Testosterone facilitates conditioning to clitoral stimulation: a conscious mouse model of responsive female genital arousal.

INTRODUCTION: Testosterone therapy is increasingly used to treat individuals assigned female at birth, but its mechanisms of action on sexual functioning are poorly characterized and existing animal models do not integrate genital and behavioral responses. We therefore developed a preclinical mouse model to study testosterone therapy's actions on responsive sexual arousal in female mice. METHODS: Young adult female mice were ovariectomized and treated with testosterone in the male range or vehicle and their genital, behavioral, and neural responses to conditioning with clitoral stimulation (4-6 sessions over the course of 2 weeks) were characterized. Mice were then euthanized following clitoral or sham stimulation and proto-oncogene Fos protein (FOS) immunoreactivity used as a proxy measure of neural activation in brain regions associated with sexual responses and reward. RESULTS: Following repeated experience with clitoral stimulation, testosterone-treated but not vehicle-treated mice exhibited clear signs of sexual arousal, including visible genital vasocongestive arousal and mounting of cage mates. Testosterone-treatment increased FOS immunoreactivity in the nucleus accumbens regardless of stimulation and in the medial preoptic nucleus and the piriform cortex only with clitoral stimulation. Neither effects of stimulation nor testosterone treatment were observed in other examined brain regions (arcuate nucleus, ventromedial nucleus, and suprachiasmatic nucleus). DISCUSSION: This preclinical mouse model allows for study of androgen action on sexual function of individuals assigned female at birth and for integration of endocrine and behavioral approaches to treatment. Limitations include uncertain generalizability to sexual functioning of humans and incomplete mechanistic understanding. Together, results indicate that testosterone treatment activates conditioned sexual arousal to rewarding genital stimulation in female mice, providing a conscious mouse model of androgenized female genital arousal.