Heightened activity in the orbitofrontal cortex (OFC), a brain region that contributes to motivation, emotion, and reward-related decision-making, is a key clinical feature of major depressive disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unclear. Here, we performed cell-type-specific profiling of human OFC and unexpectedly mapped MDD-linked epigenomic

The global spread of misinformation is undermining democracies worldwide. In this NeuroView, we explain how neuroscience can inform our basic understanding of what makes the brain susceptible to false information, how it spreads in society, and how neuroscience can help shape and optimize interventions to effectively counter it.

As animals adapt to new situations, neuromodulation is a potent way to alter behavior, yet mechanisms by which neuromodulatory nuclei compute during behavior are underexplored. The serotonergic raphe supports motor learning in larval zebrafish by visually detecting distance traveled during swims, encoding action effectiveness, and modulating motor vigor. We tracked the raphe’s input-output computations

Memories reflect the ebb and flow of experiences, capturing distinct events from our lives. Using a combination of functional magnetic resonance imaging (fMRI), neuromelanin imaging, and pupillometry, we show that arousal and locus coeruleus (LC) activation segment continuous experiences into discrete memories. As sequences unfold, encountering a context shift or event boundary triggers pupil-linked

Longitudinal studies offer a unique opportunity to characterize individual human lifespan trajectories. While challenging, their added value can advance our understanding of neurodevelopment and mental health disorders, with the aim to optimize brain health and mental health.

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate specific neuronal subtypes are still limited. Here, we performed systematic analysis of single-cell genomic data to identify enhancer candidates for each of the telencephalic

We present an enhancer-AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct- and indirect-pathway MSNs, Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, by three different routes

Nonhuman primate (NHP) neuroanatomy and cognitive complexity make NHPs ideal models to study human neurobiology and disease. However, NHP circuit-function investigations are limited by the availability of molecular reagents that are effective in NHPs. This calls for reagent development approaches that prioritize NHPs. Therefore, we derived enhancers from the NHP genome. We defined cell-type-specific

Brain endothelial cells (BECs) in brain vasculature are critical structural and functional components of the blood brain barrier (BBB). Adeno-associated virus (AAV) capsids have previously been genetically engineered to confer specificity to endothelial cells, but these capsids show limited endothelial cell specificity that varies by delivery conditions. We developed a set of new BEC-enhancer AAV vectors

Recently in Cell, Xie and Rose et al.1 revealed a role for the mechanosensory ion channel PIEZO1 in the enteric nervous system, showing that it influences colonic motility and peristalsis, and highlighted its importance in the complex immuno-mechanical control of gastrointestinal function.

This issue of Neuron, with accompanying papers in Cell, Cell Genomics, Cell Reports, and Cell Reports Methods, contains studies describing methods for access to neuronal and non-neuronal cell types within the central nervous system. Combining technologies including genetics, virology, genomic enhancers, and RNA sensing, these tools enable targeting the nervous system in an unprecedented manner.

Zolboot et al.1 developed tools to manipulate and map microRNA function in cerebellar Purkinje cells with temporal precision, revealing key roles in dendritic development and circuit connectivity. Their approach provides insight into microRNA-mediated regulation of neurodevelopment in sparse neuronal populations.

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

The α2δs are a family of extracellular synaptic molecules that are auxiliary subunits of voltage-gated Ca2+ channel (CaV) complexes. They are linked to brain disorders and are drug targets. The α2δs are implicated in controlling synapse development and function through distinct CaV-dependent and CaV-independent pathways. However, the mechanisms of action remain enigmatic since synapses contain mixtures

Genetic studies implicate clusterin (CLU) in the pathogenesis of Alzheimer’s disease (AD), yet its precise molecular impact remains unclear. Through unbiased proteomic profiling and functional validation in CLU-deficient astrocytes, we identify increased nuclear factor κB (NF-κB)-dependent signaling and complement C3 secretion. Reduction of astrocyte CLU induced microglia-dependent modulation of extracellular

The brain’s endocannabinoid signaling system modulates a diverse range of physiological phenomena and is also involved in various psychiatric and neurological disorders. The basic components of the molecular machinery underlying endocannabinoid-mediated synaptic signaling have been known for decades. However, limitations associated with the short-lived nature of endocannabinoid lipid signals had made

Nicotine stimulates ventral tegmental area (VTA) dopaminergic neurons, producing a rewarding effect that drives tobacco consumption. The interpeduncular nucleus (IPN) is thought to become engaged at high nicotine doses to limit drug intake, but its response dynamics are unknown. We developed a chemogenetic approach using a “suicide” antagonist that selectively attaches to designer β4 nicotinic acetylcholine

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

Triplications and certain point mutations in the SNCA gene, encoding alpha-synuclein (α-Syn), cause Parkinson’s disease (PD). Here, we demonstrate that the PD-causing A53T α-Syn mutation and elevated α-Syn expression perturb acetyl-coenzyme A (CoA) and p300 biology in human neurons and in the CNS of zebrafish and mice. This dysregulation is mediated by activation of ATP-citrate lyase (ACLY), a key

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

Hippocampal pyramidal neurons support episodic memory by integrating complementary information streams into new “place fields.” Distal tuft dendrites have been proposed to drive place field formation via dendritic plateau potentials. However, the relationship between distal dendritic and somatic activity is unknown in vivo. Here, we gained simultaneous optical access to distal tuft dendrites and their

The perception of the sensory world in mammals requires information flow from the thalamus to the cortex. Although the first-order sensory thalamus and its surrounding nuclei are considered the major hub for feedforward thalamocortical transmission, it remains unknown whether any other thalamic input could also contribute to this transmission. We found a thalamic region, the basal region of the ventromedial

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

Flexible behavior depends on abstract rules to generalize beyond specific instances and outcome monitoring to adjust actions. Cortical circuits are posited to read out rules from high-dimensional representations of task-relevant variables in prefrontal cortex (PFC). We instead hypothesized that converging inputs from PFC, directly or via basal ganglia (BGs), enable the thalamus to select rules. We

Memory formation requires specific neural activity in coordination with intracellular signaling mediated by second messengers such as cyclic adenosine monophosphate (cAMP). However, the real-time dynamics of cAMP remain largely unknown. Here, using a genetically encoded cAMP sensor with high temporal resolution, we found neural-activity-dependent rapid cAMP elevation during learning. Interestingly

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.