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Project description:The nervous and immune systems are intricately linked. Although psychological stress is known to affect immune function, direct mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood. Here, we show that distinct brain regions shape leukocyte distribution throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that the motor cortex induces rapid neutrophil mobilization to peripheral tissues via skeletal muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow via direct and cell-intrinsic glucocorticoid signaling. These stress-induced counter-directional and population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and precipitating their recruitment to atherosclerotic plaques. On the other hand, stress-induced leukocyte shifts impair adaptive immunity, increasing susceptibility to SARS-Cov-2 and influenza infection but protecting against autoimmunity in a model of multiple sclerosis. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, thus calibrating the immune system’s capacity to respond to physical threats.
2022-04-28 | GSE201390 | GEO
Project description:The nervous and immune systems are intricately linked. Although psychological stress is known to affect immune function, direct mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood. Here, we show that distinct brain regions shape leukocyte distribution throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that the motor cortex induces rapid neutrophil mobilization to peripheral tissues via skeletal muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow via direct and cell-intrinsic glucocorticoid signaling. These stress-induced counter-directional and population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and precipitating their recruitment to atherosclerotic plaques. On the other hand, stress-induced leukocyte shifts impair adaptive immunity, increasing susceptibility to SARS-Cov-2 and influenza infection but protecting against autoimmunity in a model of multiple sclerosis. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, thus calibrating the immune system’s capacity to respond to physical threats.
2022-04-28 | GSE201391 | GEO
Project description:Brain motor and fear circuits differentially regulate leukocyte distribution and function during acute stress
| PRJNA831428 | ENA
Project description:Brain motor and fear circuits differentially regulate leukocyte distribution and function during acute stress [bulk RNA-seq]
| PRJNA831431 | ENA
Project description:The nervous and immune systems are intricately linked1. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood2. Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats.
| S-EPMC9798885 | biostudies-literature
Project description:Brain motor and fear circuits differentially regulate leukocyte distribution and function during acute stress [single-cell RNA-seq]
| PRJNA831430 | ENA
Project description:Phospholipase D (PLD) plays important roles in cellular responses to tissue injury that are critical to acute inflammatory diseases, such as the acute respiratory distress syndrome (ARDS). We investigated the expression of PLD isoforms and related phospholipid phosphatases in patients with ARDS, and their roles in a murine model of self-limited acute lung injury (ALI). Gene expression microarray analysis on whole blood obtained from patients that met clinical criteria for ARDS and clinically matched controls (non-ARDS) demonstrated that PLD1 gene expression was increased in patients with ARDS relative to non-ARDS and correlated with survival. In contrast, PLD2 expression was associated with mortality. In a murine model of self-resolving ALI, lung Pld1 expression increased and Pld2 expression decreased 24 h after intrabronchial acid. Total lung PLD activity was increased 24 h after injury. Pld1-/- mice demonstrated impaired alveolar barrier function and increased tissue injury relative to WT and Pld2-/- , whereas Pld2-/- mice demonstrated increased recruitment of neutrophils and macrophages, and decreased tissue injury. Isoform-specific PLD inhibitors mirrored the results with isoform-specific Pld-KO mice. PLD1 gene expression knockdown in human leukocytes was associated with decreased phagocytosis by neutrophils, whereas reactive oxygen species production and phagocytosis decreased in M2-macrophages. PLD2 gene expression knockdown increased neutrophil and M2-macrophage transmigration, and increased M2-macrophage phagocytosis. These results uncovered selective regulation of PLD isoforms after ALI, and opposing effects of selective isoform knockdown on host responses and tissue injury. These findings support therapeutic strategies targeting specific PLD isoforms for the treatment of ARDS.
