A sex-specific thermogenic neurocircuit induced by predator smell recruiting cholecystokinin neurons in the dorsomedial hypothalamus

Predrag Jovanovic; Allan-Hermann Pool; Nancy Morones; Yidan Wang; Edward Novinbakht; Nareg Keshishian; Kaitlyn Jang; Yuki Oka; Celine E Riera

doi:10.1038/s41467-023-40484-7

A sex-specific thermogenic neurocircuit induced by predator smell recruiting cholecystokinin neurons in the dorsomedial hypothalamus

Nat Commun. 2023 Aug 15;14(1):4937. doi: 10.1038/s41467-023-40484-7.

Authors

Predrag Jovanovic^{1

2}, Allan-Hermann Pool³, Nancy Morones^{1

2}, Yidan Wang^{1

2}, Edward Novinbakht^{1

2}, Nareg Keshishian^{1

2}, Kaitlyn Jang^{1

2}, Yuki Oka⁴, Celine E Riera^{5

6

7}

Affiliations

¹ Center for Neural Science and Medicine, Department of Biomedical Sciences, Cedars-Sinai Medical Center, 127 South San Vicente Boulevard, Los Angeles, CA, 90048, USA.
² Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 127 South San Vicente Boulevard, Los Angeles, CA, 90048, USA.
³ Department of Neuroscience, Department of Anesthesiology and Pain Management, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
⁵ Center for Neural Science and Medicine, Department of Biomedical Sciences, Cedars-Sinai Medical Center, 127 South San Vicente Boulevard, Los Angeles, CA, 90048, USA. Celine.riera@cshs.org.
⁶ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 127 South San Vicente Boulevard, Los Angeles, CA, 90048, USA. Celine.riera@cshs.org.
⁷ Department of Neurology, Cedars-Sinai Medical Center, 127 South San Vicente Boulevard, Los Angeles, CA, 90048, USA. Celine.riera@cshs.org.

Abstract

Olfactory cues are vital for prey animals like rodents to perceive and evade predators. Stress-induced hyperthermia, via brown adipose tissue (BAT) thermogenesis, boosts physical performance and facilitates escape. However, many aspects of this response, including thermogenic control and sex-specific effects, remain enigmatic. Our study unveils that the predator odor trimethylthiazoline (TMT) elicits BAT thermogenesis, suppresses feeding, and drives glucocorticoid release in female mice. Chemogenetic stimulation of olfactory bulb (OB) mitral cells recapitulates the thermogenic output of this response and associated stress hormone corticosterone release in female mice. Neuronal projections from OB to medial amygdala (MeA) and dorsomedial hypothalamus (DMH) exhibit female-specific cFos activity toward odors. Cell sorting and single-cell RNA-sequencing of DMH identify cholecystokinin (CCK)-expressing neurons as recipients of predator odor cues. Chemogenetic manipulation and neuronal silencing of DMH^CCK neurons further implicate these neurons in the propagation of predator odor-associated thermogenesis and food intake suppression, highlighting their role in female stress-induced hyperthermia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cholecystokinin*
Female
Hypothalamus
Male
Mice
Neurons / physiology
Smell*
Thermogenesis / physiology

Substances

Cholecystokinin