Thyrotropin-releasing hormone (TRH) has an important role in the regulation of energy homeostasis not only through effects on thyroid function, but also on feeding behavior, thermogenesis, and autonomic regulation. We hypothesize that two distinct populations of TRH-producing neurons located in the medial/periventricular vs anterior parvocellular subdivision of the hypothalamic paraventricular nucleus (PVN) have critical roles in a coordinated effort to mediate the effects of TRH on energy homeostasis. To determine how these two TRH neuronal populations are integrated into energy control systems in the brain and elucidate their specific functions, we will develop transgenic mice in which Cre recombinase is selectively targeted to TRH-producing cells. This approach, together with the use of genetically modified pseudorabies virus (PRV) that exploits the Cre-loxP system for conditional replication and expression of the fluorescent marker protein, GFP, will be used to elucidate the complex, multisynaptic circuitries regulating of each of these neuronal groups and their regulation by leptin. In addition, using Cre-lox-site-specific recombination, we propose to construct a PRV derivative that is dependent on a Cre-mediated recombination event for replication, yet unable to infect other adjacent or transsynaptic neuronal populations due to a mutation in gB, a major membrane protein required for membrane fusion and transneuronal passage of virions. Thus, only neurons that express Cre will be targeted for cell death, allowing selective loss of the TRH neuronal population in each defined anatomical region of the PVN without any effects on adjacent populations. The use of these novel """"""""suicide"""""""" viruses to selectively ablate TRH neurons in each subdivision of the PVN, will ultimately allow the elucidation of the full gambit of physiologic effects exerted by TRH neurons in the anterior vs medial/periventricular subdivision in the regulation of energy homeostasis, and may become of general value as a new neuroanatomical tool for neuroscience research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK070600-01
Application #
6899416
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Sato, Sheryl M
Project Start
2005-06-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$216,301
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111