Kindel, Post et al. establish that VMH SF1 neurons in mice encode exercise history and mediate endurance gains and exercise-driven metabolic benefits. Activation of these neurons even without further exercise training su...Kindel, Post et al. establish that VMH SF1 neurons in mice encode exercise history and mediate endurance gains and exercise-driven metabolic benefits. Activation of these neurons even without further exercise training sustains benefits, suggesting they may be a target of exercise-mimetic therapies.
Major depressive disorder (MDD) is increasingly tractable through the frameworks of circuit neuroscience. We conceptualize MDD as a pathological attractor, representing a stable and self-reinforcing network configuration...Major depressive disorder (MDD) is increasingly tractable through the frameworks of circuit neuroscience. We conceptualize MDD as a pathological attractor, representing a stable and self-reinforcing network configuration orchestrated by maladaptive plasticity. This review synthesizes evidence demonstrating that the depressive state emerges from a hierarchical failure of top-down prefrontal control, which permits pathological stabilization within subcortical hubs to drive anhedonia and motivational deficits. Reinterpreting current findings through a dynamical lens reveals how these anomalies reflect biased and rigid network patterns. This framework reframes therapeutic intervention as a strategy to reshape the functional landscape of the brain, where rapid-acting pharmacology and precision neuromodulation facilitate recovery by guiding neural trajectories toward adaptive configurations. Future directions involve integrating individualized circuit fingerprinting with adaptive closed-loop systems to move psychiatry toward a predictive science grounded in the kinetic steering of global network dynamics.
Levodopa-induced dyskinesia (LID) is a debilitating complication of symptomatic therapy in Parkinson's disease. Although there is compelling evidence that striatal pathophysiology is a major driver of LID, the specific c...Levodopa-induced dyskinesia (LID) is a debilitating complication of symptomatic therapy in Parkinson's disease. Although there is compelling evidence that striatal pathophysiology is a major driver of LID, the specific circuit mechanisms governing its expression remain obscure. To address this gap, molecular, cellular, and behavioral strategies were used to interrogate circuits in a mouse model of LID. These studies revealed that LID induction led to an upregulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) in indirect pathway spiny projection neurons (iSPNs), the emergence of "silent" glutamatergic synapses, and long-term synaptic potentiation. Knocking down the expression of Grin2b mRNA in iSPNs dramatically attenuated both the development and expression of LID without compromising the beneficial effects of levodopa on movement. Taken together, these studies demonstrate that dyskinesiogenic doses of levodopa trigger cell-specific synaptic adaptations that are necessary for the network pathophysiology underlying LID and suggest that targeting GluN2B-containing NMDARs in iSPNs could be therapeutically useful.
Mitochondria represent central regulators of neuronal function, and their network is dynamically restructured via fission and fusion. The mitochondrial fission factor (MFF) serves as an adaptor protein that recruits and...Mitochondria represent central regulators of neuronal function, and their network is dynamically restructured via fission and fusion. The mitochondrial fission factor (MFF) serves as an adaptor protein that recruits and organizes the core fission machinery at the outer mitochondrial membrane. Here, we investigated the role of MFF in Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) in their regulation of systemic energy homeostasis. We demonstrated that mice lacking MFF in AgRP neurons exhibited increased mitochondrial size, both in AgRP neuron somata and their axonal compartments. This translated into increased mitochondrial Ca uptake capacity, increased mitochondrial membrane potential, and a shift toward a more reduced mitochondrial NAD(P)H redox state. Ultimately, these changes resulted in increased neuronal excitability and neurotransmitter release to functionally enhance dynamic food intake during energy state transitions. Collectively, MFF-dependent mitochondrial fission links cell-type-specific neuronal mitochondrial dynamics via mitochondrial Ca handling to control systemic metabolism.
