Key pointsr Obesity is recognized as being multifactorial in origin, involving both genetic and environmental factors. The perinatal period is known to be critically important in the development of neural circuits responsible for energy homeostasis and the integration of autonomic reflexes.r Diet-induced obesity alters the biophysical, pharmacological and morphological properties of vagal neurocircuits regulating upper gastrointestinal tract functions, including satiety. Less information is available, however, regarding the effects of a high fat diet (HFD) itself on the properties of vagal neurocircuits.r The present study was designed to test the hypothesis that exposure to a HFD during the perinatal period alters the electrophysiological, pharmacological and morphological properties of vagal efferent motoneurones innervating the stomach.r Our data indicate that perinatal HFD decreases the excitability of gastric-projecting dorsal motor nucleus neurones and dysregulates neurotransmitter release from synaptic inputs and that these alterations occur prior to the development of obesity. These findings represent the first direct evidence that exposure to a HFD modulates the processing of central vagal neurocircuits even in the absence of obesity.Abstract The perinatal period is critically important to the development of autonomic neural circuits responsible for energy homeostasis. Vagal neurocircuits are vital to the regulation of upper gastrointestinal functions, including satiety. Diet-induced obesity modulates the excitability and responsiveness of both peripheral vagal afferents and central vagal efferents but less information is available regarding the effects of diet per se on vagal neurocircuit functions. The aims of this study were to investigate whether perinatal exposure to a high fat diet (HFD) dysregulated dorsal motor nucleus of the vagus (DMV) neurones, prior to the development of obesity. Whole cell patch clamp recordings were made from gastric-projecting DMV neurones in thin brainstem slices from rats that were exposed to either a control diet or HFD from pregnancy day 13. Our data demonstrate that following perinatal HFD: (i) DMV neurones had decreased excitability and input resistance with a reduced ability to fire action potentials; (ii) the proportion of DMV neurones excited by cholecystokinin (CCK) was unaltered but the proportion of neurones in which CCK increased excitatory glutamatergic synaptic inputs was reduced; (iii) the tonic activation of presynaptic group II metabotropic glutamate receptors on inhibitory nerve terminals was attenuated, allowing modulation of GABAergic synaptic transmission; and (iv) the size and dendritic arborization of gastric-projecting DMV neurones was increased. These results suggest that perinatal HFD exposure compromises the excitability and responsiveness of gastric-projecting DMV neurones, even in the absence of obesity, suggesting that attenuation of vago-vagal reflex signalling may precede the development of obesity.

Copper plays an essential role in the function and development of the central nervous system and exocrine pancreas. Dietary copper limitation is known to result in noninflammatory atrophy of pancreatic acinar tissue. Our recent studies have suggested that vagal motoneurons regulate pancreatic exocrine secretion (PES) by activating selective subpopulations of neurons within vagovagal reflexive neurocircuits. We used a combination of in vivo, in vitro, and immunohistochemistry techniques in a rat model of copper deficiency to investigate the effects of a copper-deficient diet on the neural pathways controlling PES. Duodenal infusions of Ensure or casein, as well as microinjections of sulfated CCK-8, into the dorsal vagal complex resulted in an attenuated stimulation of PES in copper-deficient animals compared with controls. Immunohistochemistry of brain stem slices revealed that copper deficiency reduced the number of tyrosine hydroxylase-immunoreactive, but not neuronal nitric oxide synthase- or choline acetyltransferase-immunoreactive, neurons in the dorsal motor nucleus of the vagus (DMV). Moreover, a copper-deficient diet reduced the number of large (>11 neurons), but not small, intrapancreatic ganglia. Electrophysiological recordings showed that DMV neurons from copper-deficient rats are less responsive to CCK-8 or pancreatic polypeptide than are DMV neurons from control rats. Our results demonstrate that copper deficiency decreases efferent vagal outflow to the exocrine pancreas. These data indicate that the combined selective loss of acinar pancreatic tissue and the decreased excitability of efferent vagal neurons induce a deficit in the vagal modulation of PES.

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AimsTo investigate whether there is a change in i) basal RAR activity and ii) their responses to SP, in rabbits with HAPE.MethodsExperiments were performed in anesthetized, artificially ventilated and thoracotomized rabbits. After routine cannulations, the RAR activity was recorded from cervical vagus nerve. Increasing doses of SP were administered into the right atrium in control rabbits (C) breathing room air (n= 6) and in rabbits with HAPE (n= 6). To produce HAPE, rabbits were placed in a high altitude simulation chamber ‐ 15,000 feet, 36 hrs. In both the groups, SP doses were repeated after the administration of NK‐1 receptor antagonist, CP‐96345 (400 nmol/kg, Pfizer, Croton, USA).ResultsThe basal RAR activity in C was 6.34±0.46 impulses/breath and it increased to 10.0±0.64 impulses/breath (p<0.001) in HAPE. SP stimulated the RARs in both the groups. However, in HAPE, the RARs were stimulated even by sub‐threshold doses of SP. CP‐96345 attenuated the RAR activity in C but not in HAPE. RAR response to SP in C and HAPE groups. RAR activity in % Groups After SP (μg/kg) 0.02 0.04 0.08 Before CP‐96345 C 16.22±4.99 28.44±7.00 48.95±9.92 HAPE 51.14±5.10 *** 54.83±3.77** Not done After CP‐96345 C 18.10±8.59 24.44±9.27 20.58±4.98 HAPE 38.55±8.87 56.50±6.11* Not done RAR activity expressed as a percentage of their respective basal activities. p<0.05, p<0.01 and p<0.001, compared with the corresponding response in C. Conclusion1.HAPE stimulates RARs. 2. The RARs do not show adaptation to this stimulus. 3. Endogenous SP released during HAPE sensitizes the RARs to exogenous SP. Funded by DIPAS, Delhi.

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