Implanted brain–computer interfaces hold great promise for restoring communication and other functions and for revealing new aspects of human brain physiology. Yet as the number of implantations in humans expands, ethical clarity must keep pace with technical ambition. We propose that this should involve distinguishing research participation from patient care, ensuring long-term support for study participants, ensuring that research participants do not bear disproportionate risks for benefits realized mainly by others, and grounding research in meaningful clinical purpose.
Neuromodulation aims to improve brain function by altering neural activity. While many rehabilitation strategies seek to restore normal, healthy-like dynamics, some adopt a complementary strategy, using neuromodulation to strengthen repurposed processes that support function. Here we formalize these approaches as 'restorative normalization' (RN) and 'compensatory amplification' (CA), respectively. Drawing on cognitive neurophysiology, we evaluate the following four factors that enable CA to be effective: multiple realizability, multiscale neuroplasticity, precision readiness and activity selectivity. We analyze the interplay between RN and CA across clinical goals, such as stroke rehabilitation, and identify opportunities in neurodegeneration, psychiatry and aging where CA could delay decline, facilitate remission or increase neural processing capacity. We propose that positioning CA alongside RN as a core design principle can sharpen target selection, guide stratified treatments and translate known compensatory signatures into testable neuromodulation protocols.
Why some skills are easier to learn than others remains a central question in neuroscience. Busch and colleagues demonstrate that the intrinsic geometry of human brain activity shapes learning, thereby facilitating adaptation that remains within existing neural manifolds while limiting learning beyond them.
Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8+ T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8+ T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8+ T cell infiltration and glial activation. The remaining CD8+ T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8+ T cell accumulation in the brain and tau-mediated neurodegeneration.
Animals solve new, complex tasks by reusing and adapting prior knowledge. This flexibility depends not only on the content of experience but also on its structure. Early training curricula are especially important: poorly structured experiences can hinder abstraction and limit generalization. However, the neural mechanisms through which experience shapes future learning remain unclear. Here, we trained recurrent neural networks (RNNs) on an odor timing task used to study complex timing behavior in mice and then tested the model predictions with mouse behavior and medial entorhinal cortex recordings. Without structured early experience, both RNNs and mice developed rigid, error-prone strategies, whereas structured training promoted neural activity reflecting the task's temporal structure. Using dynamical systems analysis, we examined how different training curricula shaped network dynamics and whether these dynamics supported abstraction and generalization as task complexity increased. These findings demonstrate that the structure of prior experience governs how flexible, generalizable knowledge emerges in biological systems and computational models.
Addictive substances hijack the brain's reward system, driving pathological dopamine surges that underlie compulsive behavior and addiction. However, directly targeting dopamine signaling for treatment risks disrupting natural reward processes. Here we identify a bioenergetic mechanism that selectively promotes addiction-related dopamine release and behaviors. Opioids and methamphetamine, but not natural rewards, induce mitochondrial calcium (Ca2+) influx via the mitochondrial calcium uniporter (MCU) in dopaminergic terminals of the nucleus accumbens. Optogenetic stimulation reveals that this mitochondrial Ca2+ influx occurs exclusively during high-intensity dopaminergic neuronal activation. This Ca2+ influx drives rapid ATP production, compensating for energy deficits caused by neuronal hyperactivity and enabling sustained dopamine release. Genetic deletion or pharmacological inhibition of MCU in dopaminergic neurons selectively reduces drug-induced dopamine release and prevents addictive behaviors while sparing natural reward processing. These findings uncover a distinct mitochondrial bioenergetic mechanism underlying drug reward and propose MCU as a therapeutic target for addiction treatment.
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate excitatory synaptic transmission across the brain and exhibit distinct modes of opening depending on how much glutamate is bound. Despite extensive work on AMPAR conductance states and subunit composition, whether changes in glutamate levels at and around synapses regulate AMPAR function is unknown. Here we show that glutamate concentration ([glutamate]) at mouse interneuron synapses governs key biophysical features of AMPARs that are commonly used to infer subunit composition. Lower [glutamate] reduces hallmark AMPAR properties, including current-voltage rectification, polyamine block and Ca2+ permeability, highlighting a strong dependence of receptor function on synaptic [glutamate]. Recordings from isolated AMPARs combined with numerical simulations reveal differential spermine affinity across distinct conductance states and establish [glutamate], rather than solely subunit composition, as a key determinant of receptor behavior. These findings uncover a previously unrecognized mechanism through which the synaptic glutamate landscape dynamically shapes AMPAR signaling, broadening the framework for how excitatory input is encoded within neural circuits.
