Identifier

etd-04132014-153657

Degree

Doctor of Philosophy (PhD)

Department

Biological Sciences

Document Type

Dissertation

Abstract

Obesity has become a widespread concern to human health largely over the past three decades. It is thought that obesity is associated with the over consumption of calorically dense diets. The rewarding value of food is mediated through the mesolimbic dopamine system, though is less understood how appetitive control circuits relay information to existing reward circuitry. The adiposity signaling hormone, leptin, is a critical mediator of food intake and fat storage. Leptin signaling, via the long form of the leptin receptor (LepRb), is predominantly carried out within the hypothalamus. Leptin action specific to the lateral hypothalamus area (LHA) modulates reward function via direct and indirect inhibition of reward circuitry. Here, I have identified a novel leptin receptor population within the LHA that co-expresses the inhibitory neuropeptide galanin (termed Gal-LepRb neurons). To investigate the physiological function of leptin through Gal-LepRb neurons, we selectively deleted LepRb in galanin neurons (referred to as Gal-LepRbKO mice). In a two-bottle-choice paradigm, I assessed nutrient selection for isocaloric lipid and sucrose solutions. Interestingly, Gal-LepRbKO mice demonstrated a significant preference for the sucrose solution and decreased lipid intake compared to controls. Moreover, Gal-LepRbKO mice displayed stronger motivation to work for a sucrose treat. My data further indicate that Gal-LepRb neurons are inhibitory acting neurons that are stimulated by leptin. Gal-LepRb neurons strongly innervate local orexin neurons and noradrenergic neurons in the locus coeruleus (LC). Intriguingly, orexin neurons also strongly innervate the LC, and activation of orexin neurons correlates with motivational and food-seeking behaviors. My data also show that orexin neurons express the Gi-coupled GPCR galanin 1-receptor (GalR1), validating the cellular ability of orexin neurons to respond to galanin. In summary, we have characterized a novel population of LHA LepRb neurons and propose that leptin-mediated inhibition of orexin neurons, possibly via inhibitory galanin-GalR1 signaling, regulates the reward value of nutrients.

Date

2014

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Münzberg, Heike

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