PROJECT SUMMARY – New treatments for anxiety disorders are critically needed as numerous individuals fail to respond to current treatments. A more complete understanding of pathological anxiety at the molecular, cellular and circuit levels will provide a foundation for new treatment development. In this regard, nonhuman primate (NHP) models are invaluable for understanding mechanisms underlying maladaptive anxiety relevant to stress-related psychopathology. An important recent advance is the use of chemogenetic methods to modulate the primate amygdala. This work serves as an initial foundation for treatment development directed at the regulation of subcortical regions relevant to the pathophysiology of psychiatric disorders. As a translational bridge, our laboratory employs methods that provide an in-depth mechanistic understanding of brain alterations associated with extreme anxiety, including behavioral phenotyping, functional and structural neuroimaging, RNA sequencing and viral vector-mediated gene delivery. Findings from our chemogenetic studies using Designer Receptors Exclusively Activation by Designer Drugs (DREADDs) point to basolateral amygdala (BLA) neurons as potential treatment targets. The BLA processes threat-related information received from cortical and subcortical sources and transmits this information to the extended amygdala (central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis), which activates threat- related responses via its downstream targets. Within the BLA, inhibitory interneurons modulate the function and output of longer-range projecting excitatory neurons, which project to the Ce, other subcortical structures, and posterior orbitofrontal cortex (pOFC). The overall aims of this proposal are to further understand the implications of amygdala modulation in relation to treatment development focusing on BLA neurons. Neuroimaging and RNA sequencing (RNA-Seq) will provide insights into mechanisms related to therapeutic efficacy. Additionally, these studies will serve as a proof-of-concept to understand the feasibility of developing chemogenetic approaches for the future treatment of severe and refractory psychiatric disorders.

PROJECT NARRATIVE – New treatments for anxiety disorders are critically needed and a more complete understanding of pathological anxiety at the molecular, cellular and circuit level will provide a foundation for new treatment development. Using our non-human primate model of extreme anxiety, the proposed studies will use neuroimaging, molecular sequencing techniques and chemogenetics to understand the extent to which neurons in the basolateral amygdala can serve as treatment targets. Additionally, these studies will serve as a proof-of- concept to understand the feasibility of developing chemogenetic approaches for the future treatment of severe and refractory psychiatric disorders.