Inhibitory interneuron diversity is a central feature of cortical circuits. The IN-CODE consortium seeks to combine large-scale recordings of interneuron types with machine-learning tools to identify the role of their ph...Inhibitory interneuron diversity is a central feature of cortical circuits. The IN-CODE consortium seeks to combine large-scale recordings of interneuron types with machine-learning tools to identify the role of their physiological features, connectivity motifs, and cooperativity in cognitive functions.
Li D, Dai W, Li L
… +17 more, Zhou Z, Li Z, He C, Li X, Lu X, Huang Q, Zhu Y, Wu D, Lu J, Yuan Y, Zhao Y, Zhang W, Zeng Z, Huang Q, Wang X, Shi P, Zhang L
Evolutionary adaptations provide a powerful lens for discovering fundamental regulators. By studying a Retsat variant (Q247R) found in high-altitude-adapted species, we reveal a central pathway governing CNS myelination...Evolutionary adaptations provide a powerful lens for discovering fundamental regulators. By studying a Retsat variant (Q247R) found in high-altitude-adapted species, we reveal a central pathway governing CNS myelination and repair. Mice harboring this variant show reduced neonatal hypoxia-induced hypomyelination and exhibit enhanced remyelination in adulthood. The variant exhibits heightened enzymatic activity, driving increased neuronal production of all-trans-13,14-dihydroretinol (ATDR). By ruling out an intrinsic role in oligodendrocytes, we define this pathway as non-cell autonomous. ATDR is converted in neurons to all-trans-dihydroretinoic acid, which acts as a neuron-to-glia paracrine signal to activate the RXR-γ pathway in oligodendrocyte progenitor cells, thereby stimulating their differentiation and myelination. Administration of ATDR, a prodrug, potently promotes remyelination in multiple myelin injury models. Our work identifies Retsat and dihydroretinoids as pivotal regulators of white matter integrity and as a promising therapeutical avenue inspired by evolutionary genetics for white matter diseases.
Prostaglandin E2 (PGE2) is an important lipid signaling molecule that regulates a wide range of physiological and pathological processes. However, its dynamics during these processes are largely unknown due to the lack o...Prostaglandin E2 (PGE2) is an important lipid signaling molecule that regulates a wide range of physiological and pathological processes. However, its dynamics during these processes are largely unknown due to the lack of tools to directly visualize PGE2 with high spatiotemporal resolution. Here, we developed and characterized a genetically encoded G-protein-coupled receptor (GPCR) activation-based (GRAB) PGE2 sensor, which we call GRAB (PGE2-1.0), that has high specificity for PGE2, nanomolar affinity, rapid kinetics, and high spatial resolution when expressed both in vitro and in vivo. Using fiber-photometry recordings, we found that PGE2-1.0 can reliably monitor endogenous PGE2 dynamics in the preoptic area in the brain during acute inflammation. Wide-field in vivo imaging with PGE2-1.0 reveals spatial heterogeneity in cortex-wide PGE2 dynamics during acute inflammation and seizure. Thus, our PGE2-1.0 sensor can be used to detect endogenous PGE2 dynamics with high spatiotemporal resolution, providing a robust tool for studying PGE2 under specific physiological and pathological conditions.
Endocytosis actively remodels the neuronal surface proteome to drive diverse cellular processes, yet its global extent and effects on neural circuit development have defied comprehensive interrogation. Here, we introduce...Endocytosis actively remodels the neuronal surface proteome to drive diverse cellular processes, yet its global extent and effects on neural circuit development have defied comprehensive interrogation. Here, we introduce endocytome profiling: a systematic, cell-type-specific approach for mapping cell-surface protein (CSP) dynamics in situ. Quantitative proteomic analysis of developing Drosophila olfactory receptor neuron (ORN) axons generated an endocytic atlas comprising over 1,000 proteins and revealed the extent to which the cell-surface proteome is remodeled to meet developmental demands. Targeted interrogation of a junctional CSP showed that its endosome-to-surface ratio is precisely balanced to enable developmental axon pruning while preserving mature axon integrity. Multi-omic integration uncovered widespread transcellular signaling and identified a growth factor secreted by neighboring neurons to direct ORN axon targeting via endocytic regulation of its receptor. Endocytome profiling provides unprecedented access to cell-surface proteome dynamics and offers a platform to dissect proteome-scale remodeling across diverse cell types and contexts.
