In this issue of Neuron, Haenraets et al. identify spinal GABAergic interneurons necessary for stress-induced analgesia. They receive tonic inhibitory inputs from the rostral ventromedial medulla, and their disinhibition...In this issue of Neuron, Haenraets et al. identify spinal GABAergic interneurons necessary for stress-induced analgesia. They receive tonic inhibitory inputs from the rostral ventromedial medulla, and their disinhibition by stress establishes a spinal gate control of pain.
In this issue of Neuron, Dos Santos et al. identify an activity-dependent soluble ectodomain of α2δ-1 as an extracellular "sheddome" signal that tunes excitation-inhibition balance. A synthetic α2δ-1 ectodomain (SEAD1) s...In this issue of Neuron, Dos Santos et al. identify an activity-dependent soluble ectodomain of α2δ-1 as an extracellular "sheddome" signal that tunes excitation-inhibition balance. A synthetic α2δ-1 ectodomain (SEAD1) selectively enhances parvalbumin interneuron function, restores perineuronal net-associated circuitry, and rescues circuit and cognitive deficits in a schizophrenia-relevant mouse model.
Zheng et al. identify phosphatase PGAM5 as a novel promising target for the treatment of different amyotrophic lateral sclerosis subtypes. PGAM5 dephosphorylates and activates the stress-regulated mitochondrial peptidase...Zheng et al. identify phosphatase PGAM5 as a novel promising target for the treatment of different amyotrophic lateral sclerosis subtypes. PGAM5 dephosphorylates and activates the stress-regulated mitochondrial peptidase OMA1, which elicits a maladaptive mitochondrial integrated stress response in motor neurons.
Mitochondria are essential for brain energy metabolism and are increasingly recognized as key contributors to brain aging. Although neurons are exceptionally vulnerable to age-related mitochondrial decline, emerging evid...Mitochondria are essential for brain energy metabolism and are increasingly recognized as key contributors to brain aging. Although neurons are exceptionally vulnerable to age-related mitochondrial decline, emerging evidence reveals that glial and vascular cells also exhibit distinct mitochondrial impairments. This review synthesizes recent advances in our understanding of mitochondrial dysfunction across specific brain regions and diverse cell types, highlighting subcellular compartmentalization and metabolic rewiring. We further explore intercellular mitochondrial transfer as a novel form of metabolic cooperation, as well as the therapeutic potential of mitochondrial transplantation. Finally, we highlight recent clinical trials evaluating mitochondria-targeted interventions aimed at preserving brain function in older adults. Together, these findings reposition mitochondria as both integrators and amplifiers of brain aging processes across diverse cell populations. By broadening the focus beyond neurons and emphasizing translational efforts, we offer a comprehensive framework for understanding and therapeutically targeting mitochondrial dysfunction in age-related cognitive decline and neurodegeneration.
Classical theories of systems consolidation highlight the importance of hippocampal-neocortical interplay for long-term memory formation. However, how this interaction evolves during multiple days of learning remains unc...Classical theories of systems consolidation highlight the importance of hippocampal-neocortical interplay for long-term memory formation. However, how this interaction evolves during multiple days of learning remains unclear. Using day-by-day multisite intracranial electrophysiology, we examined human subjects performing a repeated picture-learning task. From day 1 today 2, the ripple rates during picture learning and free recall significantly increased in the hippocampus and neocortex, which correlated with behavioral memory performance. These enhancements persisted throughout the remaining task days. Notably, from day 2 onward, the ripple coupling between the neocortex and hippocampus not only strengthened, but the temporal sequence of these coupled ripples also reversed-from hippocampus leading to neocortex leading. This rapid strengthening and reversal of hippocampal-neocortical information flow on the second day represents a key signature of human memory formation.
