Abstract: Alcohol is a psychoactive substance with dependence-producing properties. The harmful use of alcohol causes a large social and economic burden in societies. In 2012, about 3.3 million deaths, or 5.9% of all global deaths, were attributable to alcohol consumption. Our incomplete understanding of mechanisms underlying aversion and negative affect associated with alcohol addiction impedes finding new treatment strategies. 
Repeated cycles of excessive alcohol drinking and withdrawal often result in a serious aberrant behavior disorder, inclusive of elevated anxiety level, increased pain sensitivity, and response to stress. This negative affective state is believed to play a critical role in the development of alcohol dependence and relapse. However, the underlying neuronal bases have not been well explored. A goal of my laboratory is to identify mechanisms underlying alcohol addiction, particularly the brain regions, circuits and synaptic targets responsible for the aversive consequences of alcohol withdrawal. We and others have shown that the Lateral Habenula (LHb) is a key brain structure that responds to various aversive signals, including those triggered by alcohol use.  Research carried out in my lab has focused on exploring the role of LHb in alcohol dependence and its related repercussions. We made key discoveries regarding the effects of alcohol on the LHb, providing evidence for significantly increased activity and glutamatergic transmission in the LHb neurons in brain slices of alcohol-withdrawn rats, which is accompanied by significantly increased anxiety levels, pain sensitivity, and depressive-like behaviors. Importantly, these aberrant behaviors were diminished by suppression of activity or glutamatergic transmission in the LHb. Current work in my lab is to identify the role of synaptic inputs, particularly glutamatergic, to the LHb in the chronic alcohol drinking and withdrawal-induced neuronal and behavioral changes. The LHb receives significant synaptic inputs from the Globus Pallidus (GPh), and Lateral Hypothalamus (LH), among other brain regions. I will present some evidence supporting the hypothesis that the negative affective state in alcohol-withdrawn animals is associated with circuit-specific alterations in the glutamatergic projections to the LHb. I will present evidence supporting the working hypothesis that hyper-glutamatergic state in the LHb of alcohol-withdrawn animals is associated with alterations in projections to the LHb.  Using selective gene-based glutamatergic tract-tracing methods and quantitative ex-vivo slice recording, we will determine if the characteristic changes in LHb neurons during alcohol withdrawal are activated by candidate brain regions (e.g., GPh, LH) in a circuit-specific manner. I will also report data supporting the working hypothesis that voluntary alcohol consumption and alcohol-related aberrant behaviors are regulated by the inputs to the LHb, and that specific inputs may have unique contributions to specific aspects of these behaviors. We will use a dual-virus tract labeling strategy and chemogenetic approach to determine if modulation of specific glutamatergic afferents to LHb affects specific aspects of alcohol consumption and/or other aberrant behaviors in alcohol-withdrawn animals.
Given the growing evidence of the role of LHb in addictive behaviors, ultimately, the results of our work have the potential to improve the treatment of not only alcohol use disorder but also other addictive disorders.