Synaptoproteomic Correlates of Stress-induced Acetylcholine Release in mPFC: Mechanistic Evaluation of Depression/Addiction Co-morbidity

Major depression is highly comorbid with tobacco smoking, the leading cause of preventable death in the United States. Nicotinic acetylcholine receptors are a key subgroup of receptors involved in ACh signaling and are the primary target of nicotine, the addictive component of tobacco smoke. Importantly, increased ACh signaling is implicated in the etiology of depression and chronic nicotine use has been shown to desensitize nicotinic receptors, suggesting that cigarette used by people with depression is a form of self-medication. Increases in ACh are also important in learning, memory, and attentional processes, suggesting that optimal levels of ACh are beneficial while excessive increases are detrimental to affective health. In this scenario, excessively increased ACh during stressful events would lead to a negative encoding bias, in which stronger encoding occurs, leading to increased depressive symptoms and given the co-morbidity with smoking, increased tobacco use. To test this theory, I used the GRAB ACh4.3 sensor to record ACh transients in mice subjected to inescapable shocks as part of learned helplessness testing and found that mice classified as helpless in a later active avoidance test had increased ACh signaling in the medial prefrontal cortex relative to resilient mice. Furthermore, although the number of male and female mice classified as helpless was similar, the increased ACh signaling was more robust in male mice, a potentially important sex difference. Because synaptic dysfunctions in the mPFC are a hallmark of stress response and depression, I plan to use synaptosomal proteomics and phospho-proteomics to discover the differences between helpless and resilient mice responsible for alterations in ACh signaling. The findings from the study, along with previous work detailing the nicotinic ACh receptor-associated proteome will more clearly elucidate protein-dependent mechanisms contributing to the comorbidity of tobacco smoking and depression.