Dissection of the anxiety suppression circuitry

Stanford University, Stanford CA

Investigators

Linked publications, trials & patents

Abstract

? DESCRIPTION (provided by applicant): Avoidance of potential threats is highly adaptive, and decreases unnecessary exposure to risks. However, excessive anxiety and fear leads to anxiety disorders, which impact many aspects of life, from the interpersonal to professional spheres. Although each anxiety disorder has different symptoms, they all share a core feature: mal-adaptive expression of high levels anxiety. Here, we will study how the brain suppresses anxiety. Prior studies showed the amygdala is largely responsible for generating high anxiety and fear, while the ventral medial prefrontal cortex (vmPFC) decreases these behaviors, possibly by inhibiting amygdala output. Indeed, in humans higher vmPFC activation correlates with lower amygdala activation and decreased anxiety. These data suggest the vmPFC-amygdala pathway may decrease anxiety and fear, but they rely on correlative measures, and can't directly test this hypothesis. I used optogenetics to directly test if the vmPFC-amygdala projection suppresses anxiety and fear. Remarkably, optogenetic activation of the vmPFC-amygdala pathway robustly inhibits innate anxiety and learned fear, while inhibition of this pathway increases anxiety. Intriguingly, these behavioral effects were mediated by a poorly studied region of the amygdala called the basomedial amygdala (BMA), as direct activation of the BMA also decreases anxiety. Now, I will map neural activity in the vmPFC-BMA circuit and dissect how activation of this circuit decreases anxiety. I will first investigate how vmPFC activiy affects the BMA in vitro (Aim 1), uncovering the microcircuit-level dynamics underlying our behavioral findings. Next, to map the activity of the vmPFC-BMA projection, I will monitor calcium transients in the vmPFC terminals in the BMA during exploration of control and anxiogenic environments (Aim 2), revealing how activity of this projection differs in animals with high and low anxiety. Lastly, during the independent phase, in Aim 3, I will use the skills acquired during the mentored year to characterize activity of the BMA and of its output projections during anxiety and fear. Completion of these aims will make me proficient in patch-clamping and in vivo calcium monitoring. I will learn these skills under the guidance of a mentoring (Profs. K. Deisseroth and R.C. Malenka) and consulting (Profs. A. Losonczy and M.R. Warden) teams who have pioneering experience in using these methods and in training other researchers to employ them. Combining these new skills with my prior expertise in vivo electrophysiology will ensure a methodologically strong foundation to launch an independent lab, while dissecting how the poorly-studied BMA decreases anxiety will provide new research avenues. Importantly, my mentors have a remarkable track record in training independent researchers. This project involves experiments ranging from microcircuit dissection to optogenetic control of behavior, and will give us critical insight about how the brain dampens anxiety, and how and when it fails to do so.