Title: Dissecting and modifying temporal dynamics underlying major depressive disorder Multiple human imaging studies have described aberrant spatiotemporal dynamics in specific brain networks across subjects with major depressive disorder. Furthermore, rodent studies have identified dysfunctional synchrony across cortical limbic circuits in genetic and stress- induced models of major depressive disorder. Nevertheless, it remains to be clarified whether these observed changes in neural dynamics play a causal role or simply reflect (i.e., correlate with) the behavioral-state observed in major depressive disorder. Several major challenges to addressing this question exist. 1) The brain synchronizes dynamics across multiple timescales. Rodent studies classically monitor dynamics at the millisecond time scale (reflecting circuits), and human studies typically monitor brain dynamics at the seconds time scale (reflect circuit and network level activity). 2) Rodent studies are generally limited in their ability to monitor large-scale activity from many brain regions concurrently, while human imaging studies observe activity across the whole brain. 3) To our knowledge, few approaches/models integrate changes in cell-type specific gene expression implicated in depression to changes in circuit and network- specific brain dynamics. 4) Techniques which directly manipulate brain dynamics (neural synchrony and cross-frequency coupling) have yet to be largely implemented throughout the rodent research community. To address these challenges, we propose to perform multi-circuit in vivo neural recordings in the two widely used rodent models of depression. We will then utilize machine learning to determine the spatiotemporal dynamic alterations that are shared between the two models. Next, we will test whether cellular molecular manipulations implicated in major depressive disorder are sufficient to induce the same spatiotemporal dynamic alterations. Finally, we will verify that these spatiotemporal dynamics are causal by directly inducing and suppressing them and measuring their impact on behavior. This strategy will yield an unprecedented understanding of how altered dynamics within specific brain circuits contribute to depression.
Many cortical and limbic brain regions including prefrontal cortex, amygdala, hippocampus, and thalamus work together to coordinate emotional, social and cognitive function in health and disease. In this study, we will discover the network-level mechanisms whereby fast interactions between these brain regions become altered in major depressive disorder. The discovery and validation of this ?depression brain-state? may facilitate the development of new therapeutics that ameliorate depression by directly modulating altered neural dynamics in the brain.
