Friday, April 26, 2024
4/26/2024
Project Summary / Abstract Depression is a fundamentally episodic condition, but the mechanisms mediating mood state transitions are not well understood. In our prior work, we investigated how stress and antidepressant effects on synaptic remodeling influence changes in reward-seeking behavior and anhedonia, a core feature of depression. We found that synaptogenesis in prefrontal cortex (PFC) is required for sustaining antidepressant effects on behavior but not for initiating them. Here, we will investigate the molecular, cellular, and circuit-level mechanisms that initiate antidepressant effects on effortful reward-seeking and how they interact with synaptogenesis to generate durable changes in behavior. PFC circuits support reward-seeking behavior by mediating effort valuation computations, which integrate information about the magnitude of an anticipated reward and the expected effort required to obtain it. We have shown how nucleus accumbens (NAc)-projecting PFC cells encode and integrate information about reward- and effort-predictive cues and are critical for reinforcing decisions to expend effort to obtain rewards. We will test a model based on extensive preliminary data in which G protein-coupled receptor (GPCR) signaling in somatostatin (SST) interneurons initiates rapid- acting antidepressant effects on circuit function and behavior. Our efforts will leverage newly developed photopharmacological tools for manipulating GPCR signaling in specific circuit elements with unprecedented spatiotemporal precision, in conjunction with state-of-the-art 2P imaging and optogenetic tools for visualizing and manipulating spine dynamics and circuit function in the living PFC. Our central hypothesis is that Gi/o activation in SST cells initiates antidepressant effects on effortful reward seeking by disinhibiting PFC-NAc cells, restoring coordinated activity in PFC circuits and their capacity to encode reward- and effort-related signals. This, in turn, leads subsequently to the formation of new synapses, which are required for sustaining antidepressant effects over time. Finally, we will test a strategy for identifying SST-enriched Gi/o-coupled GPCRs and validating the most promising candidates as novel therapeutic targets, enabling synergistic effects on effortful reward seeking and anhedonia. Successful completion of our aims will open new avenues for developing synergistic treatment strategies that converge on disinhibition of PFC projection neurons and restoration of lost synapses in specific circuits.
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