Exposure to stress is a fundamental aspect of human life but is also linked to increased risk for various psychiatric and medical disorders. However, not all individuals exposed to stress experience the same outcomes, un...Exposure to stress is a fundamental aspect of human life but is also linked to increased risk for various psychiatric and medical disorders. However, not all individuals exposed to stress experience the same outcomes, underscoring the complex interactions between stress exposure and genetic predisposition. Numerous studies employing diverse methodologies emphasize the significance of gene-stress interactions in influencing disease risk, which may also contribute to disease heterogeneity. Enhancing our mechanistic understanding of these interactions could advance our knowledge of psychiatric disorders and their comorbidities, enabling targeted interventions. This review examines the current state of the field, identifies existing limitations, and discusses technological advancements that facilitate focused mechanistic investigations into the interplay between stress and genetic risk.
Vision is context dependent, with neuronal responses shaped not only by local features but also by surrounding visual input. While classical studies, using grating stimuli, show that iso-oriented surrounds suppress respo...Vision is context dependent, with neuronal responses shaped not only by local features but also by surrounding visual input. While classical studies, using grating stimuli, show that iso-oriented surrounds suppress responses more than orthogonal surrounds, the role of contextual modulation under natural stimulus conditions remains less clear. Using recordings from mouse primary visual cortex (V1), we trained convolutional neural network models to predict neuronal responses to natural images and synthesized surround stimuli that selectively suppressed or facilitated responses to optimal center inputs. In vivo experiments confirmed these predictions. Facilitatory surrounds resembled naturalistic continuations of the optimal center stimulus, consistent with natural image statistics, whereas suppressive surrounds deviated from these predictions. Applying the same approach to macaque V1 revealed similar principles across species. Both models accurately predicted responses to classical grating stimuli. We formalize these results in a normative Bayesian model, showing that neuronal activity for preferred center features reflects posterior beliefs about likely center-surround configurations.
Delivanoglou N, Todd KT, Almeida F
… +19 more, Rego S, Changavi A, Spajer M, Ayuso VE, Pinho-Correia LM, Sanchez G, das Neves SP, Barber MJ, Schrader R, Sacilotto P, Martens YA, Heckman MG, Bu G, Tanzi RE, Thomas JL, Fryer JD, Oliveira TG, Shekhar K, Da Mesquita S
Sex and apolipoprotein E ε4 (APOE4) interact to alter the risk for Alzheimer's disease and other neurodegenerative disorders. Herein, we show sex-specific differences in immune activation and lymphatic function in the me...Sex and apolipoprotein E ε4 (APOE4) interact to alter the risk for Alzheimer's disease and other neurodegenerative disorders. Herein, we show sex-specific differences in immune activation and lymphatic function in the meningeal dura of humanized female and male mice expressing two alleles of APOE4 (E4/E4), when compared with their respective sex-matched E3/E3 controls. We also describe distinct effects of APOE4 on brain lipid composition and inflammation in females and males that were partially reverted upon colony-stimulating factor 1 receptor (CSF1R) inhibition. Suppressing innate immunity reduced neuroinflammation and restored cognitive function in E4/E4 females, while exacerbating neuroinflammation and accelerating cognitive decline in E4/E4 males. Finally, in line with the E4/E4 humanized mouse model data, we show that APOE4 expression is linked to sexually dimorphic leukocyte activation profiles in the human brain. This study highlights the need for personalized therapies when targeting APOE, brain immunity, and meningeal lymphatics to promote cognitive resilience in both females and males.
Chronic emotional stress (CES) impairs social behavior, but the underlying neural mechanisms remain unclear. Using a CES mouse model, we identified susceptible (SUS) individuals with social fear and diminished novelty pr...Chronic emotional stress (CES) impairs social behavior, but the underlying neural mechanisms remain unclear. Using a CES mouse model, we identified susceptible (SUS) individuals with social fear and diminished novelty preference. We further identified two distinct subpopulations of projection neurons within the dorsal part (AID) and the ventral part (AIV) of insular cortex-AID and AIV-that encode social fear and social novelty preference by targeting the frontal association (FrA) and prelimbic (PrL) cortex, respectively. Moreover, hyperactivation of AID→FrA drives social avoidance, while hypoactivity of AIV→PrL underlies social novelty preference deficits. Mechanistically, these changes are mediated by increased local inhibition from parvalbumin-positive (PV) interneurons and reduced oxytocin receptor (OXTR) signaling in PrL gamma-aminobutyric acidergic (GABAergic) interneurons. Restoring AIV→PrL activity or enhancing OXTR signaling rescues social novelty preference. Our study reveals segregated insula-prefrontal circuits that differentially regulate social fear and novelty motivation, providing circuit-specific targets for treating stress-induced social impairments.
