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A MULTI-UNIVERSITY COLLABORATIVE VENTURE

News & Events

DEARC Call for Pilot Proposals
Letter of Intent due: January 15
Proposals due: February 15
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Research for Society on Alcoholism
38th Annual Meeting
June 20-24, 2015
San Antonio, Texas
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Research Highlights

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Main Projects

Main Project 1

The cognitive deficits caused by prenatal exposure to alcohol are reflected in the specific functional and structural abnormalities found in brains of alcohol-exposed children. Many of the same molecular and cellular events that shape the early developing brain reoccur later in life during critical periods of plasticity or change. This proposal will examine the impact of alcohol (EtOH) exposure on a signaling pathway that regulates plasticity in both the developing prenatal and adolescent brain. Reelin-Dab1 signaling controls lamination and dendritogenesis in the cortex and hippocampus during prenatal development, and separately enhances long-term potentiation (LTP) of memory encoding synapses in the postnatal period. Deficiency in Reelin-Dab1 signaling causes brain malformations, mental retardation and epilepsy in humans. We find that EtOH exposure, even acute dose exposure, causes a significant reduction of Dab1 protein levels in maturing neurons. Dab1 is an adaptor protein that is a component of the Reelin receptor complex and is absolutely required for Reelin signaling. EtOH exposure can drive Dab1 levels to ~20% of their normal value, levels that are known to cause serious brain malformations during development and likely functional changes in adolescence. This proposal will 1) examine the molecular mechanisms that trigger Dab1 suppression after EtOH exposure and then determine the consequences of EtOH-induced Dab1 suppression on 2) dendritic growth during the prenatal period and 3) plasticity or long term potentiation in the hippocampus during the postnatal period. The examination of this interaction between EtOH and Reelin-Dab1 should provide new insight into key biochemical events that underlie EtOH’s negative impacts on neuronal plasticity during the critical stages of embryonic and adolescent brain development.

Main Project 2

Fetal ethanol exposure is highly predictive of ethanol abuse in adolescence, and there is an inverse correlation between the age of first experience and the likelihood of continued abuse. How does fetal exposure alter adolescent ethanol acceptability? How does adolescent re-exposure increase adult acceptance? Are the consequences of fetal and adolescent exposure distinct? The flavor attributes (smell, taste and oral irritation) of ethanol are important determinants of acceptance. We hypothesize that fetal ethanol exposure induces developmental changes in the neural systems involved in the perception and acceptability of ethanol’s flavor, thereby increasing the risk of initial ingestion and continued adolescent abuse. Further, adolescent experience with ethanol augments the fetal effect and/or perpetuates the ethanol-induced changes into adulthood. This proposition is supported by our prior studies and compelling preliminary data demonstrating the fetal ethanol exposure: (1) reduces the peripheral neural taste response to quinine (a surrogate for ethanol’s bitter taste) and (2) decreases the expression of bitter (T2r) and oral irritation (Trp) receptor genes fundamental to ethanol flavor perception and intake in adolescent rats. We also find that binge ethanol exposure in naïve adolescent rats yields similar results to the prenatal T2r findings. Our long-range goal is to apply an understanding of these cellular processes to the development of clinical treatments and strategies. Applying behavioral, genomic and neurophysiologic methods, the objectives of this proposal are to understand mechanically: (A) the ontogeny of the fetal exposure effect on oro-sensory receptor gene expression and whether the observed effects differ between the fetal and adolescent exposure:; (B) whether adolescent behavioral responses (following fetal exposure) are mediated by alterations in receptor gene expression; and (C) whether adolescent re-exposure augments the behavioral and receptor response to fetal exposure and/or perpetuates them into adulthood. We will also determine how alterations in the peripheral neural responses to ethanol and stimuli representing it’s component qualities (bitter, sweet and irritancy) parallel the foregoing behavioral and genomic effects.

