ABSTRACT The dynamic regulation of arousal is fundamental for the flexibility of inward emotional state and outward behavior. Research has revealed that the noradrenergic locus coeruleus (LC) is an important hub of arousal encoding. The activity of the LC has an important influence on stress and anxiety, highlighting the involvement of arousal on these processes. Importantly, dysregulation of the LC has been implicated in a wide range of stress-related disorders that have characteristic changes in mood, anxiety, and arousal. Accordingly, further investigation is needed in unraveling the regulatory inputs onto LC that are critical for flexible regulation of arousal that may be impacted in stress-related disorders. Attention has recently shifted towards understanding how interoception of bodily cues might influence affective and behavioral states like anxiety. The nucleus of the tractus solitarius (NTS) is a major hub of interoception of these bodily cues. Notably, the awareness and manipulation of cardiac dynamics like heart rate drive changes in anxiety-like behavior in both humans and preclinical animal models. Accordingly, there is a compelling link between interoception and affective processes like anxiety that is conserved across species. However, little is known about how interoception influences arousal as an adaptive regulator of affective and behavioral states. Here, we propose investigation of noradrenergic inputs onto the LC from A2 neurons in the nucleus of the tractus solitarius (NTS→LCNA neurons) as an important link in interoception and arousal encoding. The anatomical connection between the NTS and the LC has been previously described, and the identity of A2 NTS neurons in this projection is supported by preliminary findings shown in this proposal. Strikingly, to our knowledge, the functional nature of this projection has never been investigated. We believe that this connection may serve as an important regulator of arousal based on interoceptive feedback that may be sensitive to stress as a source of LC dysregulation underlying changes in arousal and anxiety. This link may play an important role in shaping affective and behavioral states influenced by the LC that become dysregulated in stress-related disorders. To properly treat prominent and debilitating changes in arousal and anxiety in patients with stress-related disorders, it is important to understand dysfunction in interoception and arousal as functional domains driving these phenotypes. The experimental aims laid out in this proposal will investigate the NTS as an important regulator of LC arousal encoding following interoceptive feedback of heart rate. This work will unveil interaction between noradrenergic nuclei that has yet to be described, advancing our understanding of catecholamine signaling systems in the brain and their important neuromodulatory role in shaping affective and behavioral states. Finally, the multi-disciplinary approach and utilization of novel tech...