Linking reduced cell-specific inhibition to abnormal brain activity in chronic stress

Project Overview

Depression is a leading cause of disability, with a large proportion of treatment-resistant patients. Recent studies have implicated reduced brain inhibition in human depression from a specific neuron type (SST), and new pharmacology boosting this reduced inhibition led to antidepressant and pro-cognitive effects in rodents. However, establishing a direct link between reduced inhibition and altered brain activity in depression is not possible in living humans. Mild chronic stress in mice generates symptoms that mimic human depression, as well as reduced inhibition. We thus propose to test the link between reduced inhibition and stress-related changes in brain activity and behavior in mice. We will use large-scale recordings to identify key features of stress-related changes in neuronal firing at baseline and response during cognitive tasks and acute stressors (tail pinch). We will leverage optogenetic methods in mice to track specific neuron types, including SST. We will model the stress-related firing changes in detailed computational models to test if altered inhibition can account for the observed activity changes. We will then use optogenetics to activate the specific (SST) inhibitory neurons, guided by the model-estimated inhibition reduction, and test different activation intensities to recover the level of inhibition in the network. The project will thus overcome experimental limitations of probing depression mechanisms in living humans, using large-scale recordings and genetic tools in mice together with detailed computational simulations, to mechanistically link altered inhibition in depression to stress-related effects on brain activity and behavior. The project outcome will also serve to inform new depression treatments that target the inhibition mechanism.

Partners and Donors

Brain Canada, Weizmann Canada, and the Weizmann Institute of Science