Before each of around 200,000 eye movements we make each day, the brain decides how long to fixate before shifting gaze to new information. Here we investigate this process using a large-scale scene-viewing experiment (4,080 natural scenes, five participants) that combines magnetoencephalography, eye tracking and a semantic captioning task. Using multivariate analysis of...
Rapid-eye-movement (REM) sleep is generated in the brainstem, but the brainstem population dynamics that drive transitions to REM sleep remain largely unknown. Here, combining mouse Neuropixels recordings and dimensionality reduction, we found that population activity in the midbrain and pons is dominated by two components, one of which captures strong infraslow fluctuations in...
Multiple sclerosis (MS) is a chronic neuroinflammatory disease in which demyelinating white matter lesions accumulate and expand, driving irreversible disability. Here we identify a distinct population of foamy GPNMB+ microglia/macrophages associated with lesion expansion in secondary progressive MS. Using integrated lipidomic, transcriptomic, proteomic, chemical proteomic and...
Disease-associated microglial states are thought to contribute to Alzheimer’s disease (AD) progression, but characterizing them and their relationships to pathology remains challenging. Here we introduce CODEX-CNS—a multiplexed protein imaging technology with a custom data analysis pipeline for use in human brain samples. We profiled 704,706 cells in samples from the frontal...
It is often assumed that phenotypic heterogeneity in autism reflects underlying pathobiological variation. However, direct evidence supporting this link is lacking. Leveraging cross-species functional neuroimaging, we show that brain dysconnectivity patterns in autism can be parsed into biologically dissociable subtypes. Specifically, we found that functional magnetic resonance...
Motor learning relies on signals that instruct adaptive plasticity following errors. In the cerebellum, climbing fibers (CFs) provide these instructions to Purkinje cells (PCs). Yet CFs fire continuously, even without errors, requiring molecular layer interneuron (MLI) inhibition of PCs to counteract CF excitation and prevent maladaptive plasticity. Here, to identify how this...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron (MN) degeneration in the brain and spinal cord. Although neuroinflammation is increasingly recognized as a hallmark of ALS, the precise molecular programs linking immune responses to MN pathology remain poorly defined. Using an integrated approach that combines single-cell...
Animals can learn about danger by observing conspecifics, but whether and how they acquire behaviors through positive affective states of others is not understood. Here we show that by observing a demonstrator, mice learn to take actions that benefit others and that are goal-directed and flexible. Chemogenetic silencing experiments showed that activity in hippocampal dorsal CA1...
Spatial transcriptomics has emerged as a transformative approach for in situ mapping of cellular heterogeneity and interactions, yet existing methods often compromise throughput, cost and tissue coverage. Here we introduce Imaging Reconstruction using Indexed Sequencing (IRISeq): an optics-free, cost-effective platform that leverages spatial interaction mapping by indexed...
Understanding speech in noisy environments is difficult for many people, and current hearing aids often fail because they amplify all sounds rather than the talker of interest. Auditory attention decoding (AAD) offers a potential solution by using the listener’s brain signals to identify and enhance the attended speaker, but it has been unclear whether this can provide real-time...
Hebbian neuroplasticity, which is thought to be a cellular substrate of learning and memory, can occur by means of coincidental detection of presynaptic neurotransmitter release and Ca2+ influx upon postsynaptic depolarization. This is mediated at a molecular level by N-methyl-D-aspartate-type glutamate receptors, which bind glutamate and glycine and facilitate Ca2+ influx upon...
Stereotyped dendritic arbors are shaped by dynamic and stochastic growth during neuronal development. It remains unclear how guidance receptors and ligands coordinate branch dynamic growth, retraction and stabilization to specify dendritic arbors. We previously showed that extracellular adhesion ligand SAX-7/LICAM dictates the elaborate and stereotyped shape of the Caenorhabditis...
Interictal epileptiform discharges (IEDs) are pathological bursts of brain activity between seizures in people with epilepsy. Despite their importance in diagnosis, cognitive comorbidities and therapeutic implications as biomarkers for neurostimulation, it is unknown how IEDs arise from structured large-scale neuronal firing across human cortical lamina. We used high-density...
The basal ganglia comprise interconnected subcortical nuclei essential for motor control, learning, emotion and cognition, yet how cell types relate to their circuit organization remains elusive. Here we show that spatial patterns of transcriptomic cell types in the basal ganglia and thalamic parafascicular nucleus relate to module-organized cortical inputs in the mouse. By co...
Prior memories can be integrated with novel experiences during learning to facilitate memory organization. This process must be tightly regulated to prevent inappropriate integration of unrelated memories. However, the biological mechanisms underlying such control are currently unknown. Using multiple imaging, chemogenetic and optogenetic techniques in mice, we demonstrate that...
Facial expressions and movements, from a subtle and ephemeral grimace to vigorous and rapid chewing, offer direct insights into the moment-to-moment changes of neural and physiological processes. Mice, with discernible facial responses and evolutionarily conserved mammalian facial movement control circuits, provide an ideal model in which to unravel the link between facial...
The brain moves within the skull, but the drivers and consequences of this motion are not well understood. Here we visualized motion of the dorsal cortex relative to the skull in awake head-fixed mice using high-speed, multiplane two-photon microscopy. Brain motion was directed primarily rostrally and laterally, and was correlated tightly with locomotion, but not with respiration...
Diverse risk genes have been identified for neurodevelopmental disorders (NDDs), but how these genes converge on similar biological pathways in neurons, and thus give rise to similar phenotypes, is unclear. Here we apply a pooled CRISPR approach to successfully target 23 NDD loss-of-function genes with roles in chromatin biology and examine convergent effects on gene expression...
The entorhinal cortex is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer’s disease (AD). The entorhinal cortex therefore has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly...
In a dynamic environment, sensory systems must filter out irrelevant information to construct a stable percept. Animals who rely on smell need to identify and discriminate odors despite fluctuations in concentration, yet odor receptor activation is strongly concentration dependent. Here we explored how odor signals are transformed within the mouse olfactory bulb (OB) by...
The brain must infer the state of the external world despite the inherent uncertainty of its sensory inputs and internal processes. Under conditions of heightened uncertainty, it increasingly relies on prior knowledge, derived from accumulated experience with the regularities and statistical structures of the environment. This principle has been formalized by Bayesian inference...
Neurons can collectively represent the current sensory experience during exploration or remote experiences during immobility. Remote representations can reflect learned associations and support learning. Neurons in medial entorhinal cortex (MEC) represent the animal’s current location during movement, but little is known about MEC representations during immobility. We recorded...