Major depressive disorder (MDD) is a highly prevalent and debilitating mood disorder that is diagnosed based on a mixture of symptoms, but anhedonia?decreased interest in rewarding activities?is a core feature. Anhedonia can be caused by an inability to experience pleasure or by a lack of motivation to work towards obtaining a reward. Every decision to exert effort to obtain a reward involves action valuation computations? essentially a cost-benefit analysis of whether the positive value of the expected outcome of an action outweighs the negative value of the expected effort associated with that action. The anterior cingulate cortex (ACC), a stress-sensitive region of prefrontal cortex (PFC), has been consistently implicated in action valuation computations across species. Whether and how dysfunctional action valuation computations drive anhedonic symptoms in stress-related psychiatric disease is unclear. While extensive, groundbreaking work has characterized the effects of stress on PFC glutamatergic circuitry, less is known about the role of local inhibitory circuitry in stress-induced depressive-like behaviors, despite substantial evidence for changes in the inhibitory system in MDD patients. This work will investigate the role of one cellular subtype, somatostatin (SST)-expressing interneurons, in driving both healthy reward-seeking and chronic stress-induced anhedonic behavior. Our hypothesis is that SST interneurons facilitate action valuation computations by dynamically regulating synaptic inputs to the ACC and that hyperactivity in SST cells disrupts this process in chronic stress states. To test this, we will record the activity of the ACC SST interneuron population through a chronically implanted optical fiber (fiber photometry) in awake, freely behaving mice performing an effortful reward-seeking task under normal and chronically stressed conditions. We will then optogenetically manipulate the activity of these cells to identify specific causal roles for SST interneurons in driving healthy and pathological reward processing. This investigation will fill a substantial gap in our understanding of stress-induced anhedonic behavior by focusing on a sparse but essential cell population that is understudied in the context of stress and depression. !
Identifying cellular circuit-level mechanisms by which stress disrupts brain function will provide a fundamental platform for understanding how brain circuitry is altered in mood disorders such as major depressive disorder and for developing novel targeted treatments. This work will investigate the impact of stress on somatostatin-expressing inhibitory interneurons in the prefrontal cortex and their contributions to reward-seeking behavior. By focusing on this important and understudied population of cells, these studies have the potential to open new avenues for developing novel diagnostic and therapeutic options for depression and other stress-related psychiatric disorders. !
