Mice lacking angiotensin AT1A receptors in neurons exhibit a behavioral preference for decreased ambient temperature
Authors: Grobe Connie , Freudinger Bonnie , Sherman Alexander , Burnett Colin , Segar Jeffrey , Grobe Justin 
Published: May 2023

The local tissue renin-angiotensin system (RAS) within the brain is implicated in cardiometabolic control, including core temperature and resting metabolic rate (RMR). Previously we demonstrated a critical role for the angiotensin (ANG) type 1A receptor (AT1R), localized to neurons of the hypothalamic arcuate nucleus that express Agouti-related peptide (AgRP), in the control of RMR. Further, we demonstrated that mice deficient for melanocortin type 4 receptors (MC4R) for AgRP resist stimulation of RMR by ANG in the brain. Given the known projections of AgRP neurons and RMR-regulating networks within the forebrain and hypothalamus, we hypothesize that ANG in the brain acts to sensitize the animal to the sensation of cold, rather than to directly stimulate pre-autonomic functions. To test this hypothesis, we examined the consequences of genetically deleting the AT1R gene from all neurons upon ambient temperature preference, as mice with inhibited sensation of cold should prefer a colder temperature, while mice with inhibited stimulation of pre-autonomic areas should prefer a warmer temperature. We constructed a thermal gradient that consisted of four parallel lanes with opaque white polycarbonate walls (58.4 x 7.5 cm, 20.5 cm tall) and an aluminum floor. Temperature-controlled circulating water baths supplied heating/cooling blocks on opposite ends of lanes to generate a linear temperature gradient as assessed using infrared imaging (FLIR A700: gradient range 40-15°C; T=38.40-0.04091✕D, R2=0.99, where D=distance from warmed end of lane, in mm) that was similar between lanes (within 0.87±0.31°C). Mice were placed in the center of the gradient and mouse position in the gradient was analyzed continuously for 2h by video (AnyMaze, Stoelting) during the middle of the light phase. Mice with AT1R deleted from neurons ( Syn1-Cre+/- x Agtr1a F/F, n=3m+4f) and littermate controls ( Agtr1a F/F, n=3m) on the C57BL/6 background exhibited similar decaying locomotor activity for the first 90 min before reaching a nadir in activity between 90-120 min (23±13 cm/min, p=ns between groups). Between 90-120 min, the knockout mice localized to a significantly lower ambient temperature than controls (28.1±1.0 vs 31.9±0.3°C, p=0.04). Validating our approach, others have previously reported 32-33°C as the preferred light-phase ambient temperature for adult mice. Together, these findings demonstrate our fabrication and validation of a thermal gradient system for mice and support the working hypothesis that the brain RAS functions to modify the integration of cold stimuli, ultimately to influence energy homeostasis.

HL134850, HL084207, DK133121, UL1TR001436, 18EIA33890055

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.