Across the globe, rates of mood and anxiety disorders have been increasing steadily, a trend accelerated by the COVID-19 pandemic. Stress triggers these disorders, precipitating initial episodes and provoking relapses. I...Across the globe, rates of mood and anxiety disorders have been increasing steadily, a trend accelerated by the COVID-19 pandemic. Stress triggers these disorders, precipitating initial episodes and provoking relapses. In this perspective, we argue that the stress system is not merely a threat mechanism but also an ongoing and active monitor of the environment and that resilience is not simply the lack of sensitivity to stress but an active function with an intrinsic neurobiology. Through the interplay of genetic, developmental, and experiential mechanisms, individuals evolve their own "stress-resilience algorithm" that determines their stress reactivity and the resulting adaptive or maladaptive consequences. This algorithm represents a dynamic, lifelong process that is often self-reinforcing. We underscore the importance of focusing on prevention by assessing and enhancing an individual's "stress fitness." This perspective offers a new conceptualization of the neurobiology of stress and resilience as a framework for basic and translational neuroscience research aimed at confronting the challenges of stress disorders.
Social interactions are foundational to learning, yet scalable one-on-one instructor-student interaction remains challenging in online video learning. We examine whether a brief, structured pre-lecture instructor-student...Social interactions are foundational to learning, yet scalable one-on-one instructor-student interaction remains challenging in online video learning. We examine whether a brief, structured pre-lecture instructor-student interaction, led by either a human or large language model (LLM)-powered AI instructor, can enhance student engagement and learning. Integrating behavioral testing with simultaneous eye-tracking and fMRI, we compared three groups in a between-subjects design (no interaction, human interaction, and AI interaction; n = 57). Both human- and AI-led pre-lecture interactions improved learning and enhanced neural alignment in critical brain regions (e.g., the default mode network) among students during learning. Neural and gaze alignments between instructor and students, as well as among students, jointly mediated learning gains, revealing a reciprocal eye-brain-behavior correspondence. While the AI instructor approximated the human instructor in learning gains, students reported lower social closeness and exhibited lower gaze alignment. These findings advance social learning theories and provide neurocognitive evidence that scalable LLM-powered AI can transform online education.
The nervous system drives tumor growth directly through intra-tumoral axons and indirectly through the systemic action of hormones. Yet contexts where the nervous system inhibits tumor growth are less defined. Here, we p...The nervous system drives tumor growth directly through intra-tumoral axons and indirectly through the systemic action of hormones. Yet contexts where the nervous system inhibits tumor growth are less defined. Here, we performed optical reconstruction of axonal innervation in mouse models of cutaneous melanoma, revealing progressive innervation by sympathetic axons. Local depletion of these axons accelerates while local optogenetic activation slows melanoma growth, together consistent with these axons acting as a physiological growth brake. The sympathetic nervous system is typically associated with driving tumor growth through activation of β-adrenergic receptors (ARs). Here, we find that the initial tumor seeding conditions sensitize melanomas from βAR-driven growth promotion toward α2-AR-driven growth inhibition. Mechanistically, the axonal activation of α2 ARs restricts the number and distribution of pro-tumor myeloid cells, independently of T cell activity. Together, our data reveal context-dependent, bidirectional neural control of tumor progression.
The organization of the newborn visual system constrains perception at birth and shapes how visual abilities develop across childhood. Using resting-state fMRI from 584 neonates, we provide a comprehensive systems-level...The organization of the newborn visual system constrains perception at birth and shapes how visual abilities develop across childhood. Using resting-state fMRI from 584 neonates, we provide a comprehensive systems-level characterization of the human visual cortex within hours of birth and across the third trimester of gestation. We find that the newborn visual cortex is already organized into three distinct pathways (ventral, lateral, and dorsal), each exhibiting a hierarchical structure and adult-like topographic organization. This organization becomes increasingly differentiated across gestation, with strengthening pathway segregation, hierarchical structure, and a greater alignment to adults. Individual pathways, however, follow distinct developmental trajectories, with dorsal areas showing near-adult-like organization at the earliest gestational ages examined, whereas ventral areas remained comparatively immature. The extensive intrinsic organization at birth, combined with pathway-specific maturation, provides a basis for understanding the perceptual capabilities of infants and the capacity for learning from one's environment.
