Project Summary
Depression is a fundamentally episodic form of mental illness featuring discrete symptomatic periods, interposed between periods of wellness. My research team is working to define the neurobiological mechanisms driving the induction, remission, and recurrence of depressive episodes over time. These mechanisms remain poorly understood, especially at the level of neural circuits, but converging evidence indicates that synaptic remodeling in prefrontal cortical (PFC) neurons may play an important role. In fixed tissue studies, chronic stress has been associated with a reduction in the density of postsynaptic dendritic spines in the PFC, while antidepressants increase spine density, and some may act by targeting molecular signaling pathways that promote synapse formation.
Still, despite decades of pioneering work in this area, a mechanistic understanding of how stress-induced spine remodeling contributes to changes in PFC circuit function and depression-related behaviors over time remains elusive. Recently, we found that PFC synaptogenesis plays a critical role in sustaining antidepressant behavioral effects. Depression-related behavior was associated with targeted, branch-specific spine elimination in PFC pyramidal neurons. Ketamine reversed these effects by restoring lost spines and enhancing coordinated activity in multicellular ensembles that predict motivated escape behavior. PFC synaptogenesis was required for maintaining these effects, but not for their initial induction, suggesting that interventions aimed at enhancing the restoration of lost synapses or increasing their survival could be useful for augmenting and extending the durability of ketamine’s antidepressant effects. These results also suggest that chronic stress and antidepressants might be targeting specific synapses and circuits within the PFC, but the identity of these circuits remains unclear. Furthermore, the circuit-level mechanisms that initiate ketamine’s rapid antidepressant effects are not well understood.
Using optogenetic and two-photon (2P) imaging methods for visualizing and manipulating synaptic plasticity and unbiased circuit mapping approaches, we are investigating how spine remodeling in specific PFC projection neurons contributes to the induction and remission of anhedonia. We are especially interested in understanding how early life stress confers heightened stress sensitivity in adulthood—and whether these mechanisms differ in males and females, a question of special interest given the fact that depression is approximately twice as common in women. A second area of interest for my research team involves developing neuroimaging methods for informing diagnosis and predicting treatment response to neurostimulatory antidepressant interventions. In collaboration with other members of the HDRF task force, we hope that in the long term, these approaches will eventually identify new treatment targets for depression and inform treatment selection decisions.