Perinatal High Fat Diet Exposure Alters Oxytocin and Corticotropin Releasing Factor Inputs onto Vagal Neurocircuits Controlling Gastric Motility

Perinatal high fat diet (pHFD) exposure is known to affect the development of vagal neurocircuits that control gastrointestinal (GI) motility and reduce stress resiliency in offspring. Descending oxytocin (OXT; prototypical, anti-stress peptide) and corticotropin releasing factor (CRF; prototypical, stress peptide) inputs from the paraventricular nucleus (PVN) of the hypothalamus to the dorsal motor nucleus of the vagus (DMV) modulate the GI stress response. However, how these descending inputs, and their associated changes to GI motility and stress responses, are altered following pHFD exposure are unknown. The present study used in vivo recordings of gastric tone and motility, in vivo assays of gastric emptying rates, in vitro electrophysiological recordings from brainstem slice preparations, and retrograde neuronal tracing experiments to investigate the hypothesis that pHFD alters descending PVN-DMV inputs, dysregulating DMV neuronal responses and subsequent gastric motility. Basal gastric emptying rates were found to be significantly delayed in pHFD rats, which also demonstrating an inability to mount an appropriate response to acute stress with a further delay in gastric emptying. Neuronal tracing experiments suggested that pHFD reduced PVNOXT neurons that project to the DMV but increased PVNCRF projections. Whole cell patch clamp recordings of DMV neurons demonstrated that, following pHFD, PVNCRF projections are tonically active, altering GABAergic inputs to DMV neurons. Lastly, blocking DMV CRF receptors in pHFD rats restored the appropriate gastric response to brainstem oxytocin application. Taken together, these results indicate that pHFD exposure leads to an upregulating of CRF inputs to the DMV, resulting in tonic CRF activation on the system and altering gastric motility. These results suggest that pHFD exposure leads gastric dysmotility, leading to a maladaptive gastric stress response and reduced stress resiliency.