Stress resulting from chronic uncontrollable pain has been directly linked to numerous mental health diseases. In patients exhibiting chronic pain the incidence of depression, anxiety, and addiction are a major concern and a growing health problem. The locus coeruleus (LC) noradrenergic (NE) system has been implicated in numerous affective disorders including stress-induced anxiety and depression-like behavioral states. Additionally, some have reported that the LC-NE system is also a critical component for integration of the pain neuraxis of ascending transmission and descending modulation. In this R21 proposal we focus on further dissection of this putative convergent role of noradrenergic neural circuits by examining the circuits and receptor-mediated signaling pathways involved in aversion, anxiety, and pain behavior using pharmacological and optogenetic approaches. The central hypothesis of this research proposal is that the LC-amygdala circuit is a key site of convergence for the coordination of the negative affect in response to pain. In order to better understand the role of this system in behavior we propose 2 aims. 1) To dissect the function of the locus coeruleus (LC) - Amygdala neural circuits in the control of aversive and pain-like behavioral responses. Using optogenetic, pharmacological, and behavioral approaches we will selectively express ChR2/NpH3.0 and stimulate and/or inhibit LC-noradrenergic and CeA-CRF neurons determine how cell-type specific activation or inhibition of these neurons are mediate aversion, anxiety, and chronic pain-like states in mice. 2) To determine whether noradrenergic activation of G-protein and/or arrestin-mediated signal transduction in the amygdala is sufficient for aversive and anxiety-like behaviors by using and engineering a novel optically sensitive biased G- protein coupled receptors. Together, this project and the experiments described could provide novel and important information about noradrenergic function and the intersection of negative affect and pain.
Achieving a more complete understanding of the neural circuits, receptors and signal transduction pathways in the mammalian brain is crucial for further development of effective therapeutic treatments and the identification of novel drug targets for pain-induced affective disorders including anxiety and addiction. The studies here have the potential to open new pharmacological avenues for targeting the noradrenergic system for pain and psychiatric illnesses.
