Perinatal High‐Fat Diet Exposure Alters the Development of Central Vagal Neurocircuits and Control of Gastric Functions

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Understanding how the development of vagal neurocircuits adapt to early life events, such as exposure to a perinatal high‐fat diet (pHFD), is crucial to addressing the dysregulation of feeding behaviors and the development of obesity often observed in these offspring. The excitability of dorsal motor nucleus of the vagus (DMV) innervating the stomach is regulated primarily by inhibitory GABAergic synaptic inputs, and our recent studies have shown that pHFD exposure increases this GABAergic synaptic inhibition (PMID: 28762595). Developmental studies have shown that the expression of GABAA receptor subunits change postnatally, with immature GABAA receptors expressing slower α2/3 subunits while mature GABAA receptor express faster α1 subunits. The purpose of this study was to test the hypothesis that the greater GABAergic inhibition observed following pHFD exposure is due to altered development of GABAA receptor subunits.To test this hypothesis, Sprague Dawley rats were exposed to a control diet (14% kcal from fat) or a HFD (60% kcal from fat) from embryonic day 13. The expression of GABAA α1–3 receptor subunit mRNA (GABRA1‐3. respectively) was assessed in adult (>P28) pHFD and control brainstems with qPCR. Whole cell patch clamp recordings from DMV neurons were made in thin (300μm) brainstem slices throughout postnatal development. The functional expression GABAA receptor subunits were assessed using benzodiazepines, which increase GABAA chloride channel open probability and duration. The effects of the partial positive modulator of α2/3 subunits, L838,417 (1μM), on miniature inhibitory postsynaptic current (mIPSC) decay kinetics were examined, and the effects of brainstem microinjection of L838,417 (1nmol/60nL) to inhibit in vivo gastric motility and tone were assessed, in pHFD and control rats.GABRA3, but not GABRA1 and GABRA2, mRNA expression was significantly higher in adult pHFD vs control rats (see Table). Both control and pHFD neurons responded to L838,417 with an increase in mIPSC decay kinetics at postnatal day 6 (P6) but, in contrast, significantly more pHFD neurons responded to L838,417 at P28 (see Table). Additionally, in vivo recordings of gastric motility and tone demonstrate that basal gastric motility is lower in pHFD rats, and preliminary data suggests L838,417 decreases gastric motility and tone in pHFD, but not control, rats (see Table)These data suggest that HFD exposure during critical developmental periods alters maturation of GABAA receptors on DMV neurons. Specifically, in addition to the to the α1‐subunit containing GABAA receptors present in control adult rats, pHFD prevented the loss of α2/3 subunit‐containing receptors. This contributes to the increased tonic synaptic inhibition of DMV neurons and decreased vagal efferent control of gastric functions. Understanding how early life adaptions affect development of central vagal neurocircuits is critically important to understanding why offspring exposed to pHFD have a differential responsiveness to medications, including benzodiazepines, as well as a predisposition to develop obesity.Support or Funding InformationNIH DK111667 to KNBThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.