Amyotrophic lateral sclerosis (ALS) is genetically and clinically heterogeneous, yet convergent pathogenic mechanisms remain poorly defined. A CRISPR-Cas9 screen identified phosphoglycerate mutase-5 (PGAM5) as a common m...Amyotrophic lateral sclerosis (ALS) is genetically and clinically heterogeneous, yet convergent pathogenic mechanisms remain poorly defined. A CRISPR-Cas9 screen identified phosphoglycerate mutase-5 (PGAM5) as a common mediator of ALS pathogenesis. PGAM5 activates the mitochondrial integrated stress response (mtISR) via dephosphorylation of metallopeptidase OMA1 at Ser223 and Ser237, thereby driving neuromuscular junction disruption and motor deficits. We show that PGAM5 is a substrate of valosin-containing protein (VCP) and is consistently elevated in spinal cords from sporadic ALS patients, in human spinal cord organoids derived from sporadic or familial ALS, and in ALS mouse models. The disruption of PGAM5-OMA1 interaction by a selective inhibitor (TAT-PO1) or pharmacological inhibition of PGAM5 with telmisartan suppresses mtISR activation and ameliorates ALS-related phenotypes by reshaping mtISR outputs in a manner distinct from those elicited by activation of translation initiation factor 2B (eIF2B). These findings establish PGAM5 as a convergent and actionable therapeutic target across ALS subtypes.
Du S, Ou F, Drieu A
… +25 more, Xu EZ, Cheng Y, Storck SE, Mamuladze T, Cao J, Abduljawad N, Bhattarai B, Rustenhoven J, Mortimer N, Brioschi S, Nguyen K, Rodrigues PF, Smirnov I, Gibson D, Michael White J, Beatty W, DeNardo D, Li Q, Meers M, Han CZ, Sun N, Ginhoux F, Cella M, Colonna M, Kipnis J
Microglia arise from yolk sac progenitors and are thought to persist throughout life with minimal input from adult hematopoiesis. However, whether brain-engrafted monocyte-derived macrophages (MDMs) exist at homeostasis...Microglia arise from yolk sac progenitors and are thought to persist throughout life with minimal input from adult hematopoiesis. However, whether brain-engrafted monocyte-derived macrophages (MDMs) exist at homeostasis and during turnover and how they function relative to yolk-sac-derived microglia (YSMs) remain unsettled. Here, we combine lineage tracing, pharmacological microglia depletion, and multi-omics profiling to define the ontogeny, identity, and function of brain parenchymal macrophages. Despite sharing the parenchymal milieu, MDMs display transcriptional and epigenetic landscapes distinct from YSMs. Fate-mapping reveals that brain-engrafted MDMs transiently express CD206, echoing a developmental stage of microglial precursors. MDM engraftment and polarization are modulated by interleukin (IL)-34 and C-C chemokine receptor 2 (CCR2). Furthermore, parabiosis and skull-flap transplantation reveal that both blood and skull marrow supply the niche, yielding origin-biased MDM states. Functionally, MDM engraftment enhances cuprizone-mediated demyelination. Together, our study defines the origins, molecular features, and context-dependent roles of brain parenchymal macrophages across homeostasis, turnover, and central nervous system (CNS) pathology.
I discuss human single-neuron recordings and the discovery of concept cells-i.e., neurons representing specific concepts in the hippocampus and surrounding cortex-about 20 years ago. I then present the main properties of...I discuss human single-neuron recordings and the discovery of concept cells-i.e., neurons representing specific concepts in the hippocampus and surrounding cortex-about 20 years ago. I then present the main properties of concept cells and show how these neurons are involved in forming and storing memories in coordination with complementary neocortical representations. Finally, I compare the response properties of concept cells with those reported in the hippocampus of other species and argue that the abstract representation by concept cells is exclusively human and might be a cornerstone of human cognitive abilities, such as our power for high-level abstract thinking and generalization.
