Modulation of stress-related behaviour by preproglucagon neurons and hypothalamic projections to the nucleus of the solitary tract.

Stress-induced behaviours are driven by complex neural circuits and some neuronal populations concurrently modulate diverse behavioural and physiological responses to stress. Glucagon-like peptide-1 (GLP-1)-producing preproglucagon (PPG) neurons within the lower brainstem caudal nucleus of the solitary tract (cNTS) are particularly sensitive to stressful stimuli and are implicated in multiple physiological and behavioural responses to interoceptive and psychogenic threats. However, the afferent inputs driving stress-induced activation of PPG neurons are largely unknown, and the role of PPG neurons in anxiety-like behaviour is controversial. Through chemogenetic manipulations we reveal that cNTS PPG neurons have the ability to moderately increase anxiety-like behaviours in mice in a sex-dependent manner. Using an intersectional approach, we show that input from the paraventricular nucleus of the hypothalamus (PVN) drives activation of both the cNTS as a whole and PPG neurons in particular in response to acute restraint stress, but that while this input is rich in corticotropin-releasing hormone (CRH), PPG neurons do not express significant levels of receptors for CRH and are not activated following lateral ventricle delivery of CRH. Finally, we demonstrate that cNTS-projecting PVN neurons are necessary for the ability of restraint stress to suppress food intake in male mice. Our findings reveal sex differences in behavioural responses to PPG neural activation and highlight a hypothalamic-brainstem pathway in stress-induced hypophagia.