Background

Estrogen receptor alpha (ERa) signaling in the hypothalamus modulates many aspects of homeostasis in mice, including temperature. The medial preoptic area (MPA) is rich in ERa expression and contains temperature-sensitive neurons that regulate thermoregulatory behavior and physiology. Thus, we hypothesized that ERa neurons in the MPA are sensitive to temperature and partially mediate the effects of estrogens on temperature regulation.

Methods

To define ERa+ thermoregulatory neurons, we combined electrophysiology, loss of function, and gain of function studies. To test if ERa+ MPA neurons are sensitive to ex vivo changes in temperature, we used current-clamp recordings of ERa+ neurons in ERa-zsGreen transgenic mice. To test if ERa+ MPA neurons are necessary for normal thermoregulation, we delivered AAV expressing a Cre-dependent caspase-3 to the MPA of Esr1Cre and wild-type littermates. To test if ERa+ MPA neurons are sufficient to drive changes in body temperature, we delivered AAV expressing a Cre-dependent hM3Dq DREADD to Esr1Cre and wild-type mice. Mice were monitored using intraperitoneal telemetry probes, thermo-loggers attached to the tail skin, infrared thermal photography, electrocardiography, and indirect calorimetry.

Results

Electrophysiology studies suggest that half of ERa+ MPA neurons are warmth-sensitive and that temperature modulates their response to estrogen treatment. Ablation of ERa+ MPA neurons increased core temperature compared to controls. In contrast, chemogenetic activation of ERa+ MPA neurons caused a dramatic drop in core temperature (up to 10 C), heart rate, and energy expenditure. No effects were observed in vehicle-treated mice or wild-type mice treated with ligand. Consistent with higher ERa expression in females, the effects of ERa neuron ablation and activation were female-specific and modulated by estrogen treatment, respectively.

Conclusions

These complementary studies suggest that ERa neurons in the MPA have critical roles in thermoregulation and metabolism.