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 usedin vivorecordings of gastric tone and motility,in vivoassays of gastric emptying rates,in vitroelectrophysiological 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 PVNOXTneurons that project to the DMV but increased PVNCRFprojections. Whole cell patch clamp recordings of DMV neurons demonstrated that, following pHFD, PVNCRFprojections 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.

Perinatal high fat diet (pHFD) exposure alters the development of vagal neurocircuits that control gastrointestinal (GI) motility and reduce stress resiliency in offspring. Stress causes a delay in gastric emptying that is, at least in part, vagally dependent. 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 gastric response to stress, but how these descending inputs are altered following pHFD exposure is 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 DMV neurons in brainstem slices, and retrograde tracing experiments to investigate the hypothesis that pHFD alters descending PVN-DMV inputs, dysregulating vagal efferent control of gastric functions.Basal gastric emptying rates were significantly delayed in pHFD rats (76.87±22.07min vs. 57.63±6.94min for control, p=0.0338; via two-tailed unpaired t-test), which were also unable to respond to acute stress (2hr restraint) with a further delay in gastric emptying (66.81±9.30 minutes) unlike control rats (66.07±10.79 minutes). Neuronal tracing experiments showed that pHFD reduced PVNOXT-DMV projections (10.5±6.6 control vs. 3.3±2.7 pHFD cells/section, p=0.0032; via two-tailed unpaired t-test) but increased PVNCRF-DMV projections (9.83±5.184 control vs. 19.85±12.89 pHFD cells/section, p=0.0158; via two-tailed unpaired t-test). In vitro whole cell patch clamp recordings demonstrated that OXT (100nM) application decreased the frequency of miniature inhibitory currents (mIPSCs) in pHFD but not control DMV neurons (65.18%±27.30 vs 97.89%±15.36 respectively, p=0.0101; via two-tailed unpaired t-test). Moreover, the CRF antagonist, astressin (1μM) increased mIPSC frequency in pHFD but not control DMV neurons (129.9±42.95% vs. 82.87±5.35% respectively, p=0.0411 via unpaired two-tailed t-test) suggesting pHFD PVNCRF-DMV inputs are tonically active. In vivo recordings of gastric tone showed that DMV microinjection of OXT (150pmols/60nl) decreased gastric tone in control rats, but increased tone in pHFD rats (control: -134.2±79.06 mg vs. pHFD: +142.2±244.5 mg, p=0.0070; via two-tailed unpaired t-test). Lastly, in pHFD rats, 4th ventricular astressin (10μg/2μl) application restored the appropriate gastroinhibitory response to OXT (baseline: +142.2±244.5 mg vs astressin: -75.67±271.67 mg, p=0.0015; via two-tailed paired t-test).Collectively, these results indicate that pHFD exposure upregulates, and tonically activates, PVNCRF-DMV inputs. Together with the reduced PVNOXT-DMV innervation, this leads to gastric dysmotility, maladaptive gastric stress responses and reduced stress resiliency in pHFD offspring. NIH DK111667 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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, cerebrospinal fluid extraction, 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. Key points Maternal high‐fat diet exposure is associated with gastric dysregulation and stress sensitivity in offspring. The present study demonstrates that perinatal high‐fat diet exposure downregulates hypothalamic–vagal oxytocin (OXT) inputs but upregulates hypothalamic–vagal corticotropin releasing factor (CRF) inputs. Both 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 the appropriate gastric response to OXT. The current study suggests that perinatal high‐fat diet exposure disrupts descending PVN–DMV inputs, leading to a dysregulated vagal brain–gut response to stress.