The seamless coordination of hand and mouth during feeding is a sophisticated motor skill characteristic of rodents and primates. While spinal and brainstem circuits mediate elemental forelimb and orofacial actions, whet...The seamless coordination of hand and mouth during feeding is a sophisticated motor skill characteristic of rodents and primates. While spinal and brainstem circuits mediate elemental forelimb and orofacial actions, whether dedicated neocortical circuits assemble these actions into ethological feeding movements remains unclear. Through systematic optogenetic screening, we identify the rostral forelimb-orofacial area (RFO), where activation of either pyramidal tract (PT) or intratelencephalic (IT) neurons elicits coordinated forelimb and orofacial movements resembling natural eating. RFO connects reciprocally with forelimb and orofacial sensorimotor cortices: while PTs project to subcortical motor centers driving effector movements, ITs target cortical areas and ventrolateral striatum mediating oromanual coordination. During free-moving eating behaviors, activities of both PTs and ITs are correlated with oromanual manipulation, yet silencing reveals distinct functions: PTs for dexterous hand-mouth movements and ITs for their temporal coordination. These findings define a cell-type-specific motor cortical circuit that orchestrates the multi-effector coordination underlying natural feeding.
Third wave meditation research-the study of advanced meditation-investigates states, stages, and endpoints of meditation practice that emerge with increasing mastery. We review current neuroscientific progress, outline f...Third wave meditation research-the study of advanced meditation-investigates states, stages, and endpoints of meditation practice that emerge with increasing mastery. We review current neuroscientific progress, outline future research directions, and highlight far-reaching implications of this emerging scientific subfield.
Theisen EK, Rivas-Serna IM, Cheng P
… +10 more, Lee RJ, Thomas CI, Darehshouri A, Jay TR, Kunduri G, Nguyen TT, Mazurak V, Thomas Clandinin M, Clandinin TR, Vaughen JP
The complex morphologies of neurons and glia emerge through profound changes in membrane lipids and proteins during development. Lysosomes are central regulators of membrane remodeling, and mutations that affect lipid tu...The complex morphologies of neurons and glia emerge through profound changes in membrane lipids and proteins during development. Lysosomes are central regulators of membrane remodeling, and mutations that affect lipid turnover in lysosomes are frequently associated with neurological disease. However, how these lysosomal functions might shape brain development remains incompletely understood. By analyzing lipid levels in the Drosophila brain, we discover transient increases in specific sphingolipids during development. This lipid bolus reflects biosynthetic inputs from both neurons and glia, and requires lysosomal catabolism for mature neuronal physiology to emerge. Remarkably, sphingolipid catabolism in glia is substantially driven by the phagolysosomal salvage of neuronal membranes to produce very long-chain ceramide phosphoethanolamine (CPE) lipids. CPE lipids are cell-autonomously required for glial autophagy and ramification into synaptic regions, and a genetic CPE biosensor localizes to infiltrated glial processes. Thus, developmentally regulated lysosomal activity obligately couples neuron-glia metabolic interactions to program dynamic glial morphogenesis.
