Alcohol use disorder (AUD) is one of the most co-occurring disorders among people seeking treatment for post-traumatic stress disorder (PTSD), a neuropsychiatric stress and anxiety-related disorder that often develops after experiencing traumatic or stressful life events. Many PTSD patients tend to use alcohol in an attempt to ameliorate the debilitating symptoms. However, repeated excessive alcohol consumption often leads to the development of an AUD that appears to worsen PTSD symptoms. Therefore, there is a critical need for systemic studies on the neurobiological underpinnings of the interactions between these disorders to tailor effective therapeutic strategies to reduce alcohol abuse and dependence in PTSD patients. The amygdala is a critical neural substrate of both aversive and appetitive behaviors. Recent studies in mice have indicated that distinct subpopulations of neurons within the amygdala are differentially responsible for the activation and inhibition of fear memory. In addition, divergent ensemble activity from these subpopulations seems to mediate positive or negative valence coding. The amygdala is also directly affected by a variety of acute and chronic stressors as well as addictive substances, which can lead to sensitization of its reactivity. Particularly, it has been shown that patients with comorbid AUD and PTSD exhibit hyper-reactivity of the amygdala upon presentations of both aversive/distressful stimuli and alcohol cues. These intriguing findings suggest that the amygdala is a key structure mediating the interactions between AUD and PTSD; however, molecular, cellular and neural circuit mechanisms underlying amygdala dysfunction in AUD and PTSD comorbidity are not well understood. We will employ a combination of a Cre-driver mouse line, optogenetic neural circuit manipulation, and in vivo electrophysiological recording techniques to examine: 1) whether the experience of traumatic stress alter the neuronal ensemble code in a specific Fear-Off (Dkk3/Ntsr2/Thy1+) neuronal subpopulation in the basolateral amygdala during the formation of alcohol-context associations, and 2) if stress-enhanced alcohol- context associations are mediated by changes in functional interactions between the amygdala Thy1+ neuronal projections and the nucleus accumbens (NAcc) - a central structure of substance addiction - which can consequently lead to the escalated alcohol use. The findings of these studies will provide the first insight into the crucial roles of distinct subpopulations of amygdala neurons in stress-induced alcohol seeking behavior. The results will also shed light on how the amygdala interacts with the NAcc to lead to the development of alcohol addiction. Ultimately, the findings of these studies may provide new ways for developing diagnostics and novel therapeutic interventions for AUD and PTSD patients. !!

Public Health Relevance

Alcohol use disorder (AUD) is one of the most co-occurring disorders among post-traumatic stress disorder (PTSD) patients. The proposed research will focus on the amygdala, a core brain area for fear, stress and substance abuse, and investigate how traumatic stressful experience and subsequent alcohol exposure alter the neuronal ensemble codes in the amygdala and how stress-induced alcohol seeking behavior is mediated by changes in the amygdala ensemble codes and functional interactions between the amygdala and the nucleus accumbens, a key locus for addiction. This work may provide novel insights into therapeutic intervention for the alleviation and treatment of comorbid AUD and PTSD. !!

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA027450-02
Application #
9918818
Study Section
National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
Program Officer
Patterson, Jenica Dawn
Project Start
2019-04-20
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478