The nervous and immune systems are closely related1. Although psychological stress is known to modulate immune function, the mechanistic pathways connecting stress networks in the brain with peripheral leukocytes remain poorly understood2. Here we show that individual brain regions shape the distribution and function of leukocytes in the body during acute stress in mice. Using optogenetics and hemogenetics, we demonstrate that motor chains induce rapid mobilization of neutrophils from bone marrow to peripheral tissues through chemokines that attract neutrophils derived from skeletal muscle. Conversely, the paraventricular hypothalamus controls the release of monocytes and lymphocytes from secondary lymphoid organs and blood to the bone marrow through direct inherent glucocorticoid signaling. These stress-induced, contraindicated, leukocyte shifts throughout the population are associated with altered susceptibility to disease. On the one hand, acute stress alters innate immunity by reprogramming neutrophils and directing their accumulation to injury sites. On the other hand, neuron-mediated leukocyte displacements of corticotropin-releasing hormone (CRH) prevent the acquisition of autoimmunity, but impair immunity against SARS-CoV-2 and influenza infection. Taken together, these data show that different brain regions differentiate and rapidly adapt to the leukocyte landscape during psychological stress, thus calibrating the ability of the immune system to respond to physical threats.
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