Mind affects matter: Hindbrain GLP1 neurons link stress, physiology and behaviour

The brain responds rapidly to stressful stimuli by increasing sympathetic outflow, activating the hypothalamic–pituitary–adrenal axis and eliciting avoidance behaviours to limit risks to safety. Stress responses are adaptive and essential but can become maladaptive when the stress is chronic, causing autonomic imbalance, hypothalamic–pituitary–adrenal axis hyper-reactivity and a state of hypervigilance. Ultimately, this contributes to the development of cardiovascular disease and affective disorders, including major depression and anxiety. Stress responses are often thought to be driven mainly by forebrain areas; however, the brainstem nucleus of the solitary tract (NTS) is ideally located to control both autonomic outflow and behaviour in response to stress. Here, I review the preclinical evidence that the NTS and its resident glucagon-like peptide-1 (GLP1)-expressing neurons are prominent mediators of stress responses. This Lecture introduces the reader to the idea of good and bad stress and outlines the types of stress that engage the NTS and GLP1 neurons. I describe in particular detail the recent studies by myself and others aimed at mapping sources of synaptic inputs to GLP1 neurons and consider the implications for our understanding of the role of GLP1 neurons in stress. This is followed by a discussion of the contribution of brain GLP1 and GLP1 neurons to behavioural and physiological stress responses. The evidence reviewed highlights a potentially prominent role for GLP1 neurons in the response of the brain to acute stress and reveals important unanswered questions regarding their role in chronic stress