AD) symptoms, making the CSF proteome a potential avenue to understand disease pathophysiology and facilitate reliable diagnostics and therapies. Using the AT framework and a three-stage study design (discovery, replication, and meta-analysis), we identified 2,173 analytes (2

Hypothalamic VMHdmSF1 neurons are activated by predator cues and are necessary and sufficient for instinctive defensive responses. However, such data do not distinguish which features of a predator encounter are encoded by VMHdmSF1 neural activity. To address this issue, we imaged VMHdmSF1 neurons at single-cell resolution in freely behaving mice exposed to a natural predator in varying contexts. Our

The widespread adoption of deep learning to model neural activity often relies on “black-box” approaches that lack an interpretable connection between neural activity and network parameters. Here, we propose using algorithm unrolling, a method for interpretable deep learning, to design the architecture of sparse deconvolutional neural networks and obtain a direct interpretation of network weights in

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders associated with mitogen-activated protein (MAP)-kinase-activating mutations and an increased risk of neurodegeneration. We found microglial mutant clones in LCH and ECD patients, whether or not they presented with clinical symptoms of neurodegeneration, associated with microgliosis, astrocytosis, and

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the repeat expansion in C9ORF72. Dipeptide repeat (DPR) proteins translated from both sense and antisense repeats, especially arginine-rich DPRs (R-DPRs), contribute to neurodegeneration. Through CRISPR interference (CRISPRi) screening in human-derived neurons, we identified receptor-type tyrosine-protein

Advances in neurotechnologies, including molecular tools, neural sensors, and large-scale recording, are transforming neuroscience and generating vast datasets. A recent meeting highlighted the resulting challenges in global collaboration, data management, and effective translation, emphasizing the need for innovative strategies to harness big data for diagnosing and treating brain disorders.

This paper explores the trajectory and horizons of dance neuroscience. Bridging art and science to reveal neurobiological underpinnings of skilled movement, multisensory integration, social interaction, and aesthetics, researchers in this field are creatively channeling methodological innovation to maximize interdisciplinary impact.

Pain relief is the most frequently reported motivation for opioid misuse, but it remains unclear how pain alters reward pathway function contributing to maladaptive opioid use and whether these neuroadaptations occur in a sex-specific manner. Here, we show that persistent inflammatory pain leads to augmented fentanyl self-administration in male, not female, rats. Wireless in vivo fiber photometry recordings

Primary cilia are cellular antennae emanating from vertebrate cell surfaces to sense and transduce extracellular signals intracellularly to regulate cell behavior and function. However, their signal sensing and physiological functions in neocortical neurons remain largely unclear. Here, we show that, in response to various animal stressors, primary cilia in the mouse prefrontal cortex (PFC) exhibit

Sleep loss is often regarded as an early manifestation of neurodegenerative diseases given its common occurrence and link to cognitive dysfunction. However, the precise mechanisms by which sleep disturbances contribute to neurodegeneration are not fully understood, nor is it clear why some individuals are more susceptible to these effects than others. This review addresses critical unanswered questions

Excitotoxicity is a major pathologic mechanism in patients with tauopathy and other neurodegenerative diseases. However, the key neurotoxic drivers and the most effective strategies for mitigating these degenerative processes are unclear. Here, we show that glutamate treatment of induced pluripotent stem cell (iPSC)-derived cerebral organoids induces tau oligomerization and neurodegeneration and that

In this NeuroView, we discuss challenges and best practices when dealing with disease-detection AI models that are trained on heterogeneous clinical data, focusing on the interrelated problems of model bias, causality, and rare diseases.

Pain hypersensitivity arises from the induction of plasticity in peripheral and spinal somatosensory neurons, which modifies nociceptive input to the brain, altering pain perception. We applied longitudinal calcium imaging of spinal dorsal projection neurons to determine whether and how the representation of somatosensory stimuli in the anterolateral tract, the principal pathway transmitting nociceptive

Neural hyperexcitability has been clinically associated with amyloid-β (Aβ) pathology and cognitive impairment in Alzheimer’s disease (AD). Here, we show that decreased GABAA receptor (GABAAR) currents are linked to hippocampal granule cell hyperexcitability in the AD mouse model APP23. Elevated levels of β-secretase (BACE1), the β-secretase responsible for generating Aβ peptides, lead to aberrant

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

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

Neurons are long-lived postmitotic cells that capitalize on autophagy to remove toxic or defective proteins and organelles to maintain neurotransmission and the integrity of their functional proteome. Mutations in autophagy genes cause congenital diseases, sharing prominent brain dysfunctions including epilepsy, intellectual disability, and neurodegeneration. Ablation of core autophagy genes in neurons

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

Hippocampal place cells have single, bell-shaped place fields in small environments. Recent experiments, however, reveal that, in large environments, place cells have multiple fields with heterogeneous shapes and sizes. We show that this diversity is explained by a surprisingly simple mathematical model, in which place fields are generated by thresholding a realization of a random Gaussian process

Reproduction poses a substantial burden, especially for mammalian females. Puberty onset serves as a vital checkpoint, regulated based on the body’s energy state, to prevent inappropriate reproductive activity under malnutrition. However, the neural basis of this puberty checkpoint remains poorly understood. Here, we demonstrate that peripubertal malnutrition in female mice reduces the synchronous

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

Discrete activation of N-methyl-D-aspartate receptor (NMDAR) subtypes by glutamate and the co-agonist glycine is fundamental to neuroplasticity. A distinct variant, the tri-heteromeric receptor, comprising glycine-binding GluN1 and two types of glutamate-binding GluN2 subunits, exhibits unique pharmacological characteristics, notably enhanced sensitivity to the anti-depressant channel blocker S-(+)-ketamine

Astrocytes in the spinal cord dorsal horn (SDH) play a pivotal role in synaptic transmission and neuropathic pain. However, the precise classification of SDH astrocytes in health and disease remains elusive. Here, we reveal Gpr37l1 as a marker and functional regulator of spinal astrocytes. Through single-nucleus RNA sequencing, we identified Gpr37l1 as a selective G-protein-coupled receptor (GPCR)

The axon initial segment (AIS) is a highly specialized compartment in neurons that resides in between axonal and somatodendritic domains. The localization of the AIS in the proximal part of the axon is essential for its two major functions: generating and modulating action potentials and maintaining neuron polarity. Recent findings revealed that the incredibly stable AIS is generated from highly dynamic

The cortex amplifies responses to novel stimuli while suppressing redundant ones. Novelty detection is necessary to efficiently process sensory information and build predictive models of the environment, and it is also altered in schizophrenia. To investigate the circuit mechanisms underlying novelty detection, we used an auditory “oddball” paradigm and two-photon calcium imaging to measure responses

Polymorphisms in CD2-associated protein (CD2AP) predispose to Alzheimer’s disease (AD), but the underlying mechanisms remain unknown. Here, we show that loss of CD2AP in cerebral blood vessels is associated with cognitive decline in AD subjects and that genetic downregulation of CD2AP in brain vascular endothelial cells impairs memory function in male mice. Animals with reduced brain endothelial CD2AP