Brain injury elicits complex tissue responses that are dynamically regulated between activation and resolution, yet the mechanisms that govern this balance remain elusive. We show that acute injury evokes focal extracell...Brain injury elicits complex tissue responses that are dynamically regulated between activation and resolution, yet the mechanisms that govern this balance remain elusive. We show that acute injury evokes focal extracellular ATP events (Inflares) with characteristic spatiotemporal signatures that scale quantitatively with injury severity, suggesting a glial mechanism for damage calibration. We further reveal that microglia exert negative feedback on Inflares by tuning interleukin (IL)-1β output based on extracellular ATP levels and cellular state. The IL-1β signal is directly received by astrocytes through IL-1R1 and intracellular Ca-calcineurin signaling, where it converges with injury input to shape Panx1-dependent ATP release. These bidirectional interactions form a reciprocal glial circuit that enforces a balanced injury response, while disrupting the circuit destabilizes the dynamic control, impairing the cellular reactivity and worsening early injury outcomes. Our findings uncover a glial circuit and molecular players that dynamically regulate tissue injury responses.
Cardiovascular sensory pathways are essential for maintaining tissue perfusion under physiological perturbation. A new study identifies PIEZO2-positive vagal afferents as candidate cardiac blood-volume receptors that det...Cardiovascular sensory pathways are essential for maintaining tissue perfusion under physiological perturbation. A new study identifies PIEZO2-positive vagal afferents as candidate cardiac blood-volume receptors that detect reduced filling and trigger protective responses during postural challenge and hemorrhage.
Casto et al. carried out an extensive investigation demonstrating the involvement of the cerebellum in linguistic processing and identified a language-specialized area located mainly in posterior Crus I/II. The study off...Casto et al. carried out an extensive investigation demonstrating the involvement of the cerebellum in linguistic processing and identified a language-specialized area located mainly in posterior Crus I/II. The study offers an analysis of the cerebellum's contribution to language at the level of words and sentences, in comparison with numerous other cognitive and social domains and in relation to the neocortical language network.
Estrogen enhances cognition under healthy and pathological conditions. In this issue of Neuron, Hokenson et al. describe findings that counter this view, demonstrating that high levels of brain estrogen during acute inte...Estrogen enhances cognition under healthy and pathological conditions. In this issue of Neuron, Hokenson et al. describe findings that counter this view, demonstrating that high levels of brain estrogen during acute intense stress impair memory. This preview discusses their findings in context of stress-induced pathology and resilience.
In this issue of Neuron, Ramirez et al. identify a mechanism through which astrocytes and microglia interact to refine developing thalamocortical circuits. The C-terminal fragment of astrocyte-derived Hevin binds microgl...In this issue of Neuron, Ramirez et al. identify a mechanism through which astrocytes and microglia interact to refine developing thalamocortical circuits. The C-terminal fragment of astrocyte-derived Hevin binds microglial TLR4, inducing TLR2 expression and increasing synaptic phagocytosis. This astrocyte-microglial crosstalk is essential for the refinement of synapses in the developing brain.
PLX5622 is widely used to study microglia in health and disease. In this issue of Neuron, a new manuscript from Cao et al. unveils a non-microglial driver of phenotypes previously attributed to microglia and provides a r...PLX5622 is widely used to study microglia in health and disease. In this issue of Neuron, a new manuscript from Cao et al. unveils a non-microglial driver of phenotypes previously attributed to microglia and provides a roadmap for more effectively interpreting microglia depletion studies.
