Testosterone is an essential steroid hormone that regulates the development of the male reproductive system and dimorphic reproductive behaviors in all vertebrates. Testosterone stimulates protein synthesis by regulating the expression of genes; a time-dependent process that is completed within hours. Testosterone also exerts rapid actions that take place within minutes. Rapid signaling induced by testosterone affects numerous behavioral traits in animals, including reproductive behavior, aggression, and fear. However, the molecular mechanisms underlying rapid testosterone actions are poorly understood. A recent discovery identified a novel testosterone receptor that resides on the cell surface and is responsible for rapid testosterone actions. This project is designed to investigate the intricate details of this rapid testosterone signaling mechanism and reveal its role in reproductive and social behaviors in rodents. Specifically, this project will assess how rapid signaling through the novel testosterone receptor regulates steroid synthesis, sexually dimorphic behaviors, and rewarding aspects of these behaviors. This project also offers a broader impact on society and aims to enhance educational basis in understanding organismal differences during development. It includes scientific training of students at the post-graduate, graduate, and undergraduate levels, and development of educational program among four participating universities.

It is well known that genomic steroid receptors regulate behaviors indirectly via their downstream molecular targets. A recent study revealed that the Transient Receptor Potential ion channel of the Melastatin group, TRPM8, serves as a direct ionotropic testosterone receptor. Application of picomolar testosterone concentrations elicited TRPM8 channel openings and evoked calcium influx in the cells. This finding ignited an interest in whether TRPM8 directly regulates dimorphic behaviors. The mechanism of this conceptually novel physiological role of TRPM8 in mediating testosterone-dependent behaviors and sex dimorphism is the main objective of this project. This application will use a combination of techniques, including biochemical and biophysical analysis, imaging, electrophysiology, molecular biology, fluorescent spectroscopy, and animal behavioral studies. Three specific aims will: (a) determine the mechanism of TRPM8-exerted control of steroidogenesis, (b) assess the mechanism of testosterone-TRPM8 pathway in reward; and (c) reflect on the role of TRPM8 in brain development. The study will open new avenues for understanding the role of TRPM8 in testosterone-driven behaviors and sex differences. The research and educational programs will be developed through post-graduate, graduate, and undergraduate training among four collaborative universities. The results will be published in peer-reviewed journals and presented at scientific meetings.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

National Science Foundation (NSF)
Division of Integrative Organismal Systems (IOS)
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John Godwin
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University of Illinois at Chicago
United States
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