Reviews & Analysis

Pain in rheumatoid arthritis often persists independently of joint inflammation. In this issue, Su et al. demonstrate that sustained non-canonical type 1 interferon signaling within peripheral sensory neurons maintains hypersensitivity long after inflammation subsides, revealing a potential therapeutic avenue for chronic arthritic pain.

Mice make decisions, encoded by unique cortical populations, to self-organize into group huddles for warmth. Silencing these populations in some members decreases their huddling decisions and triggers compensatory increases in other animals, which reveals how individual neural activity shapes group behavior.

We developed a generative AI framework that learns to simulate impaired consciousness from massive datasets of neural activity, revealing hidden mechanisms of disorders of consciousness. It predicted selective damage to the basal ganglia indirect pathway, abnormal inhibitory cortical wiring and promising treatments, which were confirmed in patient tissue, brain scans and clinical data.

Precision neuroimaging of repeatedly scanned individuals receiving deep brain stimulation (DBS), conducted longitudinally with long scanning durations, revealed separate globus pallidus and motor cortex (M1) circuits with distinct frequency- and time-dependent responses. DBS also evoked divergent effects in M1 functional connectivity, normalizing within the somato-cognitive action network but denormalizing in effector motor networks.

Tracking ongoing spontaneous pain in individuals with chronic pain is challenging. Using intensive longitudinal functional magnetic resonance imaging (fMRI) combined with continuous spontaneous pain ratings in two individuals with fibromyalgia, we trained personalized brain decoding models that could track moment-to-moment spontaneous pain fluctuations. Underscoring the need for precision approaches, neither decoding model generalized from one individual to the other.

Understanding how brains learn and remember remains among the most important challenges in science. Recent studies suggest that a new form of synaptic plasticity provides a basis for future explorations ranging from biochemistry to cognition.

The endothelial blood–brain barrier was discovered in the 19th century, and, since then, additional epithelial, glial and meningeal brain barriers have been described. In this issue of Nature Neuroscience, Verhaege and colleagues describe the discovery of an entirely overlooked brain barrier localized at the base of the choroid plexus.

Learning depends not only on how often stimuli are experienced but also on how they are spaced in time. Burke et al. show that infrequent, well-spaced stimuli enhance predictive learning, revealing how dopamine signaling and temporal organization shape the brain’s ability to extract causal structure from experience.

Determining what infants recognize in the things they see has been difficult. Using brain imaging and deep neural networks, we found that in 2-month-old infants the visual system represented not only how things looked but also what category they belonged to. This showed that features sufficient for object recognition are already important in early life.

Abnormally located cortical neurons, displaced in developing mice lacking cortical Eml1, retain their molecular identities, form appropriate connections and build functional sensory maps. Most strikingly, these misplaced neurons can drive behavior by themselves — showing that brain function depends on how neurons connect, and to what, more than where they live.

Adaptive intelligence envisions AI that, like animals, learns online, generalizes and adapts quickly. This Perspective reviews biological foundations, progress in AI and brain-inspired strategies for building flexible and adaptive AI algorithms.

In this Perspective, the international PAINDIFF Network makes 13 recommendations for studying sex and gender as variables in preclinical, clinical and translational pain research that are applicable across the spectrum of biomedical and psychosocial research.

Parcellation of the cortex into functionally modular brain areas is foundational to neuroscience. Here, Hayden, Heilbronner and Yoo question the central status of brain areas in neuroscience from the perspectives of neuroanatomy and electrophysiology and propose an alternative approach.

We explored how external conditions shape cognitive function. Classical olfactory learning assays revealed that Caenorhabditis elegans kept on ice or treated with lithium exhibited delayed forgetting of olfactory memories. We showed that the worm’s cold-tolerance internal state ‘switch’ and diacylglycerol (DAG) pathway activity in AWC neurons regulate memory retention.

We challenge the traditional views of sensory processing, showing that primary sensory cortex has an adaptive and flexible role that evolves with learning and context, reshaping our understanding of perception, behavior and brain function.

Gonadal hormones shape brain structure across the lifespan. Using dense sampling in two female participants with typical cycles, one with endometriosis, and one using oral contraceptives, we show that distinct hormonal milieus influence widespread, coordinated fluctuations in brain volume across the cycle. These results highlight the importance of looking beyond the ‘typical’ menstrual cycle to understand how hormones drive structural brain plasticity in different conditions.

Early tactile deficits in patients with Alzheimer disease (AD) and AD mouse models map to tau pathology in spinal cholecystokinin (CCK) neurons. In AD mice, reducing tau or c-Maf levels in spinal CCK neurons restores touch and benefits cognition, suggesting that these deficits are a noninvasive peripheral indication of early AD and offer a tractable target for intervention.

This Perspective discusses the challenges involved in translating optogenetic research into clinical practice, including clinical and pragmatic choices, potential toxicity and immune responses, regulatory issues and ethical considerations.

In this issue of Nature Neuroscience, Golden et al. unveil a mouse model that enables in vivo ‘switching’ from the Alzheimer’s risk gene APOE4 to the protective gene APOE2. This genetic conversion reshapes Alzheimer’s disease-related metabolism, reduces neuropathology, and enhances cognition, demonstrating the beneficial effects of APOE genetic targeting as a promising therapeutic strategy.

We have all heard the cliché; hormones make us unreliable and unpredictable. However, in this issue of Nature Neuroscience, Golden et al. show that higher states of endogenous estrogen enhance reward prediction errors in sophisticated ways, which promotes adaptive behavior and improves performance.