Cellular and Functional Role of Melanin-Concentrating Hormone in the Lateral Septum

Abstract

Melanin-concentrating hormone (MCH) is a neuropeptide exclusively produced in the lateral hypothalamus and zona incerta with diverse functions including prominent effects on energy balance and anxiety that can impact the development of obesity and mood disorders. MCH neurons project to many brain regions, and MCH can have site-specific effects on neuronal activity and behavioural outcomes. Thus, in addition to global manipulations of MCH function, it is important to characterize the role of MCH at specific target sites. The lateral septum (LS) possesses MCH receptors and receives the strongest projection from MCH neurons. However, the function of MCH in the LS is not known. The LS has known roles in the regulation of feeding and anxiety-related behaviours, and such overlapping functions with those of MCH suggest the LS is a key target site of MCH in the brain. This thesis focused on understanding the role of MCH in the LS by 1) determining the mechanisms of MCH action on LS cells; 2) defining the behavioural significance of MCH on feeding and anxiety-like behaviour in the LS; and 3) elucidating the properties of MCH release and action within the LS. We found that MCH directly inhibited cells in the lateral LS through a novel chloride-mediated mechanism (Chapter 2), and this inhibition promoted a context-dependent increase in feeding behaviour (Chapter 3). Furthermore, MCH was released and inhibited nearby cells predominantly separate from those that were directly innervated by MCH neurons, revealing three distinct populations of LS cells within this circuit. The activation of these parallel glutamate and MCH-mediated circuits increased feeding and decreased anxiety-like behaviour, respectively (Chapter 4). Together, we have shown that the LS is an important target of MCH neurons and that MCH and glutamate interactions are important for mediating behavioural outcomes. This work will improve our understanding of MCH action in the brain, as well as identify novel neural mechanisms underlying feeding and anxiety-like behaviour.

Part of CIRS Nexus · Curated by Lauren Lowenstein, The Biotoxin Lady

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