A major challenge involved in human-machine interfaces is developing feedback strategies that improve control and benefit patients with motor disabilities. Here, we propose, validate, and mechanistically characterize a p...A major challenge involved in human-machine interfaces is developing feedback strategies that improve control and benefit patients with motor disabilities. Here, we propose, validate, and mechanistically characterize a personalized, closed-loop strategy that delivers reinforcement feedback in real time during human-machine interface control. Across five experiments involving 106 participants and two control interfaces, fewer than 20 reinforcement trials produced immediate improvements in force control and lasting retention gains. These effects were strongest when visual and/or somatosensory feedback was limited, a finding that suggests translational relevance for tasks, technologies, and pathologies with limited sensory feedback. In chronic stroke patients, real-time reinforcement likewise improved online force control under limited visual feedback, although short training did not yield retention gains. Information-theoretic analyses further revealed that reinforcement compensates for reduced feedback control when sensory feedback is sparse and promotes motor exploitation of successful actions. Overall, these findings identify real-time reinforcement as a promising strategy for enhancing human-machine interface control.
The orbitofrontal cortex (OFC) is recognized as being responsible for constructing and representing internal models of the causal structure of the world. Current theories task the OFC with filling gaps in our experientia...The orbitofrontal cortex (OFC) is recognized as being responsible for constructing and representing internal models of the causal structure of the world. Current theories task the OFC with filling gaps in our experiential knowledge of this structure, recognizing hidden causes, making inferences, and even creating so-called belief states. Most accounts emphasize the importance of the functions assigned to the OFC in driving decisions. However, mediating such critical aspects of our internal representation of the world should also be important for learning, as adjusting our knowledge depends in part on our expectations and their violation, and constructing and revising a model of the world involves learning in the first place. Here, we will review data consistent with the proposal that the OFC is critical for performance and learning, focusing on neural correlates and OFC-dependent deficits. We will then discuss other actors comprising this circuit, including, most prominently, midbrain dopamine neurons.
Maladaptive learned fear responses to stress underlie several debilitating neuropsychiatric disorders. Here, we identify a brain-to-spleen neural pathway that mediates learned fear through coordinated neuroimmune interac...Maladaptive learned fear responses to stress underlie several debilitating neuropsychiatric disorders. Here, we identify a brain-to-spleen neural pathway that mediates learned fear through coordinated neuroimmune interactions. Using a chronic acquired olfactory stress (CAOS) model, we demonstrate that sustained enhancement of the piriform cortex (Pir) excitability contributes to the transformation of stress-associated olfactory inputs into learned fear-avoidance behavior. Through comprehensive neural tracing approaches, we mapped a functional tetrasynaptic circuit (Pir→ventral hippocampus CA1 subregion [vCA1]→CeM→DVC→spleen) regulating T helper 17 (Th17) cell-dependent fear responses. Single-nucleus RNA sequencing revealed that olfactomedin 3-expressing glutamatergic neurons in the Pir integrate olfactory stress inputs to activate this pathway. Importantly, targeted disruption of this circuit through either conditional knockdown of Olfm3 within Pir→vCA1 projecting glutamatergic neurons or chemogenetic inhibition of these projections eliminated CAOS-induced splenic Th17 cell expansion and fear avoidance. These findings provide fundamental insights into how learned fear becomes maladaptive by identifying a complete neural circuit linking olfactory perception to peripheral immunity.
Zhang H, Liu Z, Chen B
… +24 more, Zhang G, Wang L, Wei C, Zhang X, Luo Y, Peng T, Fang Q, Gu L, Ge R, Zhu J, Yang R, Shen W, Jiang Z, Sun Y, Duan W, Liu J, Li T, Wang J, Gao Z, Yu X, Chen H, Ye Z, Shi X, Li C
Microglia are brain-resident immune cells with complex physiological functions. Exploring their proteomic heterogeneity at the single-cell level has remained technically challenging. Here, we optimized a label-free singl...Microglia are brain-resident immune cells with complex physiological functions. Exploring their proteomic heterogeneity at the single-cell level has remained technically challenging. Here, we optimized a label-free single-cell proteomics (SCP) workflow using Orbitrap Astral mass spectrometry (MS) and applied it to fluorescence-activated cell sorting (FACS)-sorted microglia from the hippocampus and prefrontal cortex of young, middle-aged, and aged mice. This yielded one of the largest SCP datasets to date, comprising 3,085 single cells, with an average of 1,153 protein groups identified per cell. Compared with single-cell transcriptomic data, the SCP dataset showed higher expression completeness and moderate cross-modality correlation. This dataset revealed spatiotemporal proteomic heterogeneity of microglia during aging. Notably, we defined the microglial "phagoproteome," uncovering state-specific phagocytic preferences, and verified these results by imaging. This study underscores the potential of SCP to reveal subpopulation-specific proteomic dynamics and provides a new resource for studying microglial state transitions during aging.
