Mapping stress-regulated GPCRs in prefrontal cortex

Mood disorders are prevalent conditions, but efforts to develop new treatments are hindered by an incomplete understanding of their molecular and circuit-level mechanisms.

At the circuit level, disrupted neuromodulatory signaling and synapse loss in medial prefrontal cortex (mPFC) are key pathophysiological hallmarks in depression. Conversely, ketamine and other antidepressants rescue stress-induced spine loss and cell assembly deficits.

Ketamine has multifaceted circuit effects, but recent studies indicate that somatostatin-expressing (Sst+) interneurons are a key neuromodulatory hub, critical to its antidepressant effects.

At the molecular level, mPFC circuit dysfunction may be mediated in part by G-protein coupled-receptors (GPCRs), which sense and amplify extracellular signals. Alterations in GPCR-mediated function underscore many psychiatric diseases and serve as major drug targets. I propose to merge molecular pharmacology to microcircuit complexity to characterize GPCR-mediated neuromodulation.

With this research project I will combine state-of-the art techniques to characterize how neuronal-type enriched GPCRs modulate PFC circuit function at single-neuron and populational levels to rescue stress-sensitive, depression-related behaviors.

My hypothesis is that dysfunctional GPCR signaling in Sst+ interneurons underlies stress effects on depression-related behaviors and restoring their function with Sst-enriched GPCR-targets can lead to antidepressant effects.