Su XY, Ronan EA, Perry SK
… +14 more, Lee H, Hor CC, Fatima M, Zheng XY, Wang J, Liu S, Koecklin KHU, Wan S, Jha A, Li P, Du W, Cai D, Emrick JJ, Duan B
How hindbrain circuits integrate peripheral and central signals to regulate complex oral behaviors is poorly understood. In rodents, gnawing is essential for localized tooth wear to offset lifelong incisor growth. Whethe...How hindbrain circuits integrate peripheral and central signals to regulate complex oral behaviors is poorly understood. In rodents, gnawing is essential for localized tooth wear to offset lifelong incisor growth. Whether this process relies on specific sensory input to guide localized tooth wear and is actively regulated by neural mechanisms remains unresolved. Here, we identify somatostatin-expressing neurons in the spinal trigeminal nucleus oralis as a central relay distributing tactile input to motor execution and motivational circuits. These neurons receive input from a genetically distinct population of S100b Aβ low-threshold mechanoreceptors that innervate the incisor periodontium and project to both jaw-closing motor neurons and, via the parabrachial nucleus, the ventral tegmental area. Disruption of this pathway abolished gnawing and resulted in severe malocclusion, while activation triggered dopamine release in the nucleus accumbens. Our findings redefine dental alignment as an active, touch-dependent, circuit-governed process and reframe malocclusion as a sensorimotor-motivational integration disorder.
Preclinical Alzheimer's disease (AD) is associated with distressing neuropsychiatric symptoms (NPSs) that may accelerate progression toward dementia. Existing approaches probe the symptom-level domain-general or domain-s...Preclinical Alzheimer's disease (AD) is associated with distressing neuropsychiatric symptoms (NPSs) that may accelerate progression toward dementia. Existing approaches probe the symptom-level domain-general or domain-specific neural correlates of NPSs. However, the field lacks process-oriented models of symptom emergence for targeted treatment. We propose one pathway for symptom emergence involving the disruption of emotion regulation (ER) systems by early AD pathology. AD pathology in the ventral anterior cingulate cortex-ventromedial prefrontal cortex disrupts model-free ER that modulates negative valuations using experience-dependent reinforcement learning (e.g., fear extinction), leading to increased negative valuations and negative affect. We further propose that model-based ER competes for overtaxed executive resources and is less successful in preclinical AD, particularly in demanding real-world contexts. These changes lead to a shift toward negative affect, leading to divergent trajectories of NPSs depending on critical moderators. We discuss implications for intervention to improve NPSs and potentially slow dementia progression.
The brain has the remarkable ability to guide the performance of complex tasks. Distinct prefrontal cortical areas make specific contributions to this ability, with the orbitofrontal cortex (OFC) critical for processing...The brain has the remarkable ability to guide the performance of complex tasks. Distinct prefrontal cortical areas make specific contributions to this ability, with the orbitofrontal cortex (OFC) critical for processing information related to trial outcomes and the dorsomedial prefrontal cortex (dmPFC) critical for sustained effort and selecting the right action at the right time. Yet, in both areas, neural activity represents both outcome- and action-related quantities. How similar neural representations support different functions remains unclear. Here, we compared OFC and dmPFC activity in rats performing a spatial alternation task. We show that, in contrast to other task-related variables, task progression is represented in both areas, but with distinct patterns of across-trial reliability that match each area's previously documented functional specialization. Our results indicate that the engagement of reliable, task-phase-specific activity patterns differs across prefrontal regions in a manner well suited to engage different computations at different times.
Dimensionality reduction methods are widely used in neuroscience to investigate two complementary aspects of neural activity: the distribution of single-neuron functional properties and the low-dimensional collective dyn...Dimensionality reduction methods are widely used in neuroscience to investigate two complementary aspects of neural activity: the distribution of single-neuron functional properties and the low-dimensional collective dynamics of population activity. However, how do these two aspects of neural activity relate to the structure of the underlying neural circuit? In this work, we connect circuit structure, single-neuron functional properties, and emerging low-dimensional dynamics in spiking recurrent network models. Our models explain how topologically distinct circuit structures can produce equivalent low-dimensional dynamics. Despite this degeneracy, we find that circuit structure imposes specific constraints on both the low-dimensional dynamics of population activity and the distribution of single-neuron functional properties. These constraints yield simple criteria for comparing network models with observed neural activity. Our modeling framework not only links classical models of cortical circuits to the more recent notion of neural manifolds but also paves the way for designing tractable models of population dynamics that are better aligned with neural recordings.
In this interview with Neuron, David Sussillo reflects on his journey from a disadvantaged childhood to becoming a leading computational neuroscientist and AI researcher. He discusses the development of FORCE learning, a...In this interview with Neuron, David Sussillo reflects on his journey from a disadvantaged childhood to becoming a leading computational neuroscientist and AI researcher. He discusses the development of FORCE learning, advances in neural network interpretability, the interplay between academia and industry, and advice for aspiring scientists from non-traditional backgrounds.
