PROJECT SUMMARY Exposure to alcohol during gestation can lead to a constellation of mild to severe disabilities that includes cognitive and behavioral deficits representing a continuum referred to as Fetal Alcohol Spectrum Disorders (FASD), with a prevalence of ~4.8% in some US regions. A growing body of evidence strongly implicates the adverse impact of alcohol exposure during central nervous system (CNS) development on cellular and molecular programing of neuroimmune function. In animal models of prenatal alcohol exposure (PAE), expression of the brain's immune signaling molecules, the proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) and the chemokine CCL2, are significantly elevated. While evidence of sensory abnormalities including tactile sensitivity observed in children with FASD are thought to be a result of psychosocial factors, the underlying cause may include neurological dysfunction. Indeed, animal models of PAE reveal heightened sensitivity to light touch, a well-known pathological sensory condition mediated by aberrant neuronal actions in the spinal cord. Clinically, touch hypersensitivity is known as allodynia in chronic pain patients, and animal models of allodynia show pathological activation of pain neurons occurs in the spinal cord mediated by IL-1β, TNF-α and CCL2. Glial cells (astrocytes & microglia) are key producers of these proinflammatory cytokines. Thus, animal models of allodynia and PAE reveal a surprising neuroimmune overlap. Studies of allodynia in animals show peripheral leukocytes traffic to the spinal cord in response to CCL2. Notably, leukocytes cross spinal microvascular endothelial cells (MECs) into the CNS by the action of the β2-adhesion molecule, lymphocyte function associated antigen 1 (LFA-1), and importantly, glial cells control the healthy barrier function of MECs. Curiously, evidence shows PAE causes structural abnormalities at the glial CNS-MEC interface. Thus, the long-term goal is to identify spinal MEC & neuroimmune adaptations in PAE male and female offspring that enhance adult susceptibility to neuropathy. New therapeutic targets to alleviate aberrant neuroimmune function may be identified. The overall objective will identify the impact PAE exerts on responses of spinal immune adaptations to minor peripheral nerve & immune challenge in males & females. Overarching Hypothesis: PAE potentiates spinal and peripheral proinflammatory immune responses in the nociceptive pathway creating susceptibility for chronic neuropathy from minor insult or challenge. The Aims of the proposal will: (I) Examine the impact of PAE on cytokine profile and function in mediating neuropathy from minor insults and immune challenges in adults, (II) Determine the functional consequences of PAE-induced tight junction defects of the blood-spinal barrier on neuropathy, and (III) Determine PAE-induced defects of the peripheral immune response underlying susceptibility to neuropathy. Results wil...