KATP channel-dependent regulation of orexin neurons

Parsons, Matthew P. (2011) KATP channel-dependent regulation of orexin neurons. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

The hypothalamus performs many functions that are vital to an organism’s survival. These include, but are not limited to, the regulation and coordination of basic functions such as energy metabolism, the sleep-wake cycle and motivation. As obesity sleep disorders and/or addictions can result from the dysfunction of specific neural systems within the hypothalamus, it is important to understand the endogenous factors that regulate their activity. Neurons containing the orexin neuropeptides are located exclusively within the hypothalamus, send excitatory projections to arousal- and reward-related brain regions and have been implicated in numerous physiological and behavioral functions including feeding, sleep-wake regulation and reward and addiction. Neighbouring neurons containing melanin-concentrating hormone (MCH) also project throughout much of the neuroaxis and are implicated in similar functions. In the present thesis, I use electrophysiological recordings from acute hypothalamic slices as the main technique to investigate some of the endogenous regulators of orexin and MCH neurons. The present thesis shows that nociceptin/orphanin FQ (N/OFQ), an endogenous opioid, as well as lactate and temperature all act as regulators of orexin neuron activity. Interestingly, they all share a similar mechanism which involves the ATP-sensitive potassium (KATP) channel. These channels are metabolically-sensitive, are composed of a unique combination of subunits in orexin neurons and likely represent major contributors to the determination of orexin neuron activity. In contrast, MCH neurons were hyperpolarized by N/OFQ due to the activation of G-protein dependent inwardly rectifying potassium channels, while being insensitive to temperature changes. With regards to behavior, local injection of N/OFQ within the orexin and MCH field in vivo inhibits reward-related feeding whereas the temperature regulation of orexin neurons appears to mediate the hypophagia associated with fever. Through the identification of orexin neurons as both temperature and energy sensors, it is suggested by the present thesis that these neurons can gate brain activity according to energy supply while possessing the ability to adapt to the increased temperatures associated with infection. These data shed new light on the function of these neuronal systems and introduce the KATP channel as a critical regulator of orexin activity.

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