Increased anxiety during alcohol withdrawal is a central characteristic of alcohol dependence and has been reported as a common, underlying cause of relapse in those with alcohol dependence, which is a critical barrier to their treatment. Animal models of alcohol dependence likewise show increased anxiety-like behaviors during alcohol withdrawal, suggesting they are a valid translational model. The lateral/basolateral amygdala (BLA) has been identified as a critical component of the neural circuitry that regulates many emotional behaviors, including anxiety. Our laboratory has recently shown that chronic ethanol exposure and withdrawal produce distinct synaptic alterations in the BLA that are input- and timing-specific. For example, glutamatergic afferents arriving within the stria terminalis (ST) along the medial BLA boundary express a presynaptic form of plasticity that develops early during alcohol exposure, whereas inputs arriving via the external capsule (EC) along the lateral boarder of the BLA express postsynaptic potentiation later in alcohol exposure. These data suggest that this initial presynaptic facilitation of ST inputs may be crucial for development of the behavioral and physiologic characteristics that develop during prolonged ethanol exposure. However, little is known about how specific inputs from distinct upstream brain regions are affected by chronic ethanol exposure or how these might independently influence anxiety during alcohol withdrawal. In the current NRSA proposal, we will examine inputs to the BLA from the medial prefrontal cortex (mPFC) and the agranular insular cortex (AI), which project to the BLA via these two anatomically distinct pathways. Thus, the overall goal of this training proposal is to understand whether the mPFC and/or AI inputs to the BLA undergo similar or unique synaptic alterations following chronic ethanol exposure/withdrawal, and whether they are necessary for the expression of withdrawal-induced anxiety-like behavior. Our central hypothesis is that early presynaptic facilitation of the ST- BLA from mPFC inputs is necessary for the subsequent neurophysiologic and behavioral consequences of chronic ethanol exposure and withdrawal. We will address this hypothesis through two Specific Aims.
In Aim 1, we will use DREADD technology to manipulate these BLA inputs at different times during chronic ethanol exposure and use a variety of anxiety assays including the elevated plus maze and light/dark box. Our hypothesis is that early facilitation of mPFC-BLA inputs during chronic ethanol exposure mediate withdrawal- induced anxiety-like behavior. Using these same animals, in Aim 2, we will employ whole-cell patch clamp electrophysiology and optogenetics to characterize the temporal physiological relationships between pre- and postsynaptic potentiation of ST- and EC-BLA synapses following chronic ethanol exposure and withdrawal. The identification of specific brain regions might lead to potential novel targets for more effective treatments of alcohol withdrawal-induced anxiety in the clinical setting.

Public Health Relevance

Alcohol withdrawal-induced anxiety has been reported as a common, underlying cause of relapse in alcohol- dependent individuals. A comprehensive understanding of changes that occur in the brain as a result of chronic alcohol consumption, especially in brain regions that regulate emotional responses such as the basolateral amygdala, is critical for developing treatments for alcohol-dependent patients. The proposed studies will seek to advance the current understanding of the neural circuitry involved by using rodent models to identify upstream brain regions as potential targets for developing treatments for human alcohol abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AA025514-01A1
Application #
9396075
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Liu, Qi-Ying
Project Start
2017-08-01
Project End
2020-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157