Anxiety disorders are the most prevalent mental disorders globally, yet current treatments remain limited. Histamine is an evolutionarily conserved neuromodulator recently implicated in neuropsychiatric disorders. Howeve...Anxiety disorders are the most prevalent mental disorders globally, yet current treatments remain limited. Histamine is an evolutionarily conserved neuromodulator recently implicated in neuropsychiatric disorders. However, whether and how histaminergic signaling dynamically represents emotionally salient information and regulates anxiety remain largely unknown. We show that anxiogenic exposure triggers region-specific dynamic histamine release in ventral hippocampal CA1 (vCA1). The vCA1-projecting histaminergic circuit exhibits similar dynamics and bidirectionally regulates anxiety through engaging astrocytic H3 receptors (H3Rs). Genetic ablation of astrocytic H3Rs attenuates astrocytic responsiveness to anxiety-related contexts and directly promotes anxiety via gliotransmitter γ-aminobutyric acid (GABA) signaling. Notably, chronic stress induces adaptive upregulation of vCA1 astrocytic H3R expression, while further potentiation of astrocytic H3R signaling is sufficient to attenuate maladaptive anxiety. These findings collectively establish that vCA1 astrocytic histaminergic signaling governs natural anxiolysis in both normal and maladaptive anxiety states, identifying astrocytic H3Rs as crucial emotional regulators and a potential therapeutic target for anxiety disorders.
Leveraging large-scale neuroscience datasets requires new collaborative approaches. The International Brain Laboratory (IBL) is a distributed, open-science experiment facing these challenges. To succeed, IBL developed me...Leveraging large-scale neuroscience datasets requires new collaborative approaches. The International Brain Laboratory (IBL) is a distributed, open-science experiment facing these challenges. To succeed, IBL developed methods for shared decision-making, division of labor, authorship/credit assignment, career support, standardization, and robust data analysis. We share these lessons learned to benefit other collaborative scientific efforts.
We propose a multidimensional framework for neuroaesthetics that combines an experimental characterization of dimensions with multivariate analyses, tracing how sensory input is transformed over time through perceptual,...We propose a multidimensional framework for neuroaesthetics that combines an experimental characterization of dimensions with multivariate analyses, tracing how sensory input is transformed over time through perceptual, semantic, and affective processes while accounting for influences of media, individual differences, and expertise.
Weinreb et al. show that spontaneous behavior is hierarchically organized into self-motivated states and reusable action syllables. While the prefrontal cortex primarily encodes behavioral states, the dorsolateral striat...Weinreb et al. show that spontaneous behavior is hierarchically organized into self-motivated states and reusable action syllables. While the prefrontal cortex primarily encodes behavioral states, the dorsolateral striatum governs action sequencing, revealing a distributed neural architecture for natural behavior.
Why do opioid responses vary greatly among individuals? Leduc-Pessah et al. show that the Runx1 transcription factor is a genetic determinant of opioid analgesia and adverse effects across species, presumably operating b...Why do opioid responses vary greatly among individuals? Leduc-Pessah et al. show that the Runx1 transcription factor is a genetic determinant of opioid analgesia and adverse effects across species, presumably operating by governing microglial reactivity.
MS4A4A and MS4A6A are microglia-expressed genes linked to Alzheimer's disease risk. In this issue of Neuron, Rosner et al. show that these proteins cooperatively restrain TREM2 signaling, dampening protective microglial...MS4A4A and MS4A6A are microglia-expressed genes linked to Alzheimer's disease risk. In this issue of Neuron, Rosner et al. show that these proteins cooperatively restrain TREM2 signaling, dampening protective microglial responses and highlighting MS4A inhibition as a potential strategy to rejuvenate the brain's innate immune system in Alzheimer's disease.
In this issue of Neuron, Gomez et al. report that breast cancer disrupts diurnal glucocorticoid oscillations by disinhibiting hypothalamic CRH neurons. Time-specific neuromodulation restores rhythms and attenuates tumor...In this issue of Neuron, Gomez et al. report that breast cancer disrupts diurnal glucocorticoid oscillations by disinhibiting hypothalamic CRH neurons. Time-specific neuromodulation restores rhythms and attenuates tumor growth by enhancing CD8 T cell functions. This unveils a mechanism whereby cancer utilizes brain circuits that could be targetable with chronotherapy.