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Individuals with autism spectrum disorder show neural patterns different from those of neurotypical individuals. Here the authors show that this variation reflects a computational trade-off between accurate encoding and fast adaptation tuned by the neural population response.

Vishwanathan and colleagues have reconstructed the wiring diagram of a brainstem circuit that controls gaze in zebrafish. The authors describe an unexpected modular network organization and mechanistic insights into network function.

Lüthi and colleagues show that activity of the locus coeruleus (LC) is crucial for the cyclic alternation between non-rapid-eye-movement and rapid-eye-movement sleep. Stressful experiences during waking can disrupt LC activity in sleep, which disorganizes the sleep cycle and increases microarousals.

Launched in 2013, the BRAIN Initiative (BRAIN) in the United States aimed to unlock the mysteries of the brain and develop new treatments for neurological and neuropsychiatric disorders. The success of this program is evidenced by the accelerated discoveries and development of interventions that are happening in real time. However, a recent 40% cut in funding for BRAIN threatens this once-in-a-generation opportunity to solve fundamental mysteries of the brain and achieve treatment breakthroughs that we once thought impossible.

The authors determine the synaptic wiring diagram of a vertebrate circuit and reveal behaviorally associated modules. A model based on this connectome predicts neural coding and dynamics that are verified with calcium imaging data.

The Rett syndrome protein MeCP2 regulates gene transcription by binding to methylated DNA. Here the authors find that MeCP2 also regulates key neuronal genes by binding to nonmethylated DNA, providing new insights into the disorder.

The cerebral cortex shows complex organization across diverse biological scales, from regional chemical and cellular specializations to macroscale functional networks. Zhang et al. report that macroscopic neuroimaging maps of cortical activity align with microscopic cellular features: sensory and association regions define opposing extremes for both. The consistent identification of a sensory–association axis across multiple scales and analytic approaches underscores it as a fundamental organizational principle that raises new challenges for the field.

Using cryo-electron tomography (cryo-ET) and proteomics, this study identifies the tethering of pathological tau filaments within defined brain extracellular vesicles in Alzheimer’s disease, shining light on the link between these vesicles and tau pathology.

Here Zhang et al. establish multiscale relationships that link postmortem cell-type distributions with the in vivo functional organization of the human cerebral cortex, as assessed through functional magnetic resonance imaging.

Jhang et al. identify a prefrontal–pontomedullary pathway that slows breathing and reduces anxiety in mice, where the pontine reticular nucleus converts excitatory prefrontal inputs into inhibitory signals to brainstem respiratory networks.

The CaMKII holoenzyme was long thought to mediate memory storage via an autophosphorylation reaction that occurs between its subunits at Thr286 (pThr286). This Perspective explains shortcomings of earlier models and provides an updated view.

Brain slices offer an experimental window into human neurophysiology. Using high-density microelectrode array recordings and adeno-associated virus–mediated optogenetics, the authors demonstrate that optogenetic targeting of CAMK2A+ neurons can affect network activity in human hippocampal slices.

Lee et al. show that the development of the somatotopic map and the tonotopic map for substrate vibration is shaped by the intrinsic distribution of cutaneous end organs and selective dendritic integration within the brainstem dorsal column nuclei.

Using single-nucleus RNA sequencing from 32 donors, researchers identified distinct astrocytic gene expression programs activated across brain regions and Alzheimer’s disease stages. They also found unique subclusters of astrocytes that appear to vary over time, highlighting the complexity of astrocytic responses in AD.

Tyrosine kinase 2 (TYK2) critically regulates tau levels and aggregation by phosphorylating tau’s tyrosine 29. Partial inhibition of TYK2 mitigates tau pathologies in cells and mice, highlighting TYK2 as a potential therapeutic target for Alzheimer’s disease and other tauopathies.

We used single-soma deep RNA sequencing to generate a high-resolution atlas of human somatosensory dorsal root ganglion neurons. This work revealed human-specific molecular features, pain-sensing neuron types, properties of sensory fibers, and potential therapeutic targets, which inform understanding of human somatosensory mechanisms and could facilitate improved success in translational research.

In this issue, Alsema, Wijering, Miedema, Kotah et al. and Lerma-Martin, Badia-i-Mompel et al. demonstrate the ever-growing possibilities of spatial transcriptomics by applying it to the spatially heterogeneous disease multiple sclerosis. They validate the technique by comparison to classic pathology and reveal insights into demyelinated lesion markers, pathological cell types and lesion evolution.

Lerma-Martin et al. generated a paired single-nucleus RNA sequencing and spatial transcriptomics dataset from subcortical multiple sclerosis lesions, identifying spatial niches and key cell interactions driving inflammation and disease progression at the lesion rim.

Lesion initiation and progression in multiple sclerosis is a dynamic but unclear process. Here, the authors highlight cell type-specific gene sets characterizing the action lesion rims and identify trajectories, predicting how normal-appearing white matter can develop into active and mixed active/inactive lesions.