The cerebral cortex broadcasts its output to subcortical regions through the projections of diverse extratelencephalic (ET) neurons derived from either direct (dNG-ET) or indirect (iNG-ET) neurogenesis, but the different...The cerebral cortex broadcasts its output to subcortical regions through the projections of diverse extratelencephalic (ET) neurons derived from either direct (dNG-ET) or indirect (iNG-ET) neurogenesis, but the differential contributions of these neurogenic pathways to cortical output organization remain unknown. Establishing a lineage-based viral targeting strategy in mice, we uncover that ET massively amplifies and diversifies ET projections across the cortex. Whereas ET primarily targets the forebrain and midbrain, ET dominates the hindbrain (e.g., brainstem/spinal action centers and lemniscal sensory stations), hypothalamic, and neuromodulatory regions with cortical area-specific projections. Numerous corticofugal subpopulations derive solely from iNG-ET. Area-specific spinal projections of ET, but not of ET, emerge from the postnatal pruning of an initial cortex-wide population. In the motor cortex, ET or ET activation induced distinct movements: either head-trunk or, additionally, coordinated orofacial-forelimb movements, respectively. Thus, two foundational neurogenic pathways with distinct evolutionary histories differentially shape the area-specific diversification of cortical output channels.
The human connectome holds considerable promise for advancing an integrated, systems-level understanding of brain disorders. Critical to this ambition is accurate, reliable, and biologically informative connectome mappin...The human connectome holds considerable promise for advancing an integrated, systems-level understanding of brain disorders. Critical to this ambition is accurate, reliable, and biologically informative connectome mapping and analysis in the presence of diverse brain pathologies. However, many connectome-mapping methodologies have been established and validated using healthy, non-clinical participants. Here, we consider the challenges of structural connectome mapping in the presence of pathology. We first classify connectome abnormalities and relate them to underlying white-matter microstructure. We explain how measures of structural connectivity can quantify the impact of microstructural white-matter pathology on the macroscale connectome, including measures based on streamline counts, microstructure-informed tractography, tract-averaged metrics, and structural similarity. We consider connectome-mapping pipelines and algorithmic choices to facilitate reliable and biologically meaningful clinical connectome mapping. Our aim is to establish best practices for connectome mapping and analysis in neurology, psychiatry, and neurosurgery.
The basolateral amygdala (BLA) has been implicated in threat detection and the generation of anxiety states. While previous experiments have demonstrated the important role of BLA principal neurons in driving anxiety-rel...The basolateral amygdala (BLA) has been implicated in threat detection and the generation of anxiety states. While previous experiments have demonstrated the important role of BLA principal neurons in driving anxiety-related behaviors, population-level recordings suggest that principal neurons encode exploratory states rather than anxiety per se. This discrepancy raises the question of whether anxiety is indeed represented within the BLA. Here, using simultaneous in vivo calcium recordings in BLA astrocytes and principal neurons, we find that, in contrast to neurons, astrocyte activity provides a stable and scalable representation of anxiety states across an array of behavioral tasks. We show that driving BLA astrocyte activity increases anxiety-related behaviors and identify noradrenaline acting on α1 adrenoreceptors as responsible for endogenous astrocyte activation and subsequent modulation of anxiety. Our results shed light on a specialized encoding property of BLA astrocytes and establish these cells as key computational elements of anxiety circuits.
Novelty signals in the brain drive exploration and learning. While the perceived novelty of a stimulus is known to depend on previous experience, it remains elusive how generalization between familiar and novel stimuli i...Novelty signals in the brain drive exploration and learning. While the perceived novelty of a stimulus is known to depend on previous experience, it remains elusive how generalization between familiar and novel stimuli impacts novelty computation. Specifically, existing models of novelty computation fail to account for the effects of stimulus similarities that are abundant in naturalistic tasks. Here, we present a biologically plausible model that captures how stimulus similarities modulate novelty signals in the brain and influence novelty-driven exploration. By applying our model to two publicly available datasets, we show (1) how generalization across similar visual stimuli affects novelty responses in the mouse visual cortex and (2) how generalization across nearby locations impacts mouse exploration in an unfamiliar environment. Our model explains distinct neural and behavioral signatures of novelty, makes mechanistic predictions about synaptic plasticity rules in novelty-computing circuits, and enables theory-driven experiment design.