Obsessive-compulsive disorder (OCD) and chronic tic disorders (CTDs) are highly heritable. Rare mutations confer large risks for OCD and CTDs but only four high-confidence (hc) genes have been identified. Here we analyzed whole-exome sequencing data from 3,964 individuals with OCD, CTDs or both, including 2,418 trios. We found an excess in cases of de novo and rare protein-damaging mutations and identified 36 hc genes (false discovery rate < 0.1), including four previously identified hc genes (CELSR3, CHD8, SCUBE1 and WWC1) and four genes that overlap with OCD genome-wide association study loci (BRWD1, CELSR3, QRICH1 and SYNE1). Risk genes are shared among OCD, CTDs and other neurodevelopmental conditions. Transcriptomic and network analyses highlight mechanistic convergence and increased risk gene expression in postnatal cerebellum, prenatal and postnatal cortex and striatum. Dozens of large-effect OCD and CTD genes offer insights into pathogenesis and a path forward for illuminating pathophysiology and identifying novel treatment targets.
Understanding how information flows across distributed brain networks is central to linking brain structure, dynamics and function. Here we present a neuroimaging framework that combines integrated effective connectivity (iEC) and unconstrained signal flow mapping for data-driven identification of human cerebral functional hierarchies. Simulations and empirical validation show that iEC recovers connectome directionality and aligns with histologically defined feedforward and feedback pathways. The iEC-derived hierarchy exhibits a monotonically increasing level along the axis where the sensorimotor, association and paralimbic areas are sequentially ordered, consistent with predictions from the structural model of laminar connectivity. This hierarchy is not fixed but flexibly reorganizes across brain states; it becomes flatter during externally oriented processing and steeper during internally focused conditions, reflecting increased engagement of interoceptive regions. Our study indicates that macroscale directed functional connectivity can reveal biologically grounded, state-dependent principles of signal flow in the human brain.
Gene regulation requires coordinated control of RNA synthesis and degradation, yet measuring RNA turnover across intact tissues remains challenging. Here we present spatial NT-seq, a method that combines transgenesis-free metabolic RNA labeling with in situ chemical recoding on spatial transcriptomics platforms to co-map newly synthesized and pre-existing RNAs. Applying spatial NT-seq to the mouse brain reveals pronounced regional heterogeneity in RNA turnover and identifies the dentate gyrus as a spatial hotspot marked by coordinated upregulation of basal RNA synthesis and decay. Moreover, spatial NT-seq uncovers rapid, brain region-specific transcriptional and post-transcriptional responses to electroconvulsive stimulation, a clinically relevant treatment for refractory depression. Finally, we leverage computational modeling to identify sequence features and post-transcriptional regulators that shape transcriptome-wide mRNA stability across spatial and cellular contexts in the mouse brain. Together, this integrated 'in vivo timescope' framework provides a spatially resolved view of RNA turnover kinetics and reveals the regulatory architecture of RNA stability in vivo.
Aging-associated loss of chromatin compaction is linked to derepression of retrotransposable elements (RTEs) in mouse and human tissues. Whether such RTE transcription contributes to the microglia activation that is common in aged brains is unknown. Here, we show that DAXX, a histone chaperone and RTE repressor, is downregulated during aging, preserves microglia homeostasis and inhibits cellular senescence. Loss of Daxx in young-adult microglia drives a reactive phenotype marked by chromatin decompaction at RTEs, loss of homeostatic markers, cell cycle re-entry and behavioral changes. This state leads to DNA damage and microglial depletion, followed by replacement with DAXX-deficient/Apoehigh microglia displaying features of senescence. Sustained induction of senescence relies on promyelocytic leukemia protein, a DAXX-interacting factor and interferon target. Together, these findings highlight the importance of heterochromatin maintenance in preserving adult microglial identity and plasticity, with broader implications for brain homeostasis, healthy aging and behavior.
