The prevalence of obesity is increasing worldwide at a dramatic rate accompanied with an ominous increase in comorbid conditions including Type 2 Diabetes, heart disease, hypertension and hyperlipidemia. While it is increasingly accepted that obesity arises from a combination of environmental, genetic and epigenetic factors, several lines of evidence have suggested that the perinatal environment is critically important in the development of neural circuits responsible for energy homeostasis and the integration of autonomic reflexes regulating satiety. Vagally-mediated reflexes are recognized as playing a critical role in the neural mechanisms of energy homeostasis. We have demonstrated previously that exposure to a high fat diet (HFD) during the perinatal period (i.,e.., late pregnancy and lactation) decreases the excitability and responsiveness of central vagal motoneurons; in the present proposal, we will use a variety of electrophysiological, neurophysiological and physiological approaches to investigate the novel overarching hypothesis that perinatal exposure to a high fat diet arrests the developmental maturation of inhibitory neurocircuits within the brainstem.
Aim 1 will investigate the hypothesis that HFD exposure in the perinatal period induces permanent changes in brainstem neurocircuits by arresting the developmental decline in glycinergic synaptic inputs to dorsal motor nucleus of the vagus (DMV) neurons.
Aim 2 will investigate the hypothesis that the endogenous postnatal leptin surge is critical for the normal developmental maturation of inhibitory vagal brainstem neurocircuits, and Aim 3 will investigate the hypothesis that glucose regulates the excitability of DMV neurons from perinatal HFD, but not control, rats due to positive allosteric modulation of glycine receptors. The potential to examine permanent alterations in brainstem neurocircuitry resulting from diet- induced disruption of leptin neurotrophic signaling in the perinatal period brings with it the opportunity to uncover novel brain-gut neurosignaling pathways, the vulnerable time-points in brainstem neurocircuit development, and neuromodulation and plasticity within vagally- dependent reflexes which may be broadly applicable across autonomic homeostatic pathways.
Relevance to Public Health Obesity, and its associated co-morbidities, is a significant, and growing, public health problem. Many factors affect the development of obesity, but studies in both humans and laboratory animals have highlighted the perinatal period (pregnancy and lactation) as being critically important in the development of neural circuits that are responsible for the integration of reflexes co-ordinating food intake, satiety and energy balance. Our preliminary evidence suggests that maternal overnutrition during this period alters the development of brainstem neurocircuits controlling visceral functions, and the current proposal aims to use a variety of experimental approaches to define these alterations in nerve functions. Understanding the influence of diet exerts upon neurocircuit development may provide a mechanistic framework to explain the clinical and experimental observations that abnormal nutrition during the perinatal period predisposes offspring to develop obesity in later life.