PARC 2012 Pilot Projects

Project funding period:  January 1, 2012 - December 31, 2012

Awarded projects:

Ethanol Effects on Retinoid Signaling in the Zebra Finch
PI: Claudio V. Mello, M.D., Ph.D., Department of Behavioral Neuroscience, OHSU

Abstract: Ethanol consumption is associated with long-term cognitive deficits, yet the specific action of ethanol on the brain is poorly understood. Recently retinoic acid, a molecule with potent effects on nervous system phenotype, has been found to be elevated in the brains of mice following acute and chronic ethanol exposure.  Here we will investigate how ethanol and retinoid signaling in the brains of the zebra finch interact to affect song, a complex learned behavior. Song is easily quantifiable and easy to induce as birds are highly motivated to sing. Finches learn song from a vocal tutor, and perfect their song by a process of auditory-motor feedback, akin to human infant babbling. In preliminary tests we find that finches are voluntary consumers of ethanol in their water, and that their relatively slow metabolic clearance of ethanol makes them a highly suitable organism for ethanol studies. Here we propose two aims to examine ethanol effects at two life-stages: (1) the mature cognitive decline of song with ethanol, and (2) ethanol effects on the development of juvenile vocal learning. In Aim 1 we will expose adult male finches to chronic ethanol and examine the effects of song structure, motivation to sing, and underlying neuroanatomy of the song system (song nuclei volume, cell soma size) and gene expression of a number of enzymes that regulate levels of retinoic acid in tissues. In a separate part of Aim 1 we will directly measure levels of retinoic acid and and its precursors in subregions of the finch brain to test hypotheses regarding the location of retinoid signaling in the finch song system. In Aim 2 we will use the zebra finch model to examine the effects ethanol may have on juvenile (adolescent) song development, as well as the development of the song system neuroanatomy and on gene expression during development. In a parallel experiment in Aim 2 we will also directly measure retinoids in subregions of the brain, as in Aim 1. This proposal will introduce a well-understood and powerful model organism for studies of neurogeneis and genomics to the field of ethanol research. Furthermore it inquires into a specific mechanism that links ethanol consumption to retinoic acid-linked gene expression and cognitive decline.

Neurobiological Phenotypes of Emotional Processing in Youth with Family History Risk for Alcoholism
PI: Bonnie J. Nagel, Ph.D., Departments of Psychiatry and Behavioral Neuroscience, OHSU

Abstract: Individuals with alcohol use disorders (AUDs) have deficits in emotional processing as well as atypical function and structure in brain regions important for affective regulation. These symptoms are often associated with problems in executive functioning. Interestingly, even prior to heavy alcohol use, youth with a family history of alcoholism (FHP) are at greater risk for emotional problems and exhibit deficits in cognitive control compared to youth without a family history of alcoholism (FHN). Given that FHP youth are at much greater risk for developing an AUD than FHN youth, it is essential to clarify whether brain and behavior phenotypes related to affective processing and executive functioning may be premorbid risk factors for the development of AUDs in FHP youth. Thus, the goal of this PARC pilot proposal is to begin to investigate brain function and behavior related to emotional processing in FHP youth, as well as examine their associations with executive functioning, prior to heavy alcohol use. Specifically, this research plan will investigate emotional processing and its association with cognitive functioning using functional magnetic resonance imaging and resting state functional connectivity magnetic resonance imaging in FHP and FHN youth. By examining brain activity and behavior in FHP and FHN youth prior to heavy alcohol use, this study will provide insight into the neural and behavioral phenotypes associated with familial alcoholism, which may relate to the increased risk for developing AUDs. Understanding whether atypical emotional processing and associated deficits in cognitive control are present in FHP youth prior to heavy alcohol use will allow future research to establish prevention strategies aimed at reducing the development of AUDs.

Effects of Nicotine and Varenicline on Ethanol Behaviors
PI: Tamara J. Phillips, Ph.D., Department of Behavioral Neuroscience, OHSU, and Portland VA Medical Center

Abstract: Alcohol and nicotine, when excessively used, are associated with high rates of morbidity and mortality. Their co-abuse is common, but mechanisms leading to co-use are not well defined. One possibility is that nicotinic acetylcholine receptors (nAChR) are a common site of action for ethanol and nicotine, and that co-use results in greater reward compared to that produced by either drug alone. Our preliminary and published data show that the non-selective nAChR antagonist mecamylamine attenuates, while nicotine enhances, locomotor stimulation to ethanol in mice selectively bred for high locomotor stimulation to ethanol. The first goal of this proposal is to determine if nicotine potentiates the development of two ethanol-related behaviors: conditioned place preference (CPP), a measure of drug reward, and behavioral sensitization, a measure of drug-induced neural changes. Secondly, RT-PCR and autoradiography will be used to measure gene expression and levels of certain nAChR subtypes in mice treated with chronic nicotine, ethanol and both drugs. We hypothesize that nicotine will enhance the rewarding and sensitizing effects of ethanol and that group differences in nAChR levels, and perhaps expression, will correspond with behavioral effects. Our third aim is focused on treatment. Here, we propose to start with examination of alcohol alone, with effects of Varenicline on the alcohol-nicotine combination left as a future goal. One preliminary finding is that the FDAapproved smoking cessation drug varenicline (Chantix), a partial α4β2 nAChR agonist, decreased ethanol consumption in rodents and humans. However, there is limited research focused on how varenicline affects other behaviors that could impact consumption. For example, varenicline could influence ethanol consumption by reducing the rewarding effects of ethanol, or varenicline could increase the rewarding effects of ethanol and shift the dose response curve to the left, reducing the amount of alcohol needed to achieve the same level of reward. It could also accentuate behavioral effects that interfere with drinking. We will examine the effects of varenicline on ethanol-induced CPP and behavioral sensitization. These data could be informative with regard to the clinical use of Varenicline for the treatment of alcohol dependence.

PARC Pilot Project Application Information

Each year, the Portland Alcohol Research Center (PARC) aims to fund three pilot research projects (up to $35K each). The PARC is especially interested in encouraging investigators new to alcohol research to submit applications. Pilot proposals that focus on the neuroadaptation to ethanol exposure and those with relevance to behavioral genomics are especially welcome.

The call for pilot project applications generally is made each year on this website June 1st, with an application due date in late August, for funding to commence for selected projects the following January.

Each proposal is reviewed by at least two members of our external scientific advisory board. Based on these reviews and their own reviews, Center Director John Crabbe and Scientific Director Robert Hitzemann make recommendations to the PARC Executive Committee for funding.

Please contact the PARC Scientific Director, Robert Hitzemann, with questions at hitzeman@ohsu.edu or 503-402-2858.

 

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