Main Project 3

Activation of inflammatory signaling pathways within the CNS, including increased expression of pro-inflammatory 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 to adolescent to 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 early development in a rodent model. The proposed work will significantly advance our understanding of ethanol-induced (2-4 g/kg) expression of Interleukin-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 neuroinflammatory 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.

Main Project 4

High levels of ethanol (EtOH) consumption during adolescence may be in part biologically driven, given that adolescents often manifest 2-3 fold greater EtOH intakes than adults in a variety of mammalian species. Studies in rats have suggested that such elevated intakes may be possible in part because adolescents are less sensitive than adults to aversive effects of EtOH and other intoxicating effects that may normally serve as cues to moderate intake. Genetic studies have found that sensitivity to aversive effects of EtOH plays an important role in moderating EtOH intake, and is more strongly related to EtOH intake than sensitivity to EtOH’s rewarding properties. Despite compelling evidence for an association between insensitivity to EtOH aversion and enhanced EtOH intake, little is known about the ontogeny of these aversive sensitivities, their regional specificity and neural contributors. In conjunction with the DEARC NeuroCore and Animal/Behavior Core, the proposed work will address these critical gaps. Aim 1 will use conditioned taste aversions (CTA) to examine the ontogeny of the developmental insensitivity to EtOH’s aversive effects throughout the juvenile to adult period. Aim 2 will assess c-Fos activation patterns to aversive effects of EtOH across age and associate these activation patterns with age differences in EtOH aversion. Focusing on an aversive region where activation is strongly linked to age differences in EtOH CTA, Aim 3 will determine whether reversible inactivation of that region diminishes age differences in EtOH’s aversive effects and EtOH intake differences, while Aim 4 will examine potential neural substrates underlying the age differences in EtOH-induced activation in this region via examination of NMDA, GABA and opiate receptor regulation and intracellular signaling pathways. Aim 5 will determine whether elevations in adolescent drinking induced by prenatal EtOH exposure are accompanied by exacerbated insensitivities to EtOH’s aversive effects. Collectively, these studies will provide critical new information to further our understanding of how ontogenetic changes in the brain contribute to adolescent insensitivities to aversive properties of EtOH, and ultimately to the elevated levels of EtOH drinking characteristic of adolescence.

Main Project 5

In humans, a strong association between anxiety and alcohol use has been reported among adolescents. Enhanced vulnerability to both anxiety and alcohol use disorders in adolescence is frequently associated with prenatal alcohol exposure, however, the mechanisms contributing to this enhanced vulnerability in adolescents prenatally exposed to alcohol remain poorly understood. A main limitation of the human data is that much of the research has involved self-report questionnaires, which limits causal interpretation of the results and does not permit systematic manipulation of critical variables, due to ethical considerations. Therefore, animal models are of particular importance. The proposed studies will use a simple rat model of social anxiety induced by acute prenatal ethanol exposure to assess responsiveness to social stressors and ethanol sensitivity in adolescents with the social inhibition and/or social avoidance phenotype. Offspring tested in adulthood will be included to assess persistence of alterations in stress responsiveness and ethanol sensitivity. The proposed research will address the following aims: (1) test whether the social avoidance phenotype induced by prenatal ethanol exposure is associated with enhanced stress responsiveness; (2) test whether (a) sensitivity to ethanol-induced social facilitation and ethanol-induced anxiolysis and (b) intake of ethanol under social circumstances are enhanced following prenatal ethanol exposure; (3) test whether the social avoidance phenotype induced by prenatal ethanol exposure is associated with alterations in structural plasticity in the neurocircuitry implicated in stress and anxiety. These studies will provide critical new information regarding mechanisms involved in vulnerability to affective and alcohol use disorders among adolescents exposed to alcohol prenatally. Understanding of these mechanisms is essential for creating a new prevention and intervention strategies as well as new approaches to pharmacological treatment of alcohol use disorders during adolescence.

Last Updated: 11/3/11