Combining Designer Receptors Exclusively Activated by Designer Drugs and Resting-State Functional Magnetic Resonance Imaging to study the Salience Network in Nonhuman Primates.

Abstract

The Salience Network (SN) is a large-scale brain network identified originally in human resting-state functional magnetic resonance imaging (rs-fMRI) studies. Large-scale brain networks display patterns of highly coherent activity. The SN identifies significant attention-grabbing stimuli from both external and internal sources, allowing for the effective allocation of cognitive resources. Importantly, aberrant functional coupling in the SN has been implicated in numerous neuropsychiatric disorders. Given the limitations to invasively probe brain connectivity in humans, the studies in this body of work attempt to combine molecular and neuroimaging approaches to study the SN in nonhuman primates. Specifically, a combination of viral expression of Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) and rs-fMRI was employed. Firstly, the use of viral vectors to express DREADDs (as well as optogenetic receptors) in key circuits was evaluated in nonhuman primates. Viral vectors were successfully expressed in several target regions relevant to the study of the SN. However, there were also false negatives–regions that failed to express the virus that should have, based on prior anatomical work. This study revealed both the utility of this method for transduction and crucial virus serotype-specific findings. Secondly, deschloroclozapine (DCZ) and clozapine, chemogenetic DREADD actuator ligands, were evaluated for their impact on rs-fMRI in naive subjects before DREADD expression. Findings demonstrated that low-dose DCZ is a promising ligand for DREADD-based studies. Lastly, modulating functional connectivity via DREADD expression in a core region of the SN (anterior cingulate cortex) revealed the complexities of this approach and the need for additional studies. Moreover, the successful combination of chemo-fMRI in nonhuman primates would allow further investigation of circuit mechanisms in preclinical models.