The research proposal explores how a habit center in the brain, the dorsolateral striatum, is disinhibited by chronic alcohol exposure to foster habit formation. Understanding how this process works at molecular, neural circuit and behavioral levels is critical to devising novel therapeutic strategies targeting alcoholism, as well as comorbid habitual use of other substances of abuse. Dorsolateral striatum output is powerfully governed by the inhibitory fast-spiking interneuron (FSI) population. FSIs are in relatively high abundance in the dorsolateral striatum as compared to other striatal subregions, which positions these cells to be key modulators of dorslolateral striatum output and habit expression. As a minority population of neurons in the striatum, FSIs and their role in chronic ethanol exposure-induced habit formation is vastly understudied. This proposal seeks to understand how chronic ethanol exposure dampens FSI function to allow for dorsolateral striatum disinhibition and habitual action expression. This will be investigated in three specific experimental aims employing cutting-edge technology that allows for an unprecedented view into the function of these neurons in mice. In the first aim we test the hypothesis that chronic ethanol exposure depresses the release of the inhibitory neurotransmitter GABA from FSIs onto postsynaptic medium spiny neurons, which are the output neurons of the striatum. This will be accomplished using optogenetics coupled with brain slice electrophysiology. In the second aim we explore FSI synchrony. FSIs synchronize their activity to enhance their inhibitory authority over dorsolateral striatum output. Thus, we will test the hypothesis that FSIs desynchronize following chronic ethanol exposure. We will test this using slice electrophysiology and calcium imaging of FSI activity in awake behaving mice exposed to chronic alcohol. Finally, we will test the contribution of dampened FSI release of GABA and FSI asynchrony on alcohol drinking and generalized habit learning in mice. By examining how ethanol hijacks the neural circuitry of habit formation, the results of this study should significantly advance our knowledge toward novel therapeutic strategies targeting alcoholism and provide novel insight to myriad neuropsychiatric disorders involving striatal dysfunction.

Public Health Relevance

Alcohol abuse and alcoholism impose a substantial public health burden. Despite this, effective therapies are lacking, and treatment for habitual drinking is particularly inadequate. This research seeks to understand how chronic ethanol exposure disrupts specific brain circuits to accelerate habit formation in mice. The data gathered from this study will provide novel therapeutic strategies targeting habitual alcohol consumption.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA024845-05
Application #
9900690
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2016-07-15
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Cover, Kara K; Kerkhoff, Willa G; Mathur, Brian N (2018) The best defense is a strong offense: preventing alcohol abstinence-induced depression. Neuropsychopharmacology 43:2331-2332
Licheri, Valentina; Lagström, Oona; Lotfi, Amir et al. (2018) Complex Control of Striatal Neurotransmission by Nicotinic Acetylcholine Receptors via Excitatory Inputs onto Medium Spiny Neurons. J Neurosci 38:6597-6607
White, Michael G; Panicker, Matthew; Mu, Chaoqi et al. (2018) Anterior Cingulate Cortex Input to the Claustrum Is Required for Top-Down Action Control. Cell Rep 22:84-95
White, Michael G; Mathur, Brian N (2018) Claustrum circuit components for top-down input processing and cortical broadcast. Brain Struct Funct 223:3945-3958
White, Michael G; Mathur, Brian N (2018) Frontal cortical control of posterior sensory and association cortices through the claustrum. Brain Struct Funct 223:2999-3006
Brown, Solange P; Mathur, Brian N; Olsen, Shawn R et al. (2017) New Breakthroughs in Understanding the Role of Functional Interactions between the Neocortex and the Claustrum. J Neurosci 37:10877-10881
Chandra, Ramesh; Engeln, Michel; Schiefer, Christopher et al. (2017) Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence. Neuron 96:1327-1341.e6
Carroll, A M; Cheng, R; Collie-Duguid, E S R et al. (2017) Fine-mapping of genes determining extrafusal fiber properties in murine soleus muscle. Physiol Genomics 49:141-150