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PhD Thesis: Gregory Parks

Dissertation Abstract:
Regulation and Functions of the Melanin-Concentrating Hormone Neuropeptide System

By Gregory Scott Parks
Doctor of Philosophy in Biological Sciences
University of California, Irvine, 2012
Professor Olivier Civelli, Committee Chair

Melanin-Concentrating Hormone, MCH, is hypothalamic neuropeptide that is expressed almost exclusively in the lateral hypothalamus and zona incerta. MCH activates two G protein-coupled receptors (GPCRs), MCHR1 and MCHR2, but only MCHR1 is expressed in rodents. It is well established that MCH regulates feeding and metabolism, but more recently it has been demonstrated to be involved in a wide range of other physiological functions such as reward, endocrine signaling, and the regulation of emotional state. While the physiological functions and downstream effects of MCH have been extensively investigated, relatively little is known about how the MCH system is controlled and regulated.

In order to gain insight into how activity of MCH neurons is controlled, we have identified eleven neuropeptide receptors which are expressed by a significant amount of MCH neurons. Of these, six are entirely novel and have never been described or hypothesized to interact with the MCH system. These findings strongly suggest that these neuropeptide receptors represent novel circuits which function to regulate the MCH system. Several of these receptors have been demonstrated to regulate similar physiological functions as the MCH, indicating that they may exert their effects at least partially by modulating activity of MCH neurons.

We have discovered and characterized an entirely novel circuit which regulates the MCH system. Most MCH neurons were found to express the histamine 3 receptor (H3R).  Using cre-lox technology, we generated a novel reporter line to aid identification of MCH neurons for functional analysis of this circuit. Histamine was found to inhibit MCH neurons in hypothalamic slices, an effect which persisted in the presence of TTX, indicating that it acts on postsynaptic H3R. This effect was entirely blocked by a H3R antagonist and mimicked by a selective H3R agonist, indicating that histaminergic inhibition of MCH neurons is entirely mediated by H3R.

Finally, we have discovered that mice lacking MCHR1 are highly resistant to several types of chemically induced seizures. This finding strongly suggests that the MCH system may be involved in regulating seizure threshold.  Most strikingly, MCHR1 were found to be extremely resistant to pilocarpine induced seizures, a model for temporal lobe epilepsy, suggesting that the MCH system may be particularly important for these types of seizures. Taken together, this indicates that the MCH system may modulate susceptibility to seizures and that MCHR1 antagonists warrant investigation for potential anticonvulsant activity.