Development of a Murine Model for Hot Flashes

Abstract

Hot flashes plague millions of reproductive age men and women who have natural or iatrogenic loss of sex steroid production. Many affected individuals are left without treatment options because of contraindications to hormone replacement therapy and the lack of equally effective non-hormonal alternatives. Moreover, development of safer, more effective therapies has been stymied by the lack of an animal model that recapitulates the hot flash phenomenon and enables direct testing of hypotheses regarding the pathophysiology underlying hot flashes. To address these problems, we developed a murine model for hot flashes and a method for determining thermal preference in mice. We designed and constructed a novel instrument, a thermocline, that produces a thermal gradient that allows mice to behaviorally adapt to a thermal challenge to their core body temperature set point and permits visual tracking and recording of their thermal preference over time. We tested and validated this murine model for “hot flashes” by administration of a TRPV1 agonist and a NK3R agonist, capsaicin and senktide respectively, to unrestrained mice and observed their autonomic and behavioral responses. Following both treatments, the mice exhibited a hot flash-like response characterized by a drop in core body temperature and cold-seeking behavior on the thermocline. Attempts were made to use this positive control to guide experiments testing the hypothesis that neurons of the reproductive axis – so-called “KNDy neurons” – drive hot flashes. Unfortunately, efforts to use chemogenetic and optogenetic stimulation to stimulate KNDy neurons and induce thermoregulatory disturbances have been unsuccessful. However, we have gained insight into the limitations of these tools and conducted proof-of-concept experiments that support the use of the thermocline in studying thermoregulatory dysfunction following neuronal stimulation. This apparatus may be used to fully explore the cellular and molecular basis for hot flashes and to develop and test new therapeutic options in the future.