Complex behaviors are thought to be built by combining simpler cognitive components. Computational modeling has shown that artificial neural networks can perform a variety of tasks by flexibly combining functional modules, each specialized for a specific computation, to construct a complex task. However, it is unknown whether reusable modular networks are found in the brain. Here, we show that mice performing a delayed match-to-sample with delayed report (DMS-dr) task reuse neuronal subspaces that were specialized for stimulus processing and memory maintenance. These subspaces were reused during the task to represent new stimulus inputs and different types of memories, respectively. Clustering analyses showed each subspace was supported by a distinct cluster of neurons in prefrontal cortex and parietal cortex. Studying artificial recurrent networks constrained to neural data found silencing specific clusters disrupted specific computations, consistent with a modular and reusable organization. Altogether, our findings show that the brain can flexibly reuse computational components to perform a complex cognitive task.
In Alzheimer's disease, the protein tau is thought to redistribute from axons to the somatodendritic compartment and form fibrillar aggregates. Although tau aggregation is a hallmark of Alzheimer's disease, the dynamics of its synthesis and degradation are not well characterized. Given that nascent polypeptides are particularly susceptible to misfolding, local control of tau synthesis and degradation may be essential to prevent aggregation. Here we develop STARFISH, a method for visualizing the subcellular site of endogenous mRNA translation in primary neurons and in vivo with single-molecule sensitivity and near-codon resolution, without modifying the nascent polypeptide. Using STARFISH, we show that despite the broad distribution of Mapt mRNA, tau is translated exclusively in neuronal dendrites. About one-third of newly synthesized tau is co-translationally or peri-translationally degraded in dendrites by a neuronal-specific plasma-membrane-associated proteasome, the neuroproteasome. Failure of neuroproteasome-mediated degradation leads to the protein synthesis-dependent accumulation of somatodendritically mislocalized endogenous tau aggregates. These findings define a proteostasis mechanism that counterbalances the constitutive physiological overproduction of tau. We speculate that failure of this proteostasis system contributes to tau aggregation in dendrites in Alzheimer's disease.
High-frequency (~90-Hz) ripple oscillations may promote integrative processing in mammalian brains. Co-occurrence of ripple oscillations has been associated with enhanced temporal binding of neural activity between nearby human cortical neurons, but whether co-ripple facilitation of neuronal coupling supports cognitive processing or occurs at greater distances remains unclear. Here we analyze intracranial recordings from patients implanted with microwire electrodes in the hippocampus, amygdala, ventromedial prefrontal cortex, anterior cingulate cortex and pre-supplementary motor area, bilaterally, during a working memory task. We demonstrate that ripple rates increase in all recorded regions during encoding, maintenance and retrieval. Co-occurrence of ripples increases between brain regions, associated with ~30% increases in cross-region co-firing, without decrement over distances up to 220 mm. Cross-regional co-rippling and associated co-firing scale with memory load during maintenance and retrieval. During retrieval, co-ripples promote reinstatement of stimulus-specific, long-distance co-firing patterns observed during encoding, especially during rapid recognition. Co-occurring ripple oscillations thus coordinate long-range, stimulus-specific neural co-firing supporting distributed representations during human cognition.
Maternal immune activation (MIA) disrupts brain development and increases the risk of neurodevelopmental disorders, yet the mechanisms by which MIA impacts human cortical development remain poorly understood. Here we introduce a three-dimensional ex vivo culture system, termed 'cerebroids,' derived from the dorsolateral prefrontal cortex of human fetal brain tissue, which preserves the key developmental processes, cellular diversity and structural integrity of the developing human cortex. Using this model, we show that IL-17A, a cytokine implicated in MIA and neurodevelopmental disorders, induces premature cortical folding, increases cortical thickness and accelerates neurogenesis and neuronal maturation. We reveal that IL-17A substantially dysregulates extracellular-matrix-related pathways, including upregulation of proteoglycans. In neural stem cells, IL-17A directly activates NF-κB signaling, leading to sustained inflammatory responses that contribute to these developmental abnormalities, which are reversed by treatment with the NF-κB pathway inhibitor parthenolide. These findings delineate how IL-17A perturbs human corticogenesis while elucidating the mechanisms underlying brain disruption during MIA.
On 11 July 2026, neuroscience lost one of its most visionary scientists with the passing of Susumu Tonegawa at the age of 86. Across an extraordinary career spanning more than five decades, Tonegawa pursued biology’s deepest mysteries with relentless curiosity and unwavering conviction, inspiring generations of scientists to keep asking the hardest questions.