Memory expression fluctuates even in response to identical cues, which suggests that ongoing brain states bias memory accessibility. However, the cellular and circuit principles governing these state-dependent fluctuatio...Memory expression fluctuates even in response to identical cues, which suggests that ongoing brain states bias memory accessibility. However, the cellular and circuit principles governing these state-dependent fluctuations remain unclear. Here, we show that spontaneous pre-cue activity of histaminergic neurons in the hypothalamic tuberomammillary nucleus (TMN) modulates the expression of reward-associative memory in mice. TMN histaminergic activity exhibited infraslow dynamics (0.05-0.1 Hz) that closely tracked an integrated brain-body state. Closed-loop cue delivery during high histaminergic states enhanced memory expression. Brief optogenetic activation or inhibition of these neurons before the cue bidirectionally modulated memory expression, and direct activation of histaminergic terminals in the basolateral amygdala (BLA) was sufficient to enhance memory expression. Furthermore, histaminergic inhibition before the cue impaired the cue-evoked BLA population response. Thus, ongoing histaminergic activity exerts an infraslow, state-setting influence that primes BLA circuits for robust cue responses and, in turn, modulates moment-to-moment memory accessibility.
The mesocorticolimbic dopamine (DA) circuitry is implicated in chronic pain and comorbid depression, yet the specific receptor and circuit mechanisms distinguishing them remain unclear. Here, we show that orbitofrontal c...The mesocorticolimbic dopamine (DA) circuitry is implicated in chronic pain and comorbid depression, yet the specific receptor and circuit mechanisms distinguishing them remain unclear. Here, we show that orbitofrontal cortex (OFC) D1R- and D2R-expressing neurons serve as a checkpoint, independently mediating anxiodepression and allodynia in a trigeminal neuralgia (TN) mouse model. TN induced a hypodopaminergic state in the ventral tegmental area (VTA)-OFC circuit. Activation of the VTA-OFC pathway effectively ameliorated TN-induced allodynia and anxiodepressive-like behaviors; these therapeutic effects were abolished by selective blockade of D2Rs and D1Rs, respectively. Activation of OFC excitatory pyramidal neurons and their projections to the laterodorsal tegmental nucleus (LDTg) improved TN-induced anxiodepressive-like behaviors, whereas disinhibition or activation of OFC D2 excitatory pyramidal neurons and their projections to the basolateral amygdaloid nucleus (BLA) produced analgesia. Thus, selectively targeting VTA-OFC and VTA-OFC or OFC D1Rs and D2Rs may provide new strategies for controlling different symptoms of chronic pain.
Fructose is a simple sugar and a major component of our diet, yet its effects on gut-brain feeding circuits remain poorly understood. Here, we investigated how fructose influences activity in hypothalamic agouti-related...Fructose is a simple sugar and a major component of our diet, yet its effects on gut-brain feeding circuits remain poorly understood. Here, we investigated how fructose influences activity in hypothalamic agouti-related protein (AgRP) neurons-key regulators of hunger. Fructose was markedly less effective than equicaloric glucose at suppressing AgRP neuron activity in mice, challenging the prevailing model of AgRP neurons as indiscriminate calorie detectors. This blunted neural response to fructose did not alter short-term food consumption but was instructive for food preference, demonstrating that graded AgRP neuron activity changes are sufficient to guide food choice. Mechanistically, we discovered that fructose activates a distinct gut-brain pathway involving the release of PYY and signaling through Y2 receptor-expressing vagal afferent neurons to inhibit AgRP neurons. These findings unexpectedly reveal that AgRP neurons respond not just to calories, but to specific nutrients, and highlight how fructose engages a unique gut-brain pathway to communicate with AgRP neurons.
Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly underst...Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5×FAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of cytidine/uridine monophosphate kinase 2 (Cmpk2), a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease β-amyloid burden, restore synaptic plasticity, and improve cognitive function in 5×FAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a potential therapeutic target for AD.
Angelaki DE, Batista A, Fitzgerald T
… +17 more, Kominsky JF, Lengyel M, Mathis A, Mathis MW, Moss CF, Niell CM, Noel JP, Pitkow X, Rothkopf CA, Savin C, Stachenfeld K, Suthana N, Tolias A, Ulanovsky N, Wolpert DM, Wong A, Zimmermann J
The Simons Collaboration on Ecological Neuroscience (SCENE) seeks to uncover general principles of brain function through an ecological perspective: studying perception, cognition, and action in the context of the afford...The Simons Collaboration on Ecological Neuroscience (SCENE) seeks to uncover general principles of brain function through an ecological perspective: studying perception, cognition, and action in the context of the affordances available to different agents. Here, we introduce SCENE's goals, hypotheses, and approaches outlining a collaborative vision for the next decade.
Neurons and glia work together to dynamically regulate neural circuit assembly and maintenance. In this study, we show that Drosophila exhibit large-scale synapse formation and elimination as part of normal CNS circuit m...Neurons and glia work together to dynamically regulate neural circuit assembly and maintenance. In this study, we show that Drosophila exhibit large-scale synapse formation and elimination as part of normal CNS circuit maturation and that glia use conserved molecules to regulate these processes. Using a high-throughput ELISA-based in vivo screening assay, we identify new glial genes that regulate synapse numbers in Drosophila in vivo, including the scavenger receptor ortholog Croquemort (Crq). Crq acts as an essential regulator of glial-dependent synapse elimination during development, with glial Crq loss leading to excess CNS synapses and progressive seizure susceptibility in adults. Loss of Crq in glia also prevents age-related synaptic, but not neuronal, loss in the adult brain. This work provides new insights into the cellular and molecular mechanisms that underlie synapse development and maintenance across the lifespan and identifies glial Crq as a key regulator of these processes.
Cognitive dysfunction in conditions such as schizophrenia involves disrupted communication between the prefrontal cortex (PFC) and the mediodorsal thalamus (MD). Parvalbumin interneurons (PVIs) are known to regulate PFC...Cognitive dysfunction in conditions such as schizophrenia involves disrupted communication between the prefrontal cortex (PFC) and the mediodorsal thalamus (MD). Parvalbumin interneurons (PVIs) are known to regulate PFC microcircuits and generate synchronized gamma-frequency (∼40 Hz) neural oscillations that are recruited during many executive functions, necessary for cognitive flexibility, and deficient in schizophrenia. While targeting PVI-mediated gamma oscillations holds great therapeutic promise, their nature and specific functions, e.g., for regulating PFC→MD communication, remain elusive. Using dual-color voltage indicators and optogenetics in mice, we reveal that PVIs dynamically synchronize with MD-projecting PFC neurons both locally and contralaterally, creating multiple distinct circuit-specific patterns of distributed gamma synchronization that are recruited in a behaviorally specific manner to support particular aspects of flexible behavior. Thus, gamma oscillations are not unitary phenomena characterized by one microcircuit-wide pattern of synchrony. Rather, they comprise diverse motifs, defined by specific cell types and phase relationships, that are dynamically recruited for specific functions.
Drug cues strongly influence drug seeking and relapse to addiction. However, it is unclear how drug cues do this. We reveal that a novel pathway from ventral tegmental area dopamine (VTA) neurons to the lateral hypothala...Drug cues strongly influence drug seeking and relapse to addiction. However, it is unclear how drug cues do this. We reveal that a novel pathway from ventral tegmental area dopamine (VTA) neurons to the lateral hypothalamus (LH) is necessary and sufficient to govern learning about associations between cues and specific outcomes and the use of such associations to govern decision making. We found that prior methamphetamine self-administration enhanced the control that reward cues have over behavior in this same manner, which was correlated with bidirectional strengthening of the LH-VTA circuit. We characterized dopamine release in LH to reward cues across learning and found that this learning signal was augmented following methamphetamine experience. These data demonstrate that cues exert greater, specific control over decision making after repeated drug use, concomitant with drug-induced changes in the LH-VTA circuit. This contrasts with habit theories of addiction that assert behavior becomes automatic, without thought of possible outcomes.
