Characterizing the function of locus coeruleus and pericoerulear zone activity during avoidance behavior

PROJECT SUMMARY: This proposal is in direct response to NIMH’s Strategic Goal 1, which aims to define the brain mechanisms underlying complex behaviors by using new techniques and multidisciplinary approaches to characterize the cellular and circuit components contributing to brain organization and function. The primary goal of this training proposal is to dissect the neurocircuitry of local projections to the locus coeruleus (LC) from GABAergic pericoeruleus (peri-LC) neurons in hyperarousal and avoidance behaviors. The LC has been implicated in regulating these physiological and behavioral responses, with increased norepinephrine (NE) resulting in increased arousal levels and anxiety-like behaviors. Recent evidence from our lab suggests that peri- LCGABA neurons directly inhibit the LC and respond heterogeneously to different aversive stimuli. However, a direct relationship is not yet established between peri-LCGABA activity, LCNE activity, and aversive behavioral and physiological outputs. The central hypothesis of this proposal is that an ensemble of peri-LCGABA neurons coordinates LCNE activity during acute stress exposure in an anti-correlated manner, which induces stimulus- dependent changes in arousal levels and drives avoidance behaviors. The first aim of this training proposal seeks to characterize the modulation of noradrenergic LC activity by local GABAergic projections during acute stress exposure and examine the resulting changes in arousal levels and avoidance behaviors. Aim 1A uses in vivo 2-photon calcium imaging to observe LCNE and peri-LCGABA activity in response to acute stressors. Aim 1B uses clustering methods to assess the relationship between LCNE and peri-LCGABA activity during each stimulus, while Aim 1C reinforces the specific role of peri-LCGABA activity in the stress-induced modulation of LCNE activity by using a generalized linear model to predict LCNE activity from peri-LCGABA responses to aversive stimuli. The second aim of this training proposal seeks to determine how arousal levels and avoidance behaviors are coordinated by changes in LCNE and peri-LCGABA activity. Aim 2A uses designer receptors exclusively activated by designer drugs (DREADDs) in conjunction with 2-photon imaging to assess how tonic activation or inhibition of LCNE neurons alters avoidance behaviors and phasic LCNE activity in response to aversive stimuli. Aim 2B will modulate peri-LCGABA activity while monitoring LCNE activity using 2-photon imaging to evaluate how changes in peri-LCGABA activity during acute stress exposure alter LCNE activity, arousal levels, and avoidance behaviors. During my training period, I will learn to utilize cutting-edge biological and computational techniques to perform powerful, high-resolution investigations of neural circuitry, and I will gain valuable career development skills through a wide variety of scientific, intellectual, and mentored opportunities. This F31 proposal is specifically tailored to my needs and will allow me to fully engage in my individual development plan and prepare me for a successful career as an independent neuroscientist.