Alcohol abuse and dependence affect an estimated 8.5% of the U.S. population and are responsible for substantial health and societal costs. The overarching goal of the Alcohol Research Center at The Scripps Research Institute (TSRI-ARC) is to understand the molecular and cellular mechanisms of vulnerability to alcohol dependence, with a focus on dysregulation of excitatory neurotransmission in stress-responsive brain regions, such as the basolateral amygdala (BLA) and the bed nucleus of the stria terminalis (BNST). In addition, adult neurogenesis will be examined during withdrawal. The Viral Vector Core will be instrumental in the realization of experiments proposed in TSRI-ARC Research Components by providing validated tools to manipulate gene expression locally and to label newborn neurons in adult rats exposed to models of binge drinking or alcohol dependence.
Specific Aim 1 is to characterize the ability of seven adeno-associated virus (AAV) pseudotypes to transduce glutamatergic cells in the BLA and the ventromedial prefrontal cortex (vmPFC), which send excitatory projections to the BLA and BNST. Results from this Aim will be used to select the best-suited AAV pseudotype for the production of custom AAV vectors in Specific Aims 2 and 3.
Specific Aim 2 is to provide AAV vectors for local silencing of monoacylglycerol lipase expression in BLA and vmPFC, and for knockdown of corticotropin-releasing factor receptor type 1 selectively in BLA glutamatergic neurons.
Specific Aim 3 is to provide AAV vectors for functional knockdown or glutamatergic neuron-specific overexpression of neuronal pentraxin 2 in the BLA.
Specific Aim 4 is to provide a retroviral vector expressing EGFP. This vector will label newborn neurons in the adult rat brain and enable characterization of their morphology and physiology. For each viral vector, we propose to design and clone DNA constructs, obtain high-titer, purified viral stocks from an outside production facility and validate their silencing/overexpression efficiency in vivo. Altogether, we anticipate that the innovative molecular tools provided by the Viral Vector Core will assist in gaining novel insights into the neurobiological mechanisms of excessive alcohol drinking.

Public Health Relevance

The Viral Vector Core will provide tools to manipulate excitatory neurotransmission and label birth of new neurons in the adult rat brain. Viral vectors are an innovative and efficient approach to examine the role of genes or cells of interest in rat models of binge drinking and alcoholism. Translational implications include the identification of novel targets for the development of a more efficient treatment of alcoholism

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Comprehensive Center (P60)
Project #
Application #
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
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
Curran, H Valerie; Freeman, Tom P; Mokrysz, Claire et al. (2016) Keep off the grass? Cannabis, cognition and addiction. Nat Rev Neurosci 17:293-306
Ehlers, Cindy L; Kim, Corinne; Gilder, David A et al. (2016) Lifetime history of traumatic events in a young adult Mexican American sample: Relation to substance dependence, affective disorder, acculturation stress, and PTSD. J Psychiatr Res 83:79-85
Melroy-Greif, Whitney E; Wilhelmsen, Kirk C; Ehlers, Cindy L (2016) Genetic variation in FAAH is associated with cannabis use disorders in a young adult sample of Mexican Americans. Drug Alcohol Depend 166:249-53
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
de Guglielmo, Giordano; Crawford, Elena; Kim, Sarah et al. (2016) Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala Is Required for Alcohol Dependence. J Neurosci 36:9446-53
Buczynski, Matthew W; Herman, Melissa A; Hsu, Ku-Lung et al. (2016) Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proc Natl Acad Sci U S A 113:1086-91
Criado, José R; Gilder, David A; Kalafut, Mary A et al. (2016) Cardiovascular disease risks in adult Native and Mexican Americans with a history of alcohol use disorders: association with cardiovascular autonomic control. Clin Auton Res 26:87-95
Varodayan, Florence P; Soni, Neeraj; Bajo, Michal et al. (2016) Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala. Addict Biol 21:788-801
Herman, Melissa Ann; Roberto, Marisa (2016) Cell-type-specific tonic GABA signaling in the rat central amygdala is selectively altered by acute and chronic ethanol. Addict Biol 21:72-86

Showing the most recent 10 out of 158 publications