Neural circuits are shaped by the diverse axonal branching patterns of neurons across different cell types. To map these patterns, here we introduce POINTseq (projections of interest by sequencing), a barcoded connectomi...Neural circuits are shaped by the diverse axonal branching patterns of neurons across different cell types. To map these patterns, here we introduce POINTseq (projections of interest by sequencing), a barcoded connectomics method for rapid, cell-type-specific mapping of thousands of single-cell projections per animal. POINTseq leverages viral pseudotyping and cell-type-specific infection to integrate MAPseq-style high-throughput barcoded projection mapping with the established viral-genetic neural circuit analysis toolbox. We validated POINTseq by mapping genetically and projection-defined cell populations in the mouse motor cortex. We then used POINTseq to reconstruct the brain-wide projections of 5,902 individual dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). These neurons fall into >25 connectomic cell types, vastly exceeding the known diversity of dopaminergic cells, and form stereotyped projection motifs that may mediate parallel dopamine signaling. These data constitute the anatomical substrate on which the diverse functions of dopamine in the brain are built.
Fatima M, Lee H, Cha H
… +23 more, Hor CC, Wang F, Liu J, Damblon J, Zhang W, Qu K, Nagai Y, Dinh A, Wu Z, Ajimal R, Xiong AE, Chai M, Asmar A, Cai W, Zhou X, Balaji A, Pan H, Horwitz L, Tsoi LC, Hu H, Xu XZS, De Koninck Y, Duan B
Hairs serve as sensory structures that are crucial for perceiving environmental cues through interactions with sensory endings. Depigmented and demedullated atypical hairs exhibit a limited distribution on mammalian skin...Hairs serve as sensory structures that are crucial for perceiving environmental cues through interactions with sensory endings. Depigmented and demedullated atypical hairs exhibit a limited distribution on mammalian skin and have not been extensively studied. In this study, we identify a specific type of hair, termed vellus-like hairs (VLHs), which are enriched in the postauricular region and on the hindpaws of mice. These hairs are innervated by Aβ low-threshold mechanoreceptors (LTMRs) that co-express Toll-like receptor 5 and Calbindin1 (TLR5). Genetic ablation or silencing of these hair afferents eliminated mechanical itch generated by gentle VLH stroking or indentation under both physiological and pathological conditions. Conversely, optogenetic activation of TLR5 hair afferents evoked itch behaviors. Mechanosensitive Piezo2 channels in TLR5 Aβ-LTMRs function as key mechanotransducers for mechanical itch signaling. Our study sheds light on the previously poorly understood somatosensory physiology of unique hairs, emphasizing the significant role of TLR5 Aβ-LTMRs in itch transmission.
AgRP neurons cause hunger, the drive to seek and consume food. Their activation by fasting is key for survival and is thought to be triggered by feedback when energy stores are low. However, we know that environmental cu...AgRP neurons cause hunger, the drive to seek and consume food. Their activation by fasting is key for survival and is thought to be triggered by feedback when energy stores are low. However, we know that environmental cues can also regulate AgRP neurons since cues that predict future food intake rapidly inhibit AgRP neurons, but is the converse true: can the prediction of future fasting rapidly activate AgRP neurons? Here, we show in mice that such rapid fasting activation of AgRP neurons does occur. This rapid activation is driven by excitatory input from paraventricular hypothalamic (PVH) neurons expressing Sim2, which are bidirectionally sensitive to predictions of future energy state. Thus, cognitively processed contextual information conveyed by PVH neurons strongly activates AgRP neurons. Lastly, chronic silencing of PVH neurons causes persistent hypophagia. This PVH-to-AgRP-neuron circuit, by anticipating and preventing negative energy balance, provides an important new dimension of hunger regulation.