High-Fat Diet During the Perinatal Period Induces Loss of Myenteric Nitrergic Neurons and Increases Enteric Glial Density, Prior to the Development of Obesity.

Diet-induced obesity induces peripheral inflammation accompanied by a loss of myenteric neurons. Few studies, however, have investigated the effects of a high-fat diet (HFD) on either the development of myenteric neurons or prior to the occurrence of obesity. The present study assessed the effects of maternal HFD on the density and neurochemical phenotype of myenteric ganglia in the upper gastrointestinal tract. Sprague-Dawley rats were fed either a control or HFD (14% or 60% kcal from fat, respectively) from embryonic day 13; the fundus, corpus and duodenum were fixed thereafter at postnatal 2, 4, 6 and 12 weeks of age for subsequent immunohistochemical studies. While myenteric ganglion size did not differ throughout the study, HFD exposure decreased the number of nitrergic neurons by 6 weeks of age in all regions. This decrease was accompanied by a loss of PGP-immunoreactive neurons, suggesting a decline in myenteric neuronal number. HFD also increased myenteric plexus glial cell density in all regions by 4 weeks of age. These changes occurred in the absence of an increase in serum or gastric inflammatory markers. The present study suggests that exposure to a HFD during the perinatal time period results in glial proliferation and loss of inhibitory nitrergic neurons prior to the onset of obesity, suggesting that dietary alterations may affect gastrointestinal functions independently of increased adiposity or glycemic dysregulation.

Developmental regulation of inhibitory synaptic currents in the dorsal motor nucleus of the vagus in the rat.

Prior immunohistochemical studies have demonstrated that at early postnatal time points, central vagal neurons receive both glycinergic and GABAergic inhibitory inputs. Functional studies have demonstrated, however, that adult vagal efferent motoneurons receive only inhibitory GABAergic synaptic inputs, suggesting loss of glycinergic inhibitory neurotransmission during postnatal development. The purpose of the present study was to test the hypothesis that the loss of glycinergic inhibitory synapses occurs in the immediate postnatal period. Whole cell patch-clamp recordings were made from dorsal motor nucleus of the vagus (DMV) neurons from postnatal days 1-30, and the effects of the GABAA receptor antagonist bicuculline (1-10 µM) and the glycine receptor antagonist strychnine (1 µM) on miniature inhibitory postsynaptic current (mIPSC) properties were examined. While the baseline frequency of mIPSCs was not altered by maturation, perfusion with bicuculline either abolished mIPSCs altogether or decreased mIPSC frequency and decay constant in the majority of neurons at all time points. In contrast, while strychnine had no effect on mIPSC frequency, its actions to increase current decay time declined during postnatal maturation. These data suggest that in early postnatal development, DMV neurons receive both GABAergic and glycinergic synaptic inputs. Glycinergic neurotransmission appears to decline by the second postnatal week, and adult neurons receive principally GABAergic inhibitory inputs. Disruption of this developmental switch from GABA-glycine to purely GABAergic transmission in response to early life events may, therefore, lead to adverse consequences in vagal efferent control of visceral functions.

Inhibitory neurotransmission regulates vagal efferent activity and gastric motility.

The gastrointestinal tract receives extrinsic innervation from both the sympathetic and parasympathetic nervous systems, which regulate and modulate the function of the intrinsic (enteric) nervous system. The stomach and upper gastrointestinal tract in particular are heavily influenced by the parasympathetic nervous system, supplied by the vagus nerve, and disruption of vagal sensory or motor functions results in disorganized motility patterns, disrupted receptive relaxation and accommodation, and delayed gastric emptying, amongst others. Studies from several laboratories have shown that the activity of vagal efferent motoneurons innervating the upper GI tract is inhibited tonically by GABAergic synaptic inputs from the adjacent nucleus tractus solitarius. Disruption of this influential central GABA input impacts vagal efferent output, hence gastric functions, significantly. The purpose of this review is to describe the development, physiology, and pathophysiology of this functionally dominant inhibitory synapse and its role in regulating vagally determined gastric functions.