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

Perinatal high fat diet (pHFD) exposure alters 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. How these descending inputs, and their associated changes to GI motility and stress responses, are altered following pHFD exposure are, however, unknown. The present study used retrograde neuronal tracing experiments, in vivo recordings of gastric tone, motility, and gastric emptying rates, and in vitro electrophysiological recordings from brainstem slice preparations to investigate the hypothesis that pHFD alters descending PVN-DMV inputs and dysregulates vagal brain-gut responses to stress. Compared to controls, rats exposed to pHFD had slower gastric emptying rates and did not respond to acute stress with the expected delay in gastric emptying. Neuronal tracing experiments demonstrated that pHFD reduced the number of PVNOXT neurons that project to the DMV, but increased PVNCRF neurons. Both in vitro electrophysiology recordings of DMV neurons and in vivo recordings of gastric motility and tone demonstrated that, following pHFD, PVNCRF-DMV projections were tonically active, and that pharmacological antagonism of brainstem CRF1 receptors restored the appropriate gastric response to brainstem OXT application. These results suggest that pHFD exposure disrupts descending PVN-DMV inputs, leading to a dysregulated vagal brain-gut response to stress. Summary Figure O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/517564v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@7ad6acorg.highwire.dtl.DTLVardef@a3cd04org.highwire.dtl.DTLVardef@1e8dc9borg.highwire.dtl.DTLVardef@eb7c7c_HPS_FORMAT_FIGEXP M_FIG C_FIG KeypointsO_LIMaternal high fat diet exposure is associated with gastric dysregulation and stress sensitivity in offspring C_LIO_LIThe present study demonstrates that perinatal high fat diet exposure downregulates hypothalamic-vagal oxytocin (OXT) inputs but upregulates hypothalamic-vagal corticotropin releasing factor (CRF) inputs C_LIO_LIBoth in vitro and in vivo studies demonstrated that, following perinatal high fat diet, CRF receptors were tonically active at NTS-DMV synapses, and that pharmacological antagonism of these receptors restored appropriate gastric response to OXT C_LIO_LIThe current study suggests that perinatal high fat diet exposure disrupts descending PVN-DMV inputs, leading to a dysregulated vagal brain-gut response to stress. C_LI