Parsing the central control of thirst and hunger using a rat model of diabetes insipidus - Project Summary: Feeding and drinking are essential behaviors for the maintenance of energy and
fluid homeostasis. Failure to maintain energy balance causes obesity or malnutrition and
perturbations in fluid balance cause dehydration or hypertension. The neural circuits that control
hunger and thirst have been well studied but overlapping neural pathways in the control of hunger or
of thirst, and the strong interdependence of feeding and drinking has made it difficult to untangle the
respective circuits. To address this long-standing problem, this project takes a novel approach that
uses the Brattleboro rat to tease apart aspects of the glucagon-like peptide-1 (GLP-1) system that
control feeding and drinking. The Brattleboro rat is a well-studied rodent model of central diabetes
insipidus that originated in a colony of Long Evans rats. A naturally occurring single nucleotide
mutation in these rats results in a vasopressin precursor that cannot be secreted, causing severe
polyuria. To compensate for the polyuria, Brattleboro rats drink approximately five times that
consumed by wild-type littermates, without any observed feeding-related phenotype. A series of
studies in our laboratory suggest that at least part of the polydipsia involves disrupted satiety signals.
Specifically, licking microstructure analyses revealed differences that are consistent with altered
satiation and additional studies suggest that Brattleboro rats have altered fluid intake-relevant GLP-1
signaling, but intact feeding-related GLP-1 responses. Moreover, Brattleboro rats appear to have
different GLP-1 precursor expression in the hindbrain when compared with that of wild type
littermates. Taking advantage of these differences in fluid intake, in the absence of differences in food
intake, this project uses a variety of approaches to better elucidate circuits responsible for the control
of drinking, especially relevant for satiation of thirst, and to separate these from circuits responsible
for food intake. Accordingly, by testing for differences between wild-type and Brattleboro rats, we can
identify circuits and populations of cells in the GLP-1 system that control drinking and separate them
from those that control other functions such as feeding. As such, these data will lead to a more
complete understanding of the circuits that control fluid and food intake satiety and provide targets for
treatments of disordered energy and fluid homeostasis.
