Dissecting stress modulation of pnVTA nociceptin peptide-mediated approach-avoidance behavior

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PROJECT SUMMARY: Chronic stress contributes to the pathogenesis and exacerbation of numerous disorders that frequently present with atypical motivation during reward-seeking behavior including substance use disorder (SUD), major depressive disorder (MDD), and anxiety. The extent to which motivation is disrupted by stress can depend on the form of stress exposure. Hence, it is critical to understand the neural circuitry regulating motivated behaviors become disrupted under diverse chronic stress states to improve our understanding of how these disorders develop, what makes some individuals more susceptible, and to identify more effective molecular therapeutic targets. Our laboratory previously reported that neurons producing the endogenous opioid peptide nociceptin in the paranigral ventral tegmental area (pnVTAPnoc neurons) act locally on nociceptin receptor (NOPR) to limit motivation for reward (Parker et al, Cell, 2019), while others have identified a role for nociceptin signaling in the orchestrated stress response. Preliminary data show that pnVTA nociceptin neurons are dynamically engaged to different extents by distinct stressors. The central hypothesis of this proposal is that stress differentially engages pnVTA nociceptin signaling to regulate the expression of motivated behaviors such as approach-avoidance. This proposal is in direct response to NIDA’s Strategic Goal 1 which aims to investigate circuitry contributing to brain functions “such as reward, motivation, decision-making…and stress reactivity, ” alongside examining a NIDA high priority target for SUD. Aim 1 will determine how diverse physical and psychological stressors alter the VTA nociceptin opioid system on a molecular and functional level. Aim 1A will evaluate how various stressors acutely and chronically alter VTA nociceptin/NOPR expression and neuron activity. Aim 1B uses a new genetically encoded biosensor for the nociceptin peptide (NOPLight), and head- fixed approach-avoidance (Ap-Av) behavioral models to determine how nociceptin release in the VTA is altered during Ap-Av decision making following stress exposure. Aim 1C uses prepronociceptin (Pnoc) conditional knockout line created in-house and optogenetics to manipulate VTA nociceptin peptide expression and activity following stress. Aim 2 will determine the anatomical and functional involvement of the lateral hypothalamus (LH) as an afferent input regulating pnVTAPnoc neuron activity in naïve and stressed states using electrophysiology and fiber photometry to simultaneously record LH terminal activity and nociceptin release in the VTA following chronic stress exposure. Leveraging these new approaches will enable us to provide brand new insight into this poorly understood system. During my training period I will learn to utilize cutting-edge techniques in order to perform powerful, high-resolution investigations of neuropeptide circuitry, and gain valuable career development training across a host of scientific, intellectual, and mentored programming. This F31 mechanism will allow me to pursue my individual development plan and prepare me for a career as an independent neuroscientist.