Xie X, Huang Y, Chen R
… +13 more, Huang Z, Gangal H, Li Z, Lu J, Cruz AM, Chaiprasert A, Yu E, Hernandez N, Vierkant V, Wang R, Wang X, Smith RJ, Wang J
Relapse remains a major obstacle in treating alcohol and drug addiction and is thought to be driven by persistent drug-associated memories formed during use. Extinction training reduces relapse and is proposed to generat...Relapse remains a major obstacle in treating alcohol and drug addiction and is thought to be driven by persistent drug-associated memories formed during use. Extinction training reduces relapse and is proposed to generate a competing memory, yet where and how these opposing memories are stored is unknown. Here, we show that two anatomically and functionally distinct engram ensembles within the same striatal cell type, direct-pathway medium spiny neurons (dMSNs), encode these opposing memories in mice. Operant alcohol learning recruits a broadly distributed dMSN ensemble that encodes relapse-promoting alcohol memories. By contrast, operant extinction recruits a striosome-enriched dMSN ensemble that encodes an extinction memory to suppress relapse. We further demonstrate that relapse-promoting memory is embedded in persistently strengthened corticostriatal synapses engaged during learning and that mimicking this synaptic strengthening is sufficient to drive relapse-like behavior. Together, these findings reveal a dual-engram architecture within dorsostriatal dMSNs governing relapse and extinction.
Early-life episodic experiences, despite seeming rapidly forgotten, are stored long-term in a latent form. The contribution of this unique hidden memory storage is not understood. Here, we show that contextual memories f...Early-life episodic experiences, despite seeming rapidly forgotten, are stored long-term in a latent form. The contribution of this unique hidden memory storage is not understood. Here, we show that contextual memories formed in infant mice are recovered in adulthood following weak behavioral reminders (savings) of the infantile experience. Savings in adults also facilitates new congruent learning but fails to influence other types of hippocampus-dependent learning, and this facilitation is a developmental prerogative. Both infant memory reinstatement and facilitation of new learning in adults are context-specific and functionally re-engage subsets of the prelimbic/infralimbic (PL/IL) and anterior cingulate cortex (ACC) neural networks activated in infancy. New adult learning also re-engages the dorsal hippocampus (dHC) along with PL/IL-dHC and ACC-dHC neuronal projections that were activated during infant learning. Thus, infant memories store information for a long time as memory schemas that support relearning and the formation of new congruent memories in adulthood.
Retinitis pigmentosa (RP) is a genetically diverse blinding disorder lacking broadly effective therapies. We performed a genome-wide in vivo CRISPR knockout screen in mice carrying the P23H rhodopsin mutation, the most c...Retinitis pigmentosa (RP) is a genetically diverse blinding disorder lacking broadly effective therapies. We performed a genome-wide in vivo CRISPR knockout screen in mice carrying the P23H rhodopsin mutation, the most common cause of autosomal dominant RP in the United States, to systematically identify neuroprotective genes. We discovered multiple knockouts that accelerated rod photoreceptor loss, validated top candidates, and showed that overexpressing two genes-ubiquitin fusion degradation 1 (UFD1) and ubiquitously expressed transcript (UXT)-preserved rods and cones, maintained retinal function, and improved visual behaviors. To accelerate translation, we developed a human P23H RP model in adult retinal explants, recreating key disease features. UFD1 and UXT augmentation prevented photoreceptor degeneration in human P23H retinas. Our findings establish a pipeline for systematic identification and translational testing of neuroprotective genes in mouse and human RP models, provide a novel set of validated candidates, and underscore the therapeutic promise of UFD1 and UXT as mutation-agnostic strategies against proteotoxicity.
Humans excel at learning from sparse experience by leveraging internal models of the world to infer the values of options they have never sampled, i.e., model-based learning. However, how the brain supports such learning...Humans excel at learning from sparse experience by leveraging internal models of the world to infer the values of options they have never sampled, i.e., model-based learning. However, how the brain supports such learning remains largely unknown. Here, we recorded intracranial electrophysiology (iEEG) from 34 epilepsy patients performing a reinforcement-learning task that required using the task structure to infer the values of unvisited (non-local) paths. Hippocampal ripples were associated with prioritized non-local learning. After each outcome, ripple events carried information about which indirect experience was most valuable to update, with longer ripples showing stronger priority signals. These events coincided with stronger cortical reactivation of high-priority than low-priority paths. Importantly, lateral frontopolar cortex activity precisely synchronized with hippocampal ripples in this post-reward time window, which predicted more effective use of task structure and more accurate non-local value learning. Together, our findings suggest that ripple-centered hippocampal-prefrontal coordination supports efficient model-based learning.
