Neural stem cells persist in the adult hippocampal subgranular zone (SGZ) and generate dentate gyrus (DG) granule cell neurons (GCNs) ? a process known as adult hippocampal neurogenesis. Alcohol use disorders, commonly called alcoholism is a chronic, relapsing disorder, characterized by withdrawal syndromes of negative emotional symptoms that putatively promote relapse via pathological neuroadaptations in the hippocampus. Of notable interest is the discovery of ethanol (TSRI-ARC model of excessive drinking during chronic ethanol induced dependence (CEID))-induced inhibition of neurogenesis in the DG, and withdrawal from ethanol (CEID and binge alcohol)-induced ?aberrant? neurogenesis in the DG of the hippocampus. These studies suggest that the inhibitory effect of CEID on the regenerative capacity of the adult hippocampus can be considered as a precursor for alcohol-induced neurodegeneration, and that alcohol withdrawal-induced aberrant neurogenesis in the DG may be due to central nervous system hyperexcitability that is associated with alcohol withdrawal symptomatology resulting from termination of CEID. However, cellular mechanisms regulating alcohol withdrawal-induced aberrant neurogenesis in the DG have not been identified. Particularly interesting is the accumulating evidence from Component 02 (Zorrila) and others using the TSRI-ARC CEID model that altered corticotropin-releasing factor (CRF) signaling in the basolateral complex of the amygdala (BLA) and concurrent hyperglutamatergic activity (perhaps manifested as ?kindling-like? activity) in the BLA are evident in withdrawn dependent rats. Therefore we hypothesize that specific neuroadaptations in the CRF system in the BLA following ethanol withdrawal could produce a hyperglutamatergic state in the hippocampus that may regulate aberrant neurogenesis in the DG, and the resulting pathological plasticity could be facilitating the recruitment of new GCNs into emotional memory circuits and therefore contributing to the pathology underlying alcohol dependence via our specific hypotheses that inhibiting this process will alleviate dependence by preventing aberrant DG neurogenesis and withdrawal-associated behaviors. Integration within TSRI-ARC: Our component will use retroviral vectors produced by viral vector core (Contet) and will draw dependence models from animal models core (Koob &George). The proposed studies will require close communication and collaboration with other center components, most notably, Components 01(Roberto) and 03 (Zorrilla).

Public Health Relevance

Millions of Americans meet the diagnostic criteria for alcoholism, cutting across all socio-economic lines, increasing morbidity, mortality and economic costs. Psychopathology of the hippocampus has been implicated in alcohol abuse and alcoholism. In this proposal, we will begin to identify the cellular mechanisms underlying dependence-induced neuroadaptations in hippocampal plasticity and determine a putative role for aberrant hippocampal neurogenesis in negative affect symptoms associated with alcohol use disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
5P60AA006420-31
Application #
8616701
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
31
Fiscal Year
2014
Total Cost
$84,462
Indirect Cost
$39,891
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Matzeu, Alessandra; Martin-Fardon, Rémi (2018) Drug Seeking and Relapse: New Evidence of a Role for Orexin and Dynorphin Co-transmission in the Paraventricular Nucleus of the Thalamus. Front Neurol 9:720
Sidhu, Harpreet; Kreifeldt, Max; Contet, Candice (2018) Affective Disturbances During Withdrawal from Chronic Intermittent Ethanol Inhalation in C57BL/6J and DBA/2J Male Mice. Alcohol Clin Exp Res 42:1281-1290
Ehlers, Cindy L; Wills, Derek; Gilder, David A (2018) A history of binge drinking during adolescence is associated with poorer sleep quality in young adult Mexican Americans and American Indians. Psychopharmacology (Berl) 235:1775-1782
Pavon, Francisco J; Serrano, Antonia; Sidhpura, Nimish et al. (2018) Fatty acid amide hydrolase (FAAH) inactivation confers enhanced sensitivity to nicotine-induced dopamine release in the mouse nucleus accumbens. Addict Biol 23:723-734
Logrip, Marian L; Walker, John R; Ayanwuyi, Lydia O et al. (2018) Evaluation of Alcohol Preference and Drinking in msP Rats Bearing a Crhr1 Promoter Polymorphism. Front Psychiatry 9:28
Serrano, Antonia; Pavon, Francisco J; Buczynski, Matthew W et al. (2018) Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology 43:1840-1850
Spierling, Samantha R; Kreisler, Alison D; Williams, Casey A et al. (2018) Intermittent, extended access to preferred food leads to escalated food reinforcement and cyclic whole-body metabolism in rats: Sex differences and individual vulnerability. Physiol Behav 192:3-16
Blasio, Angelo; Wang, Jingyi; Wang, Dan et al. (2018) Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice. Biol Psychiatry 84:193-201
Kirson, Dean; Oleata, Christopher Shaun; Parsons, Loren Howell et al. (2018) CB1 and ethanol effects on glutamatergic transmission in the central amygdala of male and female msP and Wistar rats. Addict Biol 23:676-688
Matzeu, Alessandra; Kallupi, Marsida; George, Olivier et al. (2018) Dynorphin Counteracts Orexin in the Paraventricular Nucleus of the Thalamus: Cellular and Behavioral Evidence. Neuropsychopharmacology 43:1010-1020

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