| S-EPMC6375305 | biostudies-literature
Project description:Little is known about the organizational and functional connectivity of the corticospinal (CS) circuits that are essential for voluntary movement. Here, we map the connectivity between CS neurons in the forelimb motor and sensory cortices and various spinal interneurons, demonstrating that distinct CS-interneuron circuits control specific aspects of skilled movements. CS fibers originating in the mouse motor cortex directly synapse onto premotor interneurons, including those expressing Chx10. Lesions of the motor cortex or silencing of spinal Chx10+ interneurons produces deficits in skilled reaching. In contrast, CS neurons in the sensory cortex do not synapse directly onto premotor interneurons, and they preferentially connect to Vglut3+ spinal interneurons. Lesions to the sensory cortex or inhibition of Vglut3+ interneurons cause deficits in food pellet release movements in goal-oriented tasks. These findings reveal that CS neurons in the motor and sensory cortices differentially control skilled movements through distinct CS-spinal interneuron circuits.
| S-EPMC6608728 | biostudies-literature
Project description:The basal forebrain delivers extensive axonal projections to the cortical mantle regulating brain states and cognitive processing. Recent evidence has established the basal forebrain as a subcortical node of the default mode network that directionally influences cortical dynamics trough gamma oscillations, yet their synaptic origin has not been established. Here, we used optogenetic stimulation and in vivo recordings of transgenic mice to show that somatostatin neurons exert an anatomically specialized role in the coordination of subcortical gamma oscillations of the rostral basal forebrain. Indeed, the spike timing of somatostatin cells was tightly correlated with gamma oscillations in the ventral pallidum, but not in the medial septum. Consequently, optogenetic inactivation of somatostatin neurons selectively disrupted the amplitude and coupling of gamma oscillations only in the ventral pallidum. Moreover, photosupression of somatostatin cells produced specific behavioral interferences, with the ventral pallidum regulating locomotor speed and the medial septum modulating spatial working memory. Altogether, these data suggest that basal forebrain somatostatin cells can selectively synchronize local neuronal networks in the gamma band directly impinging on cortical dynamics and behavioral performance. This further supports the role of the basal forebrain as a subcortical switch commanding transitions between internally and externally oriented brain states.
| S-EPMC6384953 | biostudies-literature
Project description:ObjectiveLow testosterone in men (hypogonadism) is associated with obesity and type II diabetes. Testosterone replacement therapy has been shown to reverse these effects. However, the mechanisms by which testosterone regulates total fat mass, fat distribution, and metabolic health are unclear. In this study, we clarify the impact of hypogonadism on these parameters, as well as parse the role of testosterone from its downstream metabolites, dihydrotestosterone (DHT), and estradiol, in the regulation of depot-specific adipose tissue mass.MethodsTo achieve this objective, we utilized mouse models of male hypogonadism coupled with hormone replacement therapy, magnetic resonance imaging (MRI), glucose tolerance tests, flow cytometry, and immunohistochemical techniques.ResultsWe observed that castrated mice develop increased fat mass, reduced muscle mass, and impaired glucose metabolism compared with gonadally intact males. Interestingly, obesity is further accelerated in castrated mice fed a high-fat diet, suggesting hypogonadism increases susceptibility to obesogenesis when dietary consumption of fat is elevated. By performing hormone replacement therapy in castrated mice, we show that testosterone impedes visceral and subcutaneous fat mass expansion. Testosterone-derived estradiol selectively blocks visceral fat growth, and DHT selectively blocks the growth of subcutaneous fat. These effects are mediated by depot-specific alterations in adipocyte size. We also show that high-fat diet-induced adipogenesis is elevated in castrated mice and that this can be rescued by androgen treatment. Obesogenic adipogenesis is also elevated in mice where androgen receptor activity is inhibited.ConclusionsThese data indicate that hypogonadism impairs glucose metabolism and increases obesogenic fat mass expansion through adipocyte hypertrophy and adipogenesis. In addition, our findings highlight distinct roles for testosterone, DHT, and estradiol in the regulation of total fat mass and fat distribution and reveal that androgen signaling blocks obesogenic adipogenesis in vivo.
| S-EPMC7772371 | biostudies-literature