Investigation of the electrical and behavioral effects of chronic high-fat diet on leptin receptor neurons in the tuberomammillary nucleus in transgenic mice

Neuronal histamine generated by histaminergic neurons in tuberomammillary nucleus (TMN) in the posterior hypothalamus affects wakefulness by stimulating hypothalamic neurons. Whereas the underlying mechanisms are not yet fully understood, may be related to nutrition. Leptin has an important role in various obesity-related orexigenic and anorexigenic neural pathways. Thought that sleep and wakefulness problems experienced by obese people may be related to the leptin-histamine mechanism. Currently, no study demonstrating the relationship between histaminergic neurons and leptin receptor neurons (LepR) about food intake in TMN. In present study was intended to research the electrophysiological and behavioral effects of high-fat (HF) diet on LepR neurons in TMN region in LepR-Cre mice. Forty-eight LepR-Cre transgenic mice were used, some were fed a standard diet, and others on HF diet. For electrophysiological experiments, Cre-dependent GFP virus was intracranially injected into TMN, and electrical activity was recorded by patch-clamp technique. Behavioral effects were observed by open field and elevated plus maze tests. Chemogenetic activation/inhibition were performed by administration of N-Oxide intraperitoneally. For the statistical analysis, the GraphPad program was used. Firing frequency of LepR neurons was decreased significantly in mice fed with HF diet (p<0.0001). In behavioral tests, HF diet decreased the locomotor activity. Activation of LepR neurons decreases the locomotor activity and triggers the anxiety-like behaviors (p<0.01) in OFT. In this study, the electrophysiological and behavioral effects of LepR neurons in the TMN in mice fed with chronic HF diet were investigated for the first time. Our findings have shown that HF diet alters behavioral characteristics and neuronal activity in LepR-Cre transgenic mice.