The spread of tau pathology across the cerebral cortex is closely tied to cognitive decline in Alzheimer's disease (AD). To investigate mechanisms underlying tau spread, we measured bioactivity of tau seeds from inferior...The spread of tau pathology across the cerebral cortex is closely tied to cognitive decline in Alzheimer's disease (AD). To investigate mechanisms underlying tau spread, we measured bioactivity of tau seeds from inferior temporal gyrus (ITG) and superior frontal gyrus (SFG) synaptosomes in 128 individuals and demonstrated that tau seed bioactivity associates with tau phosphorylation, neurofibrillary tangles (NFTs), and cognitive impairment. Incorporating genotype data from the same individuals within a Mendelian randomization framework showed that tau seeds in ITG induce NFTs locally as well as drive tau seeds and NFTs in SFG. Integrating antemortem functional magnetic resonance imaging data from the same individuals showed that person-specific connectivity modulates the tau seed-NFT relationships. These findings indicate that tau seeds underlie the spread of NFTs both locally and across distal brain regions via individual-specific connectivity.
In the adult brain, hippocampal activity precisely regulates the survival of newborn hippocampal neurons. However, the mechanisms by which these neurons acquire metabolites required for survival remain unclear. Using a g...In the adult brain, hippocampal activity precisely regulates the survival of newborn hippocampal neurons. However, the mechanisms by which these neurons acquire metabolites required for survival remain unclear. Using a genetically encoded glucose biosensor and in vivo imaging in freely moving animals, we tracked cellular glucose dynamics during contextual exploration. Newborn neurons recovered intracellular glucose slowly and expressed low levels of glycolysis- and glucose transport-related genes. By contrast, astrocytes surrounding newborn neurons exhibited rapid decreases in intracellular glucose during exploration, followed by prompt recovery afterward. In vivo lactate imaging revealed concurrent increases in astrocytic and extracellular lactate during exploration. Importantly, disrupting astrocytic glucose uptake, lactate production, or lactate transport in astrocytes or newborn neurons impaired activity-dependent survival. These results identify an astrocyte-to-newborn neuron metabolic pathway in which astrocytic glucose metabolism supports newborn neuron survival through lactate, with implications for adult neurogenesis in aging and disease.
The proteinopathy of the RNA-binding protein TDP-43, characterized by nuclear clearance and cytoplasmic inclusion, is a hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), fron...The proteinopathy of the RNA-binding protein TDP-43, characterized by nuclear clearance and cytoplasmic inclusion, is a hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). Through CRISPR interference (CRISPRi) screening in human neurons, we identified the decapping scavenger enzyme (DCPS) as a novel genetic modifier of TDP-43 loss-of-function (LOF)-mediated neurotoxicity. Our findings reveal that TDP-43 LOF leads to aberrant mRNA degradation via dysregulating the properties and activity of processing bodies (P-bodies). TDP-43 interacts with P-body component proteins, potentially influencing their dynamic equilibrium and assembly into ribonucleoprotein (RNP) granules. Loss of TDP-43 hyperactivates P-bodies, increasing mRNA association and RNA decay. Reducing DCPS restores P-body integrity and RNA turnover, ultimately improving neuronal survival. Overall, this study highlights a novel role of TDP-43 in RNA processing through P-body regulation and identifies DCPS as a potential therapeutic target for TDP-43 proteinopathy-related neurodegenerative diseases.
