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-1? (IL-1?), tumor necrosis factor-alpha (TNF-?) 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-1?, TNF-? 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 ?2-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 will provide new knowledge for understanding the developmental origins of aberrant PNS- and CNS- immune interactions due to PAE, revealing susceptibilities to adult onset diseases such as neuropathic pain.
Physiological adaptations of the fetus in response to in utero ethanol exposure may enhance the risk of long- lasting disease susceptibility including immune-mediated dysregulation that impacts central nervous system function. A profound neuroimmune overlap exists with animal models of prenatal alcohol exposure and chronic neuropathic pain that includes crucial roles for immune proinflammatory cytokines. In this proposal, lifelong susceptibility to developing peripheral neuropathies as a consequence of prenatal alcohol exposure will be explored, with an emphasis on elucidating cytokine mechanisms in the peripheral and central nervous system in male and female rodent models.
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| Noor, Shahani; Sanchez, Joshua J; Vanderwall, Arden G et al. (2017) Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels. Brain Behav Immun 61:80-95 |
