Recent data demonstrate that noradrenergic neurons of the locus coeruleus (LC-NE) are required for fear-induced suppression of feeding, but the role of endogenous LC-NE activity in natural, homeostatic feeding remains unclear. Here, we found that LC-NE activity was suppressed during food consumption, and the magnitude of this neural response was attenuated as mice consumed more pellets throughout the session, suggesting that LC responses to food are modulated by satiety state. Visual-evoked LC-NE activity was also attenuated in sated mice, suggesting that satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Last, we found that activation of the LC to the lateral hypothalamus pathway suppresses feeding and enhances avoidance and anxiety-like responding. Our findings suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., satiety).

Accumulating evidence indicates that disruption of galanin signaling is associated with neuropsychiatric disease, but the precise functions of this neuropeptide remain largely unresolved due to lack of tools for experimentally disrupting its transmission in a cell typespecific manner. To examine the function of galanin in the noradrenergic system, widely thought to be an important source of galanin for modulation of emotional responses, we generated and crossed two novel knock-in mouse lines to create animals lacking galanin specifically in noradrenergic neurons (Gal cKO-Dbh ). We observed reduced levels of galanin peptide in pons, hippocampus, and prefrontal cortex of Gal cKO-Dbh mice, indicating that noradrenergic neurons are a major source of galanin to those brain regions, while midbrain and hypothalamic galanin levels were comparable to littermate controls. In these same brain regions, we observed no change in levels of norepinephrine or its major metabolite, suggesting that loss of galanin does not affect baseline noradrenergic synthesis or turnover. Gal cKO-Dbh mice had normal performance in tests of depression, learning, and motor-related behavior, but had an altered response in anxietyrelated tasks. Specifically, Gal cKO-Dbh mice showed increased marble and shock probe burying and had a reduced latency to eat in a novel environment, indicative of a more proactive coping strategy. Together, these findings indicate that noradrenergic neurons provide a significant source of galanin to discrete brain areas, and noradrenergic-specific galanin opposes adaptive coping responses.

Accumulating evidence indicates that disruption of galanin signaling is associated with neuropsychiatric disease, but the precise functions of this neuropeptide remain largely unresolved due to lack of tools for experimentally disrupting its transmission in a cell typespecific manner. To examine the function of galanin in the noradrenergic system, we generated and crossed two novel knock-in mouse lines to create animals lacking galanin specifically in noradrenergic neurons (Gal cKO-Dbh ). We observed reduced levels of galanin peptide in pons, hippocampus, and prefrontal cortex of Gal cKO-Dbh mice, indicating that noradrenergic neurons are a significant source of galanin to those brain regions, while midbrain and hypothalamic galanin levels were comparable to littermate controls. In these same brain regions, we observed no change in levels of norepinephrine or its major metabolite at baseline or after an acute stressor, suggesting that loss of galanin does not affect noradrenergic synthesis or turnover. Gal cKO-Dbh mice had normal performance in tests of depression, learning, and motor-related behavior, but had an altered response in some anxiety-related tasks. Specifically, Gal cKO-Dbh mice showed increased marble and shock probe burying and had a reduced latency to eat in a novel environment, indicative of a more proactive coping strategy. Together, these findings indicate that noradrenergic neurons provide a significant source of galanin to discrete brain areas, and noradrenergic-specific galanin opposes adaptive coping responses.

Noradrenergic neurons of the locus coeruleus (LC-NE) are known to play an important role in arousal, emotion, memory and cognition. In the present study, we use fiber photometry combined with chemogenetic and optogenetic approaches to demonstrate a previously unrecognized role for LC-NE neurons in the modulation of feeding. We show that endogenous activity of LC-NE neurons is enhanced while approaching food and suppressed during feeding. These changes in LC activity during feeding behavior are attenuated as mice approach satiety, demonstrating that nutritional state modulates LC responses to food. Direct activation of LC-NE neurons results in the suppression of feeding. Further, activation of an LC projection to the lateral hypothalamus also suppresses feeding. Together, these findings demonstrate a direct causal role for LC-NE activity in the modulation of feeding.