DMV extrasynaptic NMDA receptors regulate caloric intake in rats

Abstract

Acute high fat diet (aHFD) exposure induces a brief period of hyperphagia before caloric balance is restored. Previous studies have demonstrated this period of regulation is associated with activation of synaptic NMDA receptors (NMDARs) on dorsal motor nucleus of the vagus (DMV) neurons, which increases vagal control of gastric functions. Our aim was to test the hypothesis that activation of DMV NMDARs occurs subsequent to activation of extrasynaptic NMDA receptors (NMDARex). Sprague-Dawley rats were fed control or HFD for 3-5 days prior to experimentation.Whole cell patch clamp recordings from gastric-projecting DMV neurons, in vivo recordings of gastric motility, tone, compliance, and emptying, as well as food intake studies were used to assess the effects of NMDAR antagonism on caloric regulation. Following aHFD exposure, inhibition of NMDARex prevented the NMDARs-mediated increase in glutamatergic transmission to DMV neurons, as well as the increase in gastric tone and motility, while chronic NMDARex inhibition attenuated the regulation of caloric intake. Following aHFD exposure, the regulation of food intake involves NMDARs-mediated currents, which occur in response to NMDARex activation. Understanding these events may provide a mechanistic basis for hyperphagia and identify potential novel therapeutic targets for the treatment of obesity.

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

“…Rats were anesthetized with isoflurane (5% in air) before euthanized via administration of a bilateral pneumothorax. The brainstem was removed and sliced as previously described 4 . Briefly, the brainstems were excised quickly and mounted on a vibratome and submerged rapidly in cold (4°C) oxygenated Krebs’ solution.…”

“…A subset of 18 rats (n=9/diet from at least 2 litters) were randomly chosen to undergo gastric motility recordings as done previously 4 . Briefly, rats were fasted for 18 hours before experimentation with water available ad libitum.…”

Glial Modulation of Energy Balance: The Dorsal Vagal Complex Is No Exception

“…Moreover, the chronic blockade of brainstem extrasynaptic NMDA receptors blunted the HFD-induced delay in gastric emptying and significantly attenuated the homeostatic adaptation to HFD exposure for 3-5 days. Importantly, in the same study, it was shown that HFD maximally activated extrasynaptic NMDA receptors and that this effect could be mimicked by EAAT2 blockade in normal chow-fed rats [142]. Although the role played by DVC glial cells in short-term homeostatic adaptation to HFD has not yet been assessed, the mechanism revealed by Clyburn et al [142] at the DMNX glutamatergic synapses evidently suggests a decrease in astrocyte-mediated glutamate clearance as a plausible candidate to be explored in the near future.…”

“…Importantly, in the same study, it was shown that HFD maximally activated extrasynaptic NMDA receptors and that this effect could be mimicked by EAAT2 blockade in normal chow-fed rats [142]. Although the role played by DVC glial cells in short-term homeostatic adaptation to HFD has not yet been assessed, the mechanism revealed by Clyburn et al [142] at the DMNX glutamatergic synapses evidently suggests a decrease in astrocyte-mediated glutamate clearance as a plausible candidate to be explored in the near future. Further investigation into the possible involvement of gliotransmitters in this process is also warranted.…”

“…At this stage, it is not known whether an alteration in glial glutamate transporters and/or receptors and glutamate release takes place during the short-and long-term modulation of food intake and energy balance. Interestingly, short-term neuroplasticity has been reported within NTS-DMNX synapses and is mechanistically linked to early homeostatic adaptation to HFD [141,142]. More precisely, upon introduction to HFD exposure, rodents display an initial phase of overeating followed by a reduced food intake after 3-5 days to restore caloric balance.…”