Tavares GA, O'Reilly L, Frederick NM
… +14 more, Shapiro DA, Vicchiarelli A, Sullivan M, Jiang N, Mattes M, Goelz C, Uchegbu N, Brown H, Lubera J, Wolfe L, Boylan BT, Bergmann C, DeSilva TM, Louveau A
The meningeal lymphatic vasculature has recently emerged as a central player in the regulation of brain function under normal and pathological conditions. The dorsal meningeal/dural lymphatics expand uniquely postnatally...The meningeal lymphatic vasculature has recently emerged as a central player in the regulation of brain function under normal and pathological conditions. The dorsal meningeal/dural lymphatics expand uniquely postnatally during a critical window for brain maturation. The mechanisms driving their development and function, however, remain poorly understood. Here, we demonstrate that the developing dorsal meningeal lymphatic vasculature, contrary to peripheral counterparts, undergoes defined refinement orchestrated by cell death and phagocytosis by meningeal macrophages. Alteration of this refinement is observed in the BTBR mouse model of autism spectrum disorder (ASD) and appears to regulate ASD-like social behavior. Together, our results demonstrate a new pathway regulating meningeal lymphatic development that may contribute to brain maturation and function.
Resident myeloid cells are the main constituents of the healthy central nervous system's (CNS) immune compartment. They usually seed the developing CNS prior to birth, remain there lifelong, and essentially contribute to...Resident myeloid cells are the main constituents of the healthy central nervous system's (CNS) immune compartment. They usually seed the developing CNS prior to birth, remain there lifelong, and essentially contribute to neuronal network formation and establishment of physiology. While CNS anatomy is optimized for efficient connectivity, function, and maintenance of neuronal cells, distinct structures facilitate selective postnatal immune cell trafficking, including entry of myeloid cells. These myeloid gateways become active upon physiological need, during aging, or in pathologies. As a consequence, individual CNS compartments show variable accessibility to short-living circulating myeloid cells derived from postnatal bone marrow sources. Here, we summarize our current view of myeloid cell trafficking into the healthy CNS, spanning embryogenesis to physiological aging and highlight recent discoveries of novel routes. A precise understanding of the anatomical and molecular properties of myeloid gateways is essential to develop targeted cell therapies to treat myeloid-cell-driven CNS perturbations.
The combination of brain glucose hypometabolism and hyperphosphorylated Tau (p-Tau) pathology is the strongest known clinical predictor of imminent cognitive decline, yet how these factors cooperate to drive dementia rem...The combination of brain glucose hypometabolism and hyperphosphorylated Tau (p-Tau) pathology is the strongest known clinical predictor of imminent cognitive decline, yet how these factors cooperate to drive dementia remains unknown. Here, we show that glucose hypometabolism synergizes with p-Tau to trigger neuronal loss through necroptosis. Under low-glucose conditions, accumulated p-Tau forms a molecular scaffold that directly recruits RIPK1, while concomitant loss of the necroptosis checkpoint A20 removes a critical brake on this death pathway. This dual mechanism thereby precipitates neuronal necroptosis. Restoring A20 expression with acetyl-L-carnitine or preventing the p-Tau-RIPK1 interaction using a RIPK1-derived competitive peptide alleviates neuronal necroptosis and brain atrophy in a Tau transgenic mouse model. Collectively, our findings uncover a previously unrecognized metabolism-driven necroptotic signaling cascade initiated by a p-Tau-RIPK1 hub, providing mechanistic insight into how glucose hypometabolism synergizes with p-Tau to drive neurodegeneration.