Inherited ion channel gene mutations cause network synchronization disorders, but their early impact on circuit development is less understood. Childhood absence epilepsy features cortical spike-wave discharges driven by...Inherited ion channel gene mutations cause network synchronization disorders, but their early impact on circuit development is less understood. Childhood absence epilepsy features cortical spike-wave discharges driven by thalamocortical rebound bursting. Loss-of-function mutations in P/Q-type calcium channels impair neurotransmitter release yet paradoxically increase thalamic excitability. In tottering mice, global P/Q deficiency elevates T-type calcium and big potassium (BK) channel transcripts in thalamic relay neurons, increasing excitability before seizure onset and coincident with the N-to-P/Q exocytosis switch. Selective P/Q deletion in cortical L6 pyramidal presynaptic input to thalamus reproduced the coordinate transcript elevation, indicating a transsynaptic mechanism. Unexpectedly, tottering, but not L6 mutants, showed increased thalamic neurogenesis and β-catenin/Lef1 upregulation, linking intrinsic thalamic P/Q channel function to early structural brain development. These findings reveal that subtle inherited changes in P/Q-mediated transmitter release and postsynaptic membrane calcium dynamics disrupt a previously unrecognized embryonic homeostatic pathway regulating growth, plasticity, and excitability in thalamocortical circuits.
Rapid delivery of glutamate receptors to the postsynaptic membrane via vesicle fusion is a central component of synaptic plasticity. However, it is unknown how this process supports specific neural computations during be...Rapid delivery of glutamate receptors to the postsynaptic membrane via vesicle fusion is a central component of synaptic plasticity. However, it is unknown how this process supports specific neural computations during behavior. To bridge this gap, we combined hippocampal CA1 deletion of the t-SNARE protein Syntaxin3 (Stx3), a component of the postsynaptic membrane fusion machinery, with population in vivo calcium imaging. This approach revealed that Stx3 is necessary for neural responses to novelty and for forming stable representations of rewarded locations. By contrast, CA1 Stx3 is dispensable for maintaining aspects of the neural code that exist presynaptic to CA1, such as representations of context and space. Thus, altering the Stx3-dependent postsynaptic membrane fusion machinery identified computations that specifically require synaptic restructuring via membrane trafficking in CA1 and distinguished them from neural representations that could be inherited from upstream brain regions or learned through other mechanisms.
Shi J, Nutkovich B, Kushinsky D
… +13 more, Rao BY, Herrlinger SA, Tsivourakis E, Mihaila TS, Conde Paredes ME, Cohen-Kashi Malina K, O'Toole CK, Yong HC, Sanner BM, Xie A, Varol E, Losonczy A, Spiegel I
Neural circuits are characterized by genetically and functionally diverse cell types. A mechanistic understanding of circuit function is predicated on linking the genetic and physiological properties of individual neuron...Neural circuits are characterized by genetically and functionally diverse cell types. A mechanistic understanding of circuit function is predicated on linking the genetic and physiological properties of individual neurons. However, it remains highly challenging to map the molecular properties onto functionally heterogeneous neuronal subtypes in mammalian cortical circuits in vivo. Here, we introduce a high-throughput two-photon nuclear phototagging (2P-NucTag) approach for on-demand and stable labeling of single neurons via a photoactivatable red fluorescent protein following in vivo functional characterization in behaving mice. Using this optimized function-forward pipeline to selectively label and transcriptionally profile previously inaccessible "place" and "silent" cells in the hippocampus of behaving mice, we identify unexpected differences in gene expression. Furthermore, we demonstrate multiple downstream experimental directions that 2P-NucTag enables, including ex vivo slice electrophysiology and histology. Thus, 2P-NucTag opens a new way to uncover the molecular principles that govern the functional organization of neural circuits.
Disruption of excitatory/inhibitory (E/I) balance within the basolateral amygdala (BLA) is a critical feature of depressive and anxiety-like states, yet effective circuit-based therapies are lacking. Here, we demonstrate...Disruption of excitatory/inhibitory (E/I) balance within the basolateral amygdala (BLA) is a critical feature of depressive and anxiety-like states, yet effective circuit-based therapies are lacking. Here, we demonstrate that tactile experience enrichment (TEE)-a noninvasive sensory stimulation-ameliorates depressive- and anxiety-like behaviors in multiple post-stroke depression (PSD) mouse models by engaging a thalamic-amygdala pathway from the reuniens nucleus (Re) to BLA inhibitory neurons (Re-BLA). Activation of this compensatory circuit re-establishes E/I balance in the BLA through feedforward inhibition of excitatory neurons, thereby bypassing the impaired medial prefrontal cortex-BLA pathway. Both chemogenetic activation of the Re-BLA pathway and TEE treatment in chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models similarly restore synaptic E/I balance and significantly improve emotional behaviors. These results define a lesion-bypassing circuit mechanism through which tactile input modulates amygdala function in mice and will motivate future studies of translational relevance.
