Combing resting state functional magnetic resonance imaging with chemogenetic modulation to characterize connectivity of the Salience Network

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Project Summary We are constantly confronted with numerous stimuli that compete for limited neural resources. A salient cue is one that is important and noticeable. The Salience Network (SN), a set of brain regions that are consistently co-activated across different conditions and at rest, is involved in the detection of attention-commanding external and internal stimuli for properly allocating cognitive resources. Importantly, abnormal activity in the SN is implicated in various psychiatric disorders, including schizophrenia, anxiety disorders and major depressive disorders. The main nodes of the SN are the Anterior Cingulate Cortex (ACC), the Anterior Insular Cortex (AIC), the ventral striatum, ventral tegmental area, dorsomedial thalamus and the amygdala. These regions are anatomically and functionally connected. The experiments described in this proposal will delineate how the anatomical and functional connectivity these brain regions allow them to operate as a network. This proposal combines chemogenetic circuit-based manipulations with resting state functional magnetic resonance imaging (rs-fMRI), which measures the changes in hemodynamic signals in the brain. The goal of Specific Aim 1) Characterize the effects of chemogenetic ligands on resting state functional connectivity prior to viral expression of designer receptors exclusively activated by designer drugs (DREADDs). Because chemogenetic ligands can bind to non-DREADD receptors, this type of characterization is essential before proceeding with DREADD manipulations. In Specific Aim 2, I will combine DREADDs activation with rs-fMRI to target the ACC to probe the relationship between rs-functional connectivity and direct anatomical connections of the Salience Network. Understanding the relationship between the anatomy and the functional activity of the Salience Network will have implications for neuroimaging studies that have identified specific abnormalities in the Salience Network. Furthermore, these studies could detail generalizable rules for the biological relationship between anatomical and functional connectivity across the brain, which will have implications for understanding healthy and disordered brain functioning with the potential for developing novel treatments. This award will allow me to gain important skills in my PhD research. I will learn complex techniques, learn to design experiments, perform statistical analyses, write scientific manuscripts, and practice oral presentations of these studies. All of these will help prepare me for an academic faculty position.