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- Assessing the involvement of altered neurotensin signaling in anorexia nervosa
- Schroeder, Laura Elizabeth
- Electronic Theses & Dissertations
ABSTRACTAssessing the Involvement of Altered Neurotensin Signaling inAnorexia NervosaByLaura Elizabeth SchroederAnorexia Nervosa (AN), characterized by a persistent and detrimental drive tolose weight via restriction of food intake and excessive exercise, is the psychiatricdisorder with the highest mortality rate. Very few options exist when consideringpharmacotherapies used to treat AN patients, and no drugs have been demonstrated tosignificantly improve weight gain. This highlights the need...
Show moreABSTRACTAssessing the Involvement of Altered Neurotensin Signaling inAnorexia NervosaByLaura Elizabeth SchroederAnorexia Nervosa (AN), characterized by a persistent and detrimental drive tolose weight via restriction of food intake and excessive exercise, is the psychiatricdisorder with the highest mortality rate. Very few options exist when consideringpharmacotherapies used to treat AN patients, and no drugs have been demonstrated tosignificantly improve weight gain. This highlights the need to not only find better drugbasedtherapies for AN but to also find druggable targets for this disorder. While AN isthought to be highly heritable, with heritability estimates ranging between 50-80%, it hasbeen challenging to identify significant genetic contributors. Thus, determining thegenetic risk factors of AN will first be required for development of better therapeutics.In an effort to better understand the genetic basis of AN, recent work has beenperformed to uncover rare genetic variants that confer high risk of disease development.Loss-of-function variants in Neurotensin (Nts) and Nts Receptor 1 (NtsR1) wereidentified in individuals with eating disorders. Nts is a neuropeptide known to regulateingestive and locomotor behavior. Nts modulates these behaviors centrally, and asubset of dopamine (DA) neurons with the ventral tegmental area (VTA) that coexpressNtsR1 are known to contribute to DA-mediated weight loss behaviors. Ablation of allNtsR1 VTA neurons was shown to promote excessive locomotor activity without asufficient increase in feeding, leading to low body weight. Finally, increased fiberdensities have been found within the lateral hypothalamic area (LHA) of individuals withAN, and the LHA is a region with a significant population of Nts neurons known tomodulate both feeding and activity. We therefore hypothesized that Nts populations infeeding centers, such as the LHA, receive altered input from structures associated withAN and that alterations and/or disruption of Nts signaling promotes AN-like behaviors.This hypothesis was explored via three different approaches. First, the locationand density of Nts populations within the brains of NtsCre; Floxed GFP mice weremapped, and this revealed the presence of Nts in regions implicated in regulation offeeding and AN. The next approach involved determining if disrupted Nts signalingincreases risk for development of AN-like behaviors. This was accomplished bycharacterizing NtsR1-deficient mice both at baseline and after exposure to anadolescent-stress model of AN. This study revealed that deficiency of NtsR1 is agenetic risk factor that, when interacting with risks of being female and exposure toadolescent stress, promotes aberrant feeding, excessive locomotor behaviors, andcompulsive anxiety behaviors analogous to those observed in AN. Finally, a rabiesvirus-based method was used to identify direct inputs to LHA Nts neurons, and thishighlighted the existence of afferents, and thus top-down control, from structuresimplicated in AN. In addition, densities of these inputs were determined in mousemodels of AN, and this demonstrated that afferent inputs to LHA Nts neurons areincreased from sites associated with AN.Altogether, the data presented in this thesis highlight the possible genetic andneurocircuitry alterations to the Nts-NtsR1 system that may promote and/or be the resultof development of AN. These data also indicate the need for future studies to betterunderstand the mechanism by which such alterations in Nts signaling promote thisdisease.