Dissertation/Thesis Abstract

Identification and dynamic regulation of NF kappa B in the ventral tegmental area during metabolic challenge
by Richards, Sarah Martin, Ph.D., Yale University, 2012, 152; 3537124
Abstract (Summary)

Altered physiological states are characterized by neuroplastic responses, including changes in transcription factors and gene expression. Research suggests the food-restricted state is characterized by heightened sensitivity to rewarding stimuli as a result of neuroadaptations occurring in mesolimbic systems. C57BL6/J mice were restricted to 75% of normal daily intake. Gene expression, DNA binding assays, and western blots were performed on samples from the ventral tegmental area (VTA). Gene expression and DNA binding assays were also applied to the nucleus accumbens (NAc) and hypothalamus to determine the specificity of the observed changes. To determine the functional consequences of NFκB activity in the VTA on feeding behavior, a NFκB inhibitor (sulfasalazine) or viruses designed to increase or inhibit NFκB activity were infused into the VTA. Expression of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor (Nfkbia), which encodes the NFκB inhibitor protein IκBα, increased after 1 and 5 days food restriction in the VTA. Upregulation of Nfkbia did not occur in NAc or hypothalamus, suggesting regional specificity of this response. DNA binding of NFκB and transcription of a number of target genes was increased after 1 day of restriction. However, NFκB DNA binding and transcription of target genes was normalized by 5 days of restriction. It was hypothesized that increased corticosterone bound the glucocorticoid receptor, allowing it to be transcriptionally active and transcribe Nfkbia in the VTA. DNA binding and repeated corticosterone injections suggest this is not likely to be the mechanism regulating Nfkbia after 5 days of restriction. Manipulation of NFκB in the VTA using pharmacology or viruses had no effect on food intake or body weights during intake of normal rodent diet or response to high-fat diet. In contrast, animals with increased NFκB activity in the VTA had reduced intake and weight gain after 30 days on a high-fat diet. No differences in motivation to work for food were observed between groups during a progressive ratio operant task. In conclusion, reduced food intake during restriction results in dynamic regulation of NFκB signaling in the VTA, specifically an acute increase followed by a normalization of the response. Such regulation following restriction was not observed in other brain regions. Functional tests showed a role for VTA NFκB in the physiological response to high-fat diet. Furthermore, a response of hypothalamic NFκB, but not that of the VTA, was observed following chronic high-fat diet exposure.

Indexing (document details)
Advisor: DiLeone, Ralph J.
Commitee: Diano, Sabrina, Koleske, Anthony, Taylor, Jane
School: Yale University
Department: Interdepartmental Neuroscience
School Location: United States -- Connecticut
Source: DAI-B 74/07(E), Dissertation Abstracts International
Subjects: Neurosciences, Physiology
Keywords: Food restriction, NF-kappaB, Obesity, Stress, Ventral tegmental area
Publication Number: 3537124
ISBN: 978-1-267-96317-8
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