Activation of inflammatory signaling pathways within the CNS, including increased expression of proinflammatory cytokines, microglial activation, and other tell-tale signs of neuroinflammation, have emerged as powerful drivers of ethanol-dependent behavioral change and neuropathological consequences of ethanol exposure. While ethanol load is certainly a critical determinant of ethanol-induced cytokine changes, virtually nothing is known about how ethanol-induced inflammatory processes are impacted by cues associated with ethanol exposure, or how ethanol-induced inflammatory processes differ across key stages of development, particularly the juvenile-* adolescent?>adult continuum, where age of ethanol initiation is most predictive of later Alcohol Use Disorders (AUD). As such, the overarching goal is to identify mechanisms of plasticity in central cytokine responses evoked by ethanol challenge across eariy development in a rodent model. The proposed work will significantly advance our understanding of ethanol-induced (2-4 g/kg) expression bf Interieukin-6 (IL-6), a rapidly induced (3 hr post ethanol) cytokine effect that occurs in key CNS structures relating to learning and memory (hippocampus) and aversive processes (paraventricular nucleus;PVN). Importantly, when ethanol was paired with novel cues (lemon odor in a unique context) across 4 trials, a substantially lower dose of ethanol (0.5-g/kg) on the fifth trial led to a robust increase in IL-6 expression in the hippocampus (but not PVN). This context-dependent sensitization of IL-6 suggests that neuroinfiammatory consequences of ethanol exposure can come under the conditioned control of cues associated with ethanol exposure, thereby providing novel insight into how ethanol-related inflammatory processes transform across the first few ethanol exposures.
Three Specific Aims will (1) characterize developmental differences in ethanol-dependent changes in IL-6;(2) identify developmentally critical/sensitive periods for ethanol-induced plasticity;and (3) determine cellular mechanisms of ethanol dependent expression of IL-6. The proposed work will significantly advance our understanding of how ethanol-related inflammatory processes transform as a function of early developmental exposure to alcohol.

Public Health Relevance

Inflammatory consequences of alcohol are critical to understanding how alcohol exposure impacts acute behavioral change;the trajectory of developing neural circuits;and ultimately patterns of alcohol use and abuse later in life. This project will significantly advance our understanding of how alcohol impacts a key cytokine (IL-6) across sensitive developmental periods (juvenile, adolescent and young adult) when alcohol use is often initiated, thereby informing novel treatments for ameliorating adverse alcohol effects.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Specialized Center (P50)
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Special Emphasis Panel (ZAA1)
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State University of NY, Binghamton
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Gano, Anny; Doremus-Fitzwater, Tamara L; Deak, Terrence (2017) A cross-sectional comparison of ethanol-related cytokine expression in the hippocampus of young and aged Fischer 344 rats. Neurobiol Aging 54:40-53
Fernandez, Gina M; Lew, Brandon J; Vedder, Lindsey C et al. (2017) Chronic intermittent ethanol exposure leads to alterations in brain-derived neurotrophic factor within the frontal cortex and impaired behavioral flexibility in both adolescent and adult rats. Neuroscience 348:324-334
Vore, Andrew S; Doremus-Fitzwater, Tamara; Gano, Anny et al. (2017) Adolescent Ethanol Exposure Leads to Stimulus-Specific Changes in Cytokine Reactivity and Hypothalamic-Pituitary-Adrenal Axis Sensitivity in Adulthood. Front Behav Neurosci 11:78
Deak, Terrence; Kudinova, Anastacia; Lovelock, Dennis F et al. (2017) A multispecies approach for understanding neuroimmune mechanisms of stress. Dialogues Clin Neurosci 19:37-53
Gano, Anny; Pautassi, Ricardo Marcos; Doremus-Fitzwater, Tamara L et al. (2017) Conditioned effects of ethanol on the immune system. Exp Biol Med (Maywood) 242:718-730
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Lovelock, D F; Deak, T (2017) Repeated exposure to two stressors in sequence demonstrates that corticosterone and paraventricular nucleus of the hypothalamus interleukin-1? responses habituate independently. J Neuroendocrinol 29:
Gano, Anny; Doremus-Fitzwater, Tamara L; Deak, Terrence (2016) Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure. Brain Res 1646:62-72
Diaz, Marvin R; Mooney, Sandra M; Varlinskaya, Elena I (2016) Acute prenatal exposure to ethanol on gestational day 12 elicits opposing deficits in social behaviors and anxiety-like behaviors in Sprague Dawley rats. Behav Brain Res 310:11-9
Fernandez, Gina M; Stewart, William N; Savage, Lisa M (2016) Chronic Drinking During Adolescence Predisposes the Adult Rat for Continued Heavy Drinking: Neurotrophin and Behavioral Adaptation after Long-Term, Continuous Ethanol Exposure. PLoS One 11:e0149987

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