Dos Santos M, Forrest MP, Bomba-Warczak E
… +15 more, Dey S, Parnell E, Christiansen JM, Edassery SL, Yang K, Hayes LN, Coughlin JM, Eckman BL, Lammert CR, Martin-de-Saavedra MD, Barbolina MV, Martina M, Sawa A, Savas JN, Penzes P
Excitation-inhibition (E/I) balance depends on dynamic communication between neuronal subtypes, potentially beyond classical neurotransmission. While membrane-bound ion channels are essential for neuronal function, their...Excitation-inhibition (E/I) balance depends on dynamic communication between neuronal subtypes, potentially beyond classical neurotransmission. While membrane-bound ion channels are essential for neuronal function, their potential roles as extracellular regulators of network dynamics remain largely unexplored. Here, we identify a soluble form of the voltage-gated Ca channel subunit α2δ-1 in human cerebrospinal fluid (CSF) and show that it acts as an activity-regulated intercellular modulator of network homeostasis. Soluble α2δ-1 is reduced in the CSF of individuals with schizophrenia (SZ). Its synthetic analog, synthetic ectodomain of Alpha2Delta-1 (SEAD1), modulates cortical activity by enhancing the function of parvalbumin-positive (PV+) interneurons and restoring E/I balance. A single SEAD1 injection into the prefrontal cortex of a genetic mouse model of SZ reversed synaptic and behavioral deficits, including memory and social impairments. These findings reveal soluble synaptic ectodomains as a previously underappreciated class of extracellular signaling molecules with therapeutic potential in neuropsychiatric disorders.
The sympathetic nervous system has emerged as a critical regulator of cancer progression, yet the underlying mechanisms remain unclear. Here, we compare genetic, pharmacological (6-hydroxydopamine [6-OHDA]), and surgical...The sympathetic nervous system has emerged as a critical regulator of cancer progression, yet the underlying mechanisms remain unclear. Here, we compare genetic, pharmacological (6-hydroxydopamine [6-OHDA]), and surgical denervation in mouse breast cancer models. While all methods deplete sympathetic nerves, only 6-OHDA suppresses tumor growth, revealing a disconnect between sympathetic ablation and antitumor effect. Mechanistic investigations reveal that 6-OHDA suppresses tumor growth through immune activation rather than sympathetic ablation. 6-OHDA induces cancer cell interferon (IFN)-β production, which promotes monocyte differentiation into pro-inflammatory macrophages characterized by interferon-stimulated gene (ISG) expression. These ISG macrophages are essential for the expansion of type 1 T helper (T1) cells, which mediate prolonged tumor suppression. By contrast, sympathetic ablation alone does not affect macrophage differentiation or tumor growth. Our findings uncover an immunomodulatory function of 6-OHDA beyond its established neurotoxic activity and suggest the therapeutic potential of harnessing the macrophage-T1 axis for breast cancer.
In this issue of Neuron, Fenstermacher et al. reveal that subregions of the descending serotonin system innervate separate structures in the spinal cord and are differentially active during locomotion. The results sugges...In this issue of Neuron, Fenstermacher et al. reveal that subregions of the descending serotonin system innervate separate structures in the spinal cord and are differentially active during locomotion. The results suggest fine-grained neuromodulatory control of sensation and movement.
Partial cellular reprogramming can modulate aging-associated decline across multiple tissues. However, whether targeting memory-encoding ensembles within specific brain regions is sufficient to restore cognitive function...Partial cellular reprogramming can modulate aging-associated decline across multiple tissues. However, whether targeting memory-encoding ensembles within specific brain regions is sufficient to restore cognitive function has remained unknown. In this issue of Neuron, Berdugo-Vega et al. show that engram rejuvenation rescues memory deficits and restores epigenetic-transcriptional features and intrinsic excitability.
Enteric glia are key components of the nervous system, contributing to many aspects of gastrointestinal function. In this issue of Neuron, Muppirala and colleagues reveal that anatomical niches dictate enteric glial tran...Enteric glia are key components of the nervous system, contributing to many aspects of gastrointestinal function. In this issue of Neuron, Muppirala and colleagues reveal that anatomical niches dictate enteric glial transcriptional identity, identifying Tacr3 as a specific marker for intraganglionic glia.
