Alcohol use disorder (AUD) is a major public health concern characterized by the loss of control over alcohol drinking and the emergence of negative emotionality during abstinence from alcohol. The transition to alcohol dependence is associated with the concomitant dysregulation of executive function by the medial prefrontal cortex (mPFC) and the recruitment of corticotropin releasing factor (CRF) and its CRF receptor 1 (CRF1) in the central nucleus of the amygdala (CeA), but much less is known about the role of CRF/CRF1 signaling in cortical areas. Critically, the development of new tools to access subpopulations of CRF1 neurons has facilitated our studies of function and connectivity of CRF/CRF1 systems. In the original grant, we use an innovative transgenic mouse models in which CRF1 expressing (CRF1+) neurons co-express green fluorescent protein (GFP) (CRF1:GFP mice) to understand the cell type-specific effects of acute and chronic alcohol in local and downstream CeA microcircuits. Preliminary data have revealed that the CRF1+ neurons are highly expressed in mPFC layer 2/3 and undergo specific neuroadaptations following chronic alcohol compared to unlabeled (CRF1-) neurons. Thus, in this renewal, we will continue to use CRF1:GFP and CRF1:Cre mice to characterize the electrophysiological, neurochemical and morphological properties of both CRF1+ and CRF1- neurons in the mPFC, and elucidate the role of mPFC CRF1+ circuitry in anxiety-like and drinking behaviors. Through a systems biology approach, we will delineate the CRF1-dependent effects of ethanol in mPFC, as well as amygdala-mPFC connectivity that may regulate ethanol dependence and withdrawal and contribute to associated anxiety-related behaviors. In addition, we will use fluorescence activated cell sorting (FACS) followed by whole transcriptome analysis to reveal molecular signatures and neuroadaptations of this specific CRF1 cortical population, which may identify new promising targets for treatment strategies for alcoholism.

Public Health Relevance

Despite the importance of extrahypothalamic corticotropin releasing factor (CRF) and its type 1 receptor (CRF1) in the development of ethanol dependence, the role of this system in amygdala-cortical circuits has not yet been delineated. The present application will provide new molecular and circuit information on CRF function and neuroadaptation that may drive ethanol dependence and withdrawal. The results could be invaluable in the development of new pharmacotherapeutics for the treatment of alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA021491-07
Application #
10077812
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2013-07-01
Project End
2024-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
7
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Schmeichel, Brooke E; Matzeu, Alessandra; Koebel, Pascale et al. (2018) Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats. Neuropsychopharmacology 43:2373-2382
McClatchy, Daniel B; Yu, Nam-Kyung; Martínez-Bartolomé, Salvador et al. (2018) Structural Analysis of Hippocampal Kinase Signal Transduction. ACS Chem Neurosci :
Varodayan, Florence P; Sidhu, Harpreet; Kreifeldt, Max et al. (2018) Morphological and functional evidence of increased excitatory signaling in the prelimbic cortex during ethanol withdrawal. Neuropharmacology 133:470-480
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
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
Verheij, Michel M M; Contet, Candice; Karel, Peter et al. (2018) Median and Dorsal Raphe Serotonergic Neurons Control Moderate Versus Compulsive Cocaine Intake. Biol Psychiatry 83:1024-1035
Roberto, Marisa; Spierling, Samantha R; Kirson, Dean et al. (2017) Corticotropin-Releasing Factor (CRF) and Addictive Behaviors. Int Rev Neurobiol 136:5-51
Natividad, Luis A; Buczynski, Matthew W; Herman, Melissa A et al. (2017) Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype. Biol Psychiatry 82:500-510
Varodayan, Florence P; Bajo, Michal; Soni, Neeraj et al. (2017) Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala. Addict Biol 22:766-778
Roberto, Marisa; Varodayan, Florence P (2017) Synaptic targets: Chronic alcohol actions. Neuropharmacology 122:85-99

Showing the most recent 10 out of 25 publications