Stress has been directly linked to numerous mental health diseases. In patients stress increases pain incidence of depression and anxiety, and are a major concern and a growing health problem. Anxiety disorders currently affect 18% of the US population. The locus coeruleus (LC) noradrenergic (NE) system has been implicated in numerous affective disorders including stress-induced anxiety. Additionally, some have reported that the LC-NE system is also a critical component for integration of stress-induced anxiety-like responses through its elevated activity and output to downstream circuits. In addition, recent evidence suggests that the central amygdala corticotropin-releasing factor positive cells may provide discrete input and regulation of the LC during stress. In this proposal we focus on further dissection of this putative convergent role of corticotropin-release factor and noradrenergic neural circuits in the LC, and its output to the basolateral amygdala by examining the circuits and receptor-mediated signaling pathways involved in aversion and anxiety. Here we use a multi-disciplinary approach that includes pharmacology, chemogenetics, optogenetics, and in vivo imaging approaches to define the specific cells, circuits, and receptors with the noradrenergic LC system that mediate stress-induced anxiety. The central hypothesis of this research proposal is that an LC- amygdala circuit is a key site of convergence for the coordination of the negative affective behavior in response to stress. In order to better understand the role of this system in behavior we propose 3 aims: 1) To dissect the function of the CeA - locus coeruleus (LC) ?neural circuit in the control of stress-induced aversion and anxiety- like behavioral responses; 2) to determine the necessity and sufficiency of the locus coeruleus (LC) ? BLA neural circuit, cell types, adrenergic receptors, and their signaling pathways in the control of stress-induced aversion and anxiety-like behaviors and 3) to determine and decode the network dynamics of specific BLA neuronal populations in response to stress, chemogenetic modulation upstream, and pharmacological disruption of receptor signaling. Together, this project and the experiments described could provide novel and important information about noradrenergic function and the intersection of negative affect and stress.
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 affective disorders including anxiety. The studies here have the potential to open new pharmacological avenues for targeting the noradrenergic system for psychiatric illnesses.
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