Alcohol-use disorders create a substantial global healthcare burden and it is imperative to identify novel therapeutic targets for their prevention and treatment. An interesting phenomenon with alcohol is the variability of consumption that occurs within individuals of the human population: some individuals drink alcohol in a controlled manner without developing dependence while others develop severe alcohol addiction. To understand this phenomenon of alcohol drinking variability, I propose to utilize a mouse model to investigate the neurophysiological basis of evidently distinct alcohol drinking behaviors. In C57BL/6J mice, an inbred mouse strain typically used to study high alcohol drinking behaviors, I have found a stable low alcohol drinking population. This mouse model provides me with a unique opportunity to investigate the neurophysiological mechanisms that underlie low and high alcohol drinking behaviors in a genetically identical mouse line without the challenge of variable gene background interactions. It is known that a hallmark of the progression of alcohol-use disorders is the dysfunction of dopamine (DA) neurons in the ventral tegmental area (VTA), an area critical to encoding the salience of drug stimuli. The VTA sends functionally diverse DA projections to two neural substrates highly involved in drug reward and motivation - the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC). In my preliminary studies, I demonstrate that the in vivo firing activity and burst activity of all VTA DA neurons are higher in low C57BL/6J alcohol drinkers compared to high alcohol drinking and EtOH nave mice. Furthermore, optogenetically mimicking this observed increase of VTA DA activity in previously high drinking TH-Cre mice reduced alcohol drinking behaviors. Because of the increasing body of evidence suggesting functional diversity of VTA DA neurons based on their target neural projection site, I hypothesize, based on my preliminary findings, that individual drinking differences in genetically identical mice arise from projection-specific (NAc versus mPFC) neuronal alterations of VTA DA neurons during alcohol consumption. My project will use a systematic approach to investigate the neural circuit functional roles VTA DA neurons have in generating different alcohol-drinking behaviors in C57BL/6J mice. To characterize projection-specific neuronal alterations between low and high alcohol drinking mice, I will use retrograde fluorescent beads to differentiate VTA DA neurons during in vitro electrophysiological investigations (Aim 1). I will then use innovative, circuit-specific optogenetic techniques to mimi the identified neurophysiological alterations observed in VTA neurons in order to drive specific alcohol drinking behaviors (Aim 2). This project will identify the neuroadaptations of VTA DA neuron firing underlying individual alcohol drinking behaviors. Furthermore, this proposed state-of-the-art neural circuit dissection will provide novel insight to identify more effective therapeuic target sites for alcohol-use disorders.

Public Health Relevance

Alcohol-use disorders have been identified as the second-most prevalent mental-health burden worldwide, highlighting the need for novel therapeutic strategies. This proposal will identify the neural circuit alterations that drive individual alcoho drinking behaviors. We anticipate that our findings will provide novel therapeutic targets, which are highly relevant to the mission of the NIH, particularly of the NIAAA.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Biomedical Research Review Subcommittee (AA)
Program Officer
Cui, Changhai
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code
Zhang, Song; Zhang, Hongxing; Ku, Stacy M et al. (2018) Sex Differences in the Neuroadaptations of Reward-related Circuits in Response to Subchronic Variable Stress. Neuroscience 376:108-116
Juarez, Barbara; Morel, Carole; Ku, Stacy M et al. (2017) Midbrain circuit regulation of individual alcohol drinking behaviors in mice. Nat Commun 8:2220
Calipari, Erin S; Juarez, Barbara; Morel, Carole et al. (2017) Dopaminergic dynamics underlying sex-specific cocaine reward. Nat Commun 8:13877
Juarez, Barbara; Han, Ming-Hu (2016) Diversity of Dopaminergic Neural Circuits in Response to Drug Exposure. Neuropsychopharmacology 41:2424-46
Friedman, Allyson K; Juarez, Barbara; Ku, Stacy M et al. (2016) KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun 7:11671
Wook Koo, Ja; Labonté, Benoit; Engmann, Olivia et al. (2016) Essential Role of Mesolimbic Brain-Derived Neurotrophic Factor in Chronic Social Stress-Induced Depressive Behaviors. Biol Psychiatry 80:469-478