Early childhood adversity accounts for over 30% of all mental illnesses and is associated heightened risk for later psychopathology. In particular, recent reports suggested that exposure to early life stress (ELS) increases an individual’s vulnerability to substance abuse, especially of nicotine. They showed that people with early childhood adversity had a 3.5-fold greater likelihood of smoking than those without childhood abuse. Several studies have found mechanisms in the brain underlying the strong correlation between ELS and smoking behaviors such as alterations of brain chemicals including dopamine (DA) and serotonin. However, the drug treatments that were developed to function in this manner have many side effects and remain ineffective for certain individuals.
To date, the specific intervening mechanisms for ELS-induced vulnerability to nicotine consumption remained unexplored, although the investment into identifying therapeutic targets continued. This lack of clarity is largely due to our limited knowledge of the specific adaptations in the circuitry (connections) within the brain leading to increased vulnerability to nicotine consumption that can be attributed to ELS. Therefore, the identification of specific connections in the brain underlying ELS-induced increased vulnerability to nicotine consumption is a critical step for the development of therapeutics of nicotine addiction.
Here, we propose a multi-faceted approach to tackle this issue. We will focus on the lateral septum (LS), an area of the brain that governs feelings of reward and motivation. The LS is thought to be an important component for regulating ELS-induced vulnerability to nicotine consumption for three reasons. First, traumatic stress triggers a increase of LS immediate early gene (IEG) induction, indicating that the LS is a critical brain region for processing the stressful episode. Second, the LS physically connects to the prominent central site of nicotine action and its influence on motivation (ventral tegmental area or VTA). Third, the LS is known to have an abundance of nicotinic acetylcholine receptors (nAChRs) which mediate the nicotine’s action. Despite of these issues, the LS has been largely neglected for a long time in nicotine addiction research.
In this proposal, we aim to dissect the LS circuitry in the brain underlying ELS-induced vulnerability to nicotine consumption using multiple cutting-edge techniques including optogenetics, viral mediated tracing, and single cell level molecular screening methods. Understanding the circuit-specific brain adaptations and underlying molecular changes that occur during nicotine consumption will provide invaluable insights in understanding and treating nicotine addiction and can serve as a basis for studies for many other early childhood adversity-induced psychiatric diseases.