In this Neuron issue, Liu et al. show that the C9orf72 expanded G4C2 repeat RNA forms hybrid G-quadruplexes with CG-rich promoter regions, which impedes RNA polymerase II. This process causes global transcriptional dysre...In this Neuron issue, Liu et al. show that the C9orf72 expanded G4C2 repeat RNA forms hybrid G-quadruplexes with CG-rich promoter regions, which impedes RNA polymerase II. This process causes global transcriptional dysregulation in C9orf72 amyotrophic lateral sclerosis patient-derived cells.
Myelin injury, a hallmark of several neurological diseases, is highly sensitive to glucose metabolism disruptions. Here, we reveal that oligodendrocytes (OLs) within demyelinating lesions exhibit reduced glycolytic effic...Myelin injury, a hallmark of several neurological diseases, is highly sensitive to glucose metabolism disruptions. Here, we reveal that oligodendrocytes (OLs) within demyelinating lesions exhibit reduced glycolytic efficiency and lactate production compared with mature OLs. Administration of lactate, the product of glycolysis, or specific overexpression of lactate dehydrogenase A (LDHA), the enzyme in lactate production, in Olig1 OLs significantly enhances remyelination. In contrast, conditional knockout of LDHA in the Olig1 lineage or CNPase premyelinating OLs leads to severe neuropathy with dysmyelination in a development-dependent and cell-specific manner. Mechanistic insights show that OLs within demyelinating lesions undergo lactylation silencing, a lactate-induced epigenetic modification that impedes myelin restoration. Furthermore, lactylation of LDHA and carbonic anhydrase II (CAII) couples glycolysis with OL maturation. Our findings elucidate the metabolic interplay among glycolysis, lactylation, and OL maturation and provide novel enzymatic therapeutic perspectives for demyelinating disorders, for which effective therapies are currently lacking.
Acute stress is a powerful inducer of endogenous analgesia. Several brainstem and midbrain areas have been identified that are activated during stress and send descending axons to suppress spinal nociception. The spinal...Acute stress is a powerful inducer of endogenous analgesia. Several brainstem and midbrain areas have been identified that are activated during stress and send descending axons to suppress spinal nociception. The spinal effector circuits and neurons have, however, remained largely elusive. Here, we demonstrate that GABAergic interneurons of the superficial dorsal horn expressing the transcription factor gastrulation brain homeobox 1 (Gbx1) are key elements of these circuits. Their inhibition had little effect on nociception under resting conditions but completely abolished swim stress-induced analgesia. Retrograde monosynaptic tracing revealed input from several brain areas, most prominently from the rostral ventromedial medulla (RVM). Optogenetic circuit tracing demonstrated that this input is inhibitory and that Gbx1 neurons in turn inhibit projection neurons targeting the lateral parabrachial nucleus, a key area in supraspinal pain relay. Our results thus identify a subpopulation of GABAergic neurons in the superficial dorsal horn as key elements of a disinhibitory circuit for stress-induced analgesia.
Wimmer R, Brunet Avalos C, Lestienne P
… +14 more, Coquand L, Di Cicco A, Chehade C, Artioli A, Cortes M, Macé AS, Wang X, Manneville JB, Bessière B, Roy A, Forsberg-Nilsson K, Ladewig J, Guimiot F, Baffet AD
The strong increase in the size of the human neocortex is supported by a neural stem cell population, the basal radial glial (bRG) cells. Using live imaging of human fetal tissue and cortical organoids, we identify two t...The strong increase in the size of the human neocortex is supported by a neural stem cell population, the basal radial glial (bRG) cells. Using live imaging of human fetal tissue and cortical organoids, we identify two translocation mechanisms for bRG cell colonization of the human neocortex. On top of an actomyosin-dependent movement called mitotic somal translocation (MST), we identify a microtubule-dependent motion occurring during interphase that we call interphasic somal translocation (IST). We show that IST is driven by the dynein motor and its activator LIS1, which are recruited to the nuclear envelope by the LINC complex, while MST is controlled by the mitotic cell-rounding pathway. Eighty-five percent of bRG cell translocation is due to IST, resulting in a total movement of 0.67 mm per month of gestation. Our work identifies how bRG cells colonize the human fetal cortex and further shows that IST and MST also occur in bRG-related glioblastoma cells.