Alcohol use disorders, generally known as alcoholism, have taken emotional and financial tolls on American society, cutting across ages, races, ethnicities, and genders, with over 17 million Americans meeting the diagnostic criteria for alcohol abuse or dependence. Clinical data demonstrate alterations in brain structure and function in chronic alcoholics, injuries that may promote the individual s decline to meeting diagnostic criteria for alcohol dependence. Alcohol dependence is characterized by cycles of repeated high alcohol intake and negative emotional consequences of withdrawal that contribute to excessive drinking and susceptibility to relapse. There is a high likelihood that alcohol-dependent individuals will relapse to drinking even after long periods of abstinence, making treatment options challenging. One promising approach for the treatment of relapse to drinking is the identification of mechanisms that contribute to alcohol-induced reductions in brain mass and neurodegeneration. Recent evidence demonstrates that alcohol-induced neurodegeneration is affected by the decreased production of neural and glial progenitors in the adult brain. In the proposed studies, our research will specifically focus on alcohol s effects on the birth and survival of progenitors (glial stem cells and gliogenesis) in the medial prefrontal cortex (mPFC), a brain region implicated in the acute reinforcing effects of alcohol and relapse to alcohol-seeking behavior. Preliminary evidence from our laboratory demonstrated that excessive drinking in a rodent model of alcohol vapor-induced dependence decreased the proliferation and survival of adult-generated mPFC progenitors. Such regulation was not observed in nondependent alcohol self-administering rats, suggesting that the mPFC gliogenic niche is more vulnerable to dysregulation of the homeostatic system during dependence. These results raise a number of fundamental questions about the neuroplastic changes that contribute to alcohol dependence and the neuroplastic mechanisms that underlie the relapse stage of alcoholism. Therefore, this proposal will identify whether reduced gliogenesis in the mPFC could be a vulnerability factor for alcohol dependence and relapse. Animal models of excessive drinking during vapor-induced alcohol dependence and nondependent drinking will be used to (1) determine the cellular mechanisms underlying reduced mPFC plasticity during alcohol dependence (Specific Aim 1), (2) determine impairments in memory and cognitive function dependent on the mPFC during alcohol dependence (Specific Aim 2), and (3) demonstrate a causal relationship between newly born glial progenitors and relapse to alcohol seeking (Specific Aim 3). Immunohistochemical, biochemical, neuroanatomical, and behavioral measures will be used to determine the functional relationships between neocortical gliogenesis and alcohol dependence. The proposed aims will reveal new vulnerability markers for alcohol dependence and impart significant information about targets for medication development.

Public Health Relevance

In the past decade, about 17 million Americans met the diagnostic criteria for alcoholism, cutting across age, race, ethnicity and gender, and eventual dependence to alcohol has increased mortality, morbidity, and economic costs. Psychopathology of the medial prefrontal cortex has been implicated in such dependence-like syndromes. In this proposal, using a well established rodent model of alcohol dependence we will begin to identify the cellular mechanisms underlying dependence-induced decreases in medial prefrontal cortical plasticity, and determine a causal role for the newly generated prefrontocortical glia in alcohol use disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020098-02
Application #
8549933
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Regunathan, Soundar
Project Start
2012-09-25
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$308,413
Indirect Cost
$145,662
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Somkuwar, Sucharita S; Fannon, McKenzie J; Staples, Miranda C et al. (2016) Alcohol dependence-induced regulation of the proliferation and survival of adult brain progenitors is associated with altered BDNF-TrkB signaling. Brain Struct Funct 221:4319-4335
Sobieraj, Jeffery C; Kim, Airee; Fannon, McKenzie J et al. (2016) Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons. Brain Struct Funct 221:261-76
Somkuwar, Sucharita S; Fannon-Pavlich, McKenzie J; Ghofranian, Atoosa et al. (2016) Wheel running reduces ethanol seeking by increasing neuronal activation and reducing oligodendroglial/neuroinflammatory factors in the medial prefrontal cortex. Brain Behav Immun 58:357-368
Somkuwar, Sucharita S; Fannon, McKenzie J; Head, Brian P et al. (2016) Methamphetamine reduces expression of caveolin-1 in the dorsal striatum: Implication for dysregulation of neuronal function. Neuroscience 328:147-56
Galinato, M H; Orio, L; Mandyam, C D (2015) Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus. Neuroscience 286:97-108
Staples, Miranda C; Kim, Airee; Mandyam, Chitra D (2015) Dendritic remodeling of hippocampal neurons is associated with altered NMDA receptor expression in alcohol dependent rats. Mol Cell Neurosci 65:153-62
Cui, Changhai; Noronha, Antonio; Warren, Kenneth R et al. (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49:435-52
Staples, M C; Somkuwar, S S; Mandyam, C D (2015) Developmental effects of wheel running on hippocampal glutamate receptor expression in young and mature adult rats. Neuroscience 305:248-56
Navarro, A I; Mandyam, C D (2015) Protracted abstinence from chronic ethanol exposure alters the structure of neurons and expression of oligodendrocytes and myelin in the medial prefrontal cortex. Neuroscience 293:35-44
Kim, Airee; Zamora-Martinez, Eva R; Edwards, Scott et al. (2015) Structural reorganization of pyramidal neurons in the medial prefrontal cortex of alcohol dependent rats is associated with altered glial plasticity. Brain Struct Funct 220:1705-20

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