The hippocampal dentate gyrus (DG) segregates input patterns aided by inhibitory circuits. Despite their importance, few studies have recorded identified DG interneurons in behaving animals. Here, we used electrophysiolo...The hippocampal dentate gyrus (DG) segregates input patterns aided by inhibitory circuits. Despite their importance, few studies have recorded identified DG interneurons in behaving animals. Here, we used electrophysiological recordings, bidirectional optogenetic manipulations, and modeling to characterize parvalbumin (PV)- and somatostatin (SST)-expressing interneurons in freely behaving mice. We employed machine learning to classify granule cells (GCs), mossy cells (MCs), and PV and SST interneurons simultaneously and studied their synaptic interactions in shaping spatial information and responses to entorhinal synaptic inputs. We demonstrated a central role for SST interneurons in regulating the impact of entorhinal excitation and for PV interneurons in feedback inhibition. Finally, optogenetic manipulations revealed a paradoxical observation: instead of merely suppressing firing in the surrounding network, DG interneuron stimulation exacerbated "winner-take-all" dynamics, including paradoxical polysynaptic excitation of some excitatory neurons. Such use-dependent modulation of winner-take-all dynamics may support the selection of content-bearing neuronal ensembles during cognitive processes.
The sleep-wake cycle subdivides brain activity into distinct states of neural circuit activity, fluid transport, and interstitial-volume fraction. We used in vivo two-photon imaging of mice to ask whether cortical astroc...The sleep-wake cycle subdivides brain activity into distinct states of neural circuit activity, fluid transport, and interstitial-volume fraction. We used in vivo two-photon imaging of mice to ask whether cortical astrocytes exhibit state-dependent volume changes. Our analysis showed that the astrocyte volume expands during wakefulness and shrinks during non-rapid eye movement (NREM) sleep and even more during rapid eye movement (REM) sleep. Norepinephrine (NE) exhibited state-dependent fluctuations that were mirrored by the corresponding changes in astrocytic volume. Pharmacologically blockage of α1-adrenergic, but not α2- or β-adrenergic, receptors, resulted in astrocyte shrinkage. Both chemogenetic and optogenetic stimulation of tyrosine hydroxylase (TH)-positive neurons in the locus coeruleus (LC) significantly increased cortical astrocytic cell volume, which was abolished by the α1-receptor antagonist prazosin. We propose that astrocytic expansion during wakefulness, driven by NE leads to a corresponding shrinkage of the interstitial-volume fraction, increasing neuroglia interactions and suppressing glymphatic flow.
Spontaneous memory replay during sleep is crucial for cognition but challenging to capture because distinct sleep rhythms hinder the generalization of wake-trained electroencephalogram (EEG) decoders. To address this, we...Spontaneous memory replay during sleep is crucial for cognition but challenging to capture because distinct sleep rhythms hinder the generalization of wake-trained electroencephalogram (EEG) decoders. To address this, we developed the Sleep Interpreter (SI), which uses neural contrastive learning to isolate shared semantic content from background rhythms. We collected a dataset of 135 participants undergoing targeted reactivation of 15 semantic categories, yielding approximately 1,000 h of overnight sleep and 400 h of wake EEG. During non-rapid eye movement (NREM) sleep, SI achieved high decoding accuracy for cue-evoked semantic responses, with accuracy peaking during slow oscillation and spindle coupling at 40.02% top-1 accuracy on unseen participants (chance 6.7%). We demonstrated SI generalizability in two independent nap experiments involving targeted and spontaneous reactivation, where decoded reactivations correlated with post-sleep memory performance. Finally, we implemented SI for real-time sleep staging and stage-specific NREM and REM decoding. The dataset and codebase are shared as open resources for future clinical applications.
The nicotinamide adenine dinucleotide (NAD) hydrolase sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is the central executioner of pathological axon degeneration and is allosterically activated...The nicotinamide adenine dinucleotide (NAD) hydrolase sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is the central executioner of pathological axon degeneration and is allosterically activated by an increased nicotinamide mononucleotide (NMN)/NAD ratio. DNA damage induces NAD loss and an increased NMN/NAD ratio by hyperactivating poly(ADP-ribose) polymerase 1 (PARP1), which triggers the parthanatos cell death pathway. Multiple mechanistically distinct DNA-damaging agents activate SARM1 and induce axon degeneration following PARP1 activation. Remarkably, SARM1 is required for key steps downstream of hyperactivated PARP1, which are pathognomonic of parthanatos, including mitochondrial depolarization, nuclear translocation of apoptosis-inducing factor (AIF), and cell death. Hence, SARM1 is an essential component of neuronal parthanatos. Moreover, complex neurodegenerative stimuli whose mechanisms include activation of parthanatos, such as 1-methyl-4-phenyl-pyridinium (MPP) dopaminergic neuron toxicity and N-methyl-D-aspartate (NMDA) excitotoxicity, are potently protected by SARM1 inhibition. These findings place SARM1 at the nexus of multiple mechanisms driving neuronal cell death, thereby greatly expanding the potential clinical utility of SARM1 inhibitors beyond diseases of axon loss.