Multimodal large language models (MLLMs) have demonstrated an extraordinary capacity to bridge textual and visual inputs. Nonetheless, MLLMs still face limitations in situated physical and social interactions in sensoria...Multimodal large language models (MLLMs) have demonstrated an extraordinary capacity to bridge textual and visual inputs. Nonetheless, MLLMs still face limitations in situated physical and social interactions in sensorially rich and multimodal real-world settings, where the embodied experience of a living organism appears fundamental. We suggest that the next frontiers for MLLM development require the incorporation of both internal and external embodiment-modeling not only external interactions with the world but also internal states and drives. Here, we describe mechanisms of internal and external embodiment in humans and relate these to current advances in MLLMs in the early stages of aligning to human representations. Our dual-embodied framework proposes to model interactions between these forms of embodiment in MLLMs so as to bridge the gap between multimodal data and world experience.
Kim B, Tate MD, Karahan H
… +13 more, Wijeratne HRS, Sharify AD, Wang SS, Kim JR, Al-Amin MM, Hartigan K, Chung S, Dabin LC, Acri DJ, Doud EH, John SK, Mosley AL, Kim J
Recent human genetic studies have highlighted the potential role of microglial genes and their regulatory functions in the pathogenesis of Alzheimer's disease (AD). The transcription factor PU.1 (encoded by SPI1) is expr...Recent human genetic studies have highlighted the potential role of microglial genes and their regulatory functions in the pathogenesis of Alzheimer's disease (AD). The transcription factor PU.1 (encoded by SPI1) is expressed mainly in microglia in the central nervous system and has been reported to be a genetic risk factor for AD. However, the role of microglial SPI1 in AD etiology is still poorly understood. Here, we demonstrate that the selective deletion of Spi1 in microglia exacerbates AD-related pathologies in an amyloid mouse model. Specifically, microglial Spi1 deletion increases amyloid deposition, gliosis, and dystrophic neurites while decreasing the microglial response to plaques. By combining proteomics and functional analyses, we reveal that the loss of microglial Spi1 impairs phagocytosis through Syk, Lyn, and Fcgr1. Furthermore, directly activating these genes rescues the impaired amyloid-beta (Aβ) uptake caused by Spi1 knockdown, unveiling the potential mechanism of SPI1 in amyloid pathology.
Algermissen J, Rascu M, Weber LA
… +10 more, den Boer T, Martin E, Treeby B, Gray MD, Cleveland RO, Wittmann MK, Clarke WT, Fouragnan E, Rushworth MFS, Klein-Flügge MC
The amygdala shows abnormal metabolism in depression, a disorder marked by altered emotion, motivation, and learning. Yet its causal role in these processes remains unclear because non-invasive, reversible perturbation i...The amygdala shows abnormal metabolism in depression, a disorder marked by altered emotion, motivation, and learning. Yet its causal role in these processes remains unclear because non-invasive, reversible perturbation in humans has not been possible. We used transcranial focused ultrasound stimulation (TUS) to modulate basolateral amygdala (BLA) activity. In separate sessions, healthy volunteers received offline TUS to bilateral BLA, mid-insula, or sham before completing a novel emotional learning task validated online. 7T-resting-state connectivity and metabolite measures confirmed target engagement: BLA-TUS reduced the BLA's connectivity fingerprint and lowered its excitation/inhibition balance. Behaviorally, BLA-TUS increased approach tendencies toward neutral, emotionally ambiguous faces in a stimulation-volume-dependent manner and slowed responses to neutral and happy faces. These effects were functionally and regionally specific and suggest a causal role for the amygdala in resolving emotional ambiguity. Our findings inform studies of mood disorders, where difficulty resolving ambiguity may contribute to emotional and learning biases.