Applications for whole-brain imaging in the study of depression- and opioid withdrawal-related behavior
Abstract
Mental illnesses like substance use and depression impact large portions of the population. Despite extensive research efforts, effective therapeutics for both substance use disorders and depression remain elusive. To fully address this crisis, we need to understand the complex nature of these disorders, which often involve networks that span the entire brain. This complexity underscores the importance of using comprehensive whole-brain imaging and analysis techniques in tandem with functional behavioral assays to develop therapeutic interventions and ultimately improve treatment outcomes. In the following studies, we investigate the relationship between depression- and drug-induced changes to whole-brain activity and resulting behavior. In the first two studies we identify networks of key structures that contribute to improved outcomes in treatment-resistant depression, and determine that these effects are likely modulated by direct input/output connectivity in identified network hubs. We next investigate how adolescent cannabis exposure impacts future withdrawal behaviors. We find that early life cannabis exposure reduces opioid-induced withdrawal symptoms but increases reinstatement of reward, and identify potential brain regions contributing to these results. In the final study, we demonstrate the ability to identify differentially activated populations during opioid withdrawal and specifically modulate them to improve behavioral outcomes. We apply whole-brain cFos imaging, immunohistochemical analysis, fiber photometry, and viral inhibition to demonstrate our ability to gain genetic access to key regions that go on to be important for opioid induced withdrawal behaviors. Together, these studies demonstrate the utility of employing whole-brain activity-based screens in behavioral studies that involve complex networks. These tools can be applied to a wide variety of questions related to drugs of abuse and neuropsychiatric conditions to identify novel target regions and customize treatment options. Future work applying these techniques could provide a key to developing improved therapeutics for a wide range of disorders.