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Assessing the Involvement of Altered Neurotensin Signaling in Anorexia Nervosa
Başlık:
Assessing the Involvement of Altered Neurotensin Signaling in Anorexia Nervosa
Yazar:
Schroeder, Laura Elizabeth, author.
ISBN:
9780438128514
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (308 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Gina M. Leinninger; Hongbing Wang Committee members: Cynthia Jordan; Kelly Klump; Fredric Manfredsson; Hongbing Wang.
Özet:
Assessing the Involvement of Altered Neurotensin Signaling in Anorexia Nervosa By Laura Elizabeth Schroeder Anorexia Nervosa (AN), characterized by a persistent and detrimental drive to lose weight via restriction of food intake and excessive exercise, is the psychiatric disorder with the highest mortality rate. Very few options exist when considering pharmacotherapies used to treat AN patients, and no drugs have been demonstrated to significantly improve weight gain. This highlights the need to not only find better drugbased therapies for AN but to also find druggable targets for this disorder. While AN is thought to be highly heritable, with heritability estimates ranging between 50--80%, it has been challenging to identify significant genetic contributors. Thus, determining the genetic 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 been performed to uncover rare genetic variants that confer high risk of disease development. Loss-of-function variants in Neurotensin (Nts) and Nts Receptor 1 (NtsR1) were identified in individuals with eating disorders. Nts is a neuropeptide known to regulate ingestive and locomotor behavior. Nts modulates these behaviors centrally, and a subset of dopamine (DA) neurons with the ventral tegmental area (VTA) that coexpress NtsR1 are known to contribute to DA-mediated weight loss behaviors. Ablation of all NtsR1 VTA neurons was shown to promote excessive locomotor activity without a sufficient increase in feeding, leading to low body weight. Finally, increased fiber densities have been found within the lateral hypothalamic area (LHA) of individuals with AN, and the LHA is a region with a significant population of Nts neurons known to modulate both feeding and activity. We therefore hypothesized that Nts populations in feeding centers, such as the LHA, receive altered input from structures associated with AN and that alterations and/or disruption of Nts signaling promotes AN-like behaviors.
This hypothesis was explored via three different approaches. First, the location and density of Nts populations within the brains of Nts Cre; Floxed GFP mice were mapped, and this revealed the presence of Nts in regions implicated in regulation of feeding and AN. The next approach involved determining if disrupted Nts signaling increases risk for development of AN-like behaviors. This was accomplished by characterizing NtsR1-deficient mice both at baseline and after exposure to an adolescent-stress model of AN. This study revealed that deficiency of NtsR1 is a genetic risk factor that, when interacting with risks of being female and exposure to adolescent stress, promotes aberrant feeding, excessive locomotor behaviors, and compulsive anxiety behaviors analogous to those observed in AN. Finally, a rabies virus-based method was used to identify direct inputs to LHA Nts neurons, and this highlighted the existence of afferents, and thus top-down control, from structures implicated in AN. In addition, densities of these inputs were determined in mouse models of AN, and this demonstrated that afferent inputs to LHA Nts neurons are increased from sites associated with AN.
Altogether, the data presented in this thesis highlight the possible genetic and neurocircuitry alterations to the Nts-NtsR1 system that may promote and/or be the result of development of AN. These data also indicate the need for future studies to better understand the mechanism by which such alterations in Nts signaling promote this disease.
Notlar:
School code: 0128
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(695451.1) | 695451-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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