Leptin, a hormone that regulates appetite and energy expenditure, is increased in obese individuals, although these individuals exhibit leptin resistance. Obesity is characterized by sleep/wake disturbances, such as excessive daytime sleepiness, increased REM sleep, increased nighttime arousals, and decreased percentage of total sleep time. Several studies have shown that short sleep duration is highly correlated with leptin levels in both animal and human models. Arousal and REM sleep are regulated by the cholinergic arm of the reticular activating system, the pedunculopontine nucleus (PPN). The goal of this project is to determine the role of leptin in the PPN (and thus in obesity-related sleep disorders) by investigating the effects of leptin on single PPN neurons and on the PPN population as a whole. Whole-cell patch-clamp recordings and population responses were conducted on PPN neurons/slices in 9-17 day old rat brainstem slices. Population recordings showed a that leptin significantly potentiated the NMDA response of the PPN and could be blocked by a selective NMDA receptor antagonist and the leptin triple antagonist (TA), indicating that leptin enhances NMDA receptor function via leptin receptor signaling. Leptin increased glutamate-induced miniature excitatory postsynaptic currents, and decreased action potential (AP) amplitude, AP frequency and hyperpolarization-activated current (IH). Na+ current amplitudes were decreased in a dose response manner, suggesting a direct effect of leptin on Na+ channels. We also investigated the mechanisms by which leptin acts on PPN cells, utilizing TA and G-protein modulators. TA significantly reduced the blockade of INa and IH caused by leptin. Intracellular GDP-beta (a G-protein inhibitor) blocked the effect of leptin on INa but not on IH. Intracellular GTP-gamma-S (a G-protein activator) blocked the effect of leptin on both INa and IH. These results suggest that the effects of leptin on the intrinsic properties of PPN neurons are G-protein dependent and can be blocked by TA.
In conclusion, we hypothesize that leptin normally decreases activity in the PPN by reducing IH and Na+ currents, and that in states of leptin dysregulation (i.e., leptin resistance) this effect may be blunted, therefore causing increased arousal and REM sleep drive, and ultimately leading to sleep-related disorders.
|Commitee:||Childs, Gwen, Hayar, Abdallah, Skinner, Robert, Wessinger, William|
|School:||University of Arkansas for Medical Sciences|
|Department:||Neurobiology and Developmental Science|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 74/09(E), Dissertation Abstracts International|
|Keywords:||Arousal, Hyperpolarization-activated current, Leptin, Pedunculopontine nucleus, REM sleep, Sodium current|
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