Dissecting the role of caudal brainstem corticotropin-releasing hormone signalling and preproglucagon neurons in anxiety-related sympathoexcitation

For decades the comorbidity of affective disorders and cardiovascular disease (CVD) was simply attributed to poorer health choices, including smoking and obesogenic diets.

While this is part of the cause, evidence suggests there is a physiological link between affective disorders and CVD, likely at the level of the brain. However, the neural circuits underlying this link remain virtually unexplored.

The neuropeptides corticotropin-releasing hormone (CRH) and glucagon-like peptide-1 (expressed by preproglucagon [PPG] neurons) are involved in autonomic control and stress.

This fellowship project uses transgenic mice and state-of-the-art neuroscience tools to investigate the importance of CRH and PPG neurons in cardiovascular responses to stress.

Experiments test the hypothesis that acute stress activates hypothalamic paraventricular nucleus (PVN) CRH neurons leading to sympathoexcitation via recruitment of NTS(PPG) neurons and long-term, persistent recruitment of this PVN(CRH)→NTS(PPG) circuit contributes to cardiovascular pathology following chronic stress.

Optogenetics, rabies virus-mediated tracing, chemogenetics, patch-clamp electrophysiology, and ex vivo calcium imaging, will reveal 1) the role of NTS-projecting PVN(CRH) neurons and NTS(PPG) neurons in cardiovascular responses to acute stress and 2) how chronic psychosocial stress leads to cardiovascular pathology.

The results may explain the comorbidity of CVD and affective disorders and could reveal novel therapeutic targets and preventative strategies.