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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
2P50AA017823-06
Application #
8599921
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
State University of NY, Binghamton
Department
Type
DUNS #
City
Binghamton
State
NY
Country
United States
Zip Code
13902
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
Doremus-Fitzwater, Tamara L; Spear, Linda P (2016) Reward-centricity and attenuated aversions: An adolescent phenotype emerging from studies in laboratory animals. Neurosci Biobehav Rev 70:121-134
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
Eade, Amber M; Youngentob, Lisa M; Youngentob, Steven L (2016) The Interaction of Ethanol Ingestion and Social Interaction with an Intoxicated Peer on the Odor-Mediated Response to the Drug in Adolescent Rats. Alcohol Clin Exp Res 40:734-42
Fernández, Macarena Soledad; Fabio, María Carolina; Miranda-Morales, Roberto Sebastián et al. (2016) Age-related effects of chronic restraint stress on ethanol drinking, ethanol-induced sedation, and on basal and stress-induced anxiety response. Alcohol 51:89-100
Spear, Linda Patia (2016) Consequences of adolescent use of alcohol and other drugs: Studies using rodent models. Neurosci Biobehav Rev 70:228-243
Saalfield, Jessica; Spear, Linda (2016) The ontogeny of ethanol aversion. Physiol Behav 156:164-70
Santerre, J L; Kolitz, E B; Pal, R et al. (2015) Cytoplasmic phospholipase Aâ‚‚ modulation of adolescent rat ethanol-induced protein kinase C translocation and behavior. Neurochem Res 40:1023-31
Deak, Terrence; Hunt, Pamela S (2015) Early ontogeny as a unique developmental epoch for learning, memory and consequences of alcohol exposure: A Festschrift to honor the work of Dr. Norman E. Spear. Physiol Behav 148:1-5
Doremus-Fitzwater, Tamara L; Gano, Anny; Paniccia, Jacqueline E et al. (2015) Male adolescent rats display blunted cytokine responses in the CNS after acute ethanol or lipopolysaccharide exposure. Physiol Behav 148:131-44

Showing the most recent 10 out of 73 publications