Placebo analgesia, in which expectation and prior experience suppress pain in response to an inert treatment, is a powerful clinical phenomenon whose causal neural basis remains unclear. By reverse-translating a human pl...Placebo analgesia, in which expectation and prior experience suppress pain in response to an inert treatment, is a powerful clinical phenomenon whose causal neural basis remains unclear. By reverse-translating a human placebo paradigm to mice, we identify neural circuits linking the cortex to the brainstem that causally mediate placebo pain relief. Placebo conditioning suppresses both nociceptive and affective-motivational pain behaviors and generalizes to unconditioned forms of pain. Descending neurons in the ventrolateral periaqueductal gray (vlPAG) are indispensable for both morphine and placebo analgesia, but the placebo effect additionally requires medial prefrontal and anterior cingulate cortical inputs to the vlPAG. Conditioning potentiates noxious stimulus-evoked endogenous opioid release in the vlPAG, which causally gates descending pain modulation. Remarkably, conditioning in pain-naive animals produces lasting placebo analgesia after injury. These findings identify a central circuit mechanism of placebo analgesia and suggest a translational strategy in which preventive placebo conditioning can build resilience to pain.
Piantadosi PT, Coden KM, Choi H
… +12 more, Perry SJ, Halfeld M, Schaffer JA, Goff JP, Spitz NA, Schwab NR, Sandon R, Sadiq S, Devine MM, Costa VD, da Silva D, Holmes A
Modifying behavior in response to changing environmental conditions is a crucial adaptive function. This capacity is evident when animals curtail the pursuit of a valued outcome that risks being punished, but the mediati...Modifying behavior in response to changing environmental conditions is a crucial adaptive function. This capacity is evident when animals curtail the pursuit of a valued outcome that risks being punished, but the mediating brain mechanisms remain poorly understood. Here, using in vivo cellular-resolution calcium (Ca) imaging, optogenetics, and chemogenetics, we show that punishment risk dramatically alters choice between a large/risky and small/safe reward and produces novel, causally necessary patterns of activity in basolateral amygdala (BLA) neurons of male mice. We find that punishment generates a BLA representation that is reactivated when mice execute or abort the choice of a large/risky reward option. Additionally, we show that risk leads to the incorporation of newly encoding BLA neurons into the pre-choice representation and that this modification predicts avoidance of the large/risky option. Collectively, these findings reveal how dynamic reshaping of choice-related BLA representations underpins behavioral flexibility in the face of risk.
Ingesting pathogens poses a threat to survival, driving the evolution of avoidance behaviors across species. The mechanisms linking immune detection to behavioral responses remain poorly understood. Here, we identify a b...Ingesting pathogens poses a threat to survival, driving the evolution of avoidance behaviors across species. The mechanisms linking immune detection to behavioral responses remain poorly understood. Here, we identify a bidirectional fat body-brain communication pathway that mediates pathogen avoidance in Drosophila melanogaster. Immune receptors and a specific antimicrobial peptide (AMP) are required in both the fat body and neuromodulatory neurons to suppress pathogen intake. We show that pathogen-sensing octopaminergic neurons innervate the fat body, activating calcium signaling via an octopamine receptor, thereby triggering fat body dopamine release. Dopamine then acts through Dop1R1 receptors in mushroom body output neurons to drive avoidance behavior. Two-photon calcium imaging reveals that pathogen ingestion modulates odor responses in these neurons, linking immune system activation to behavioral change. Our findings uncover a previously unrecognized immune-to-brain communication loop, illustrating how fat tissue and the innate immune system can drive behavioral adaptation to enhance survival during infection.