Stimulating a NTS to LC circuit elicits anxiety-like behavior and state-dependent autonomic output

Understanding how the brain integrates internal bodily signals to shape behavior is essential for characterizing the neural basis of interoception. Here, we investigate whether the nucleus of the solitary tract (NTS), a brainstem hub for viscerosensory input, communicates with the locus coeruleus (LC) to influence anxiety-like behavior. We utilized viral-induced optogenetics combined with electrocardiography and diaphragmatic electromyography to monitor heart rate and respiratory frequency. Prior to behavioral testing we photoactivated transduced NTS neurons either at their somata, or at their axonal terminals in the LC. Anxiety-related behaviors were assessed using the elevated plus maze (EPM) and novelty-suppressed feeding test (NSFT). Stimulation of the NTS somata, or their terminals in the LC, increased aspects of anxiety-like behaviors in the EPM and NSFT, including freezing time during the EPM and latency to eat in the center of the NSFT. Importantly, only NTS somal activation suppressed post-NSFT feeding. This suggests that the anxiety-like behaviors observed from activating NTS projections to the LC are not secondary to activating feeding circuits. Additionally, activation of NTS terminals in the LC decreased heart rate only following food deprivation. These findings reveal that the NTS to LC circuit enhances anxiety-like behavior and modulates cardiovascular dynamics state dependently, thereby identifying a likely brainstem pathway through which viscerosensory signals influence interoception. Significance Statement Interoception is a fundamental brain function that allows sensory signals from internal organs to shape perception and behavior. Despite its importance, the circuit mechanisms that distribute viscerosensory signals across the brain remain poorly understood. Here, we show that a projection from the nucleus of the solitary tract (NTS) to the locus coeruleus (LC) increases aspects of anxiety-like behavior and alters heartrate in a state-dependent manner. These findings causally identify a novel pathway that enables visceral signals to access a major neuromodulatory center and influence behavior and cardiovascular dynamics, thereby providing a foundational framework for understanding how interoceptive signals and circuits shape both anxiety and automatic output.