The long-term goal of this project is to further characterize, expand and improve the usefulness of a unique ram model to study the neuroendocrine determinants of sexual orientation. The ram is an exceptional model because variations in male-typical sexual partner preference occur spontaneously, with as many as 8% of the population exhibiting a preference for same-sex mating partners. Sheep have a long period of gestation making them an excellent experimental model for the study of possible links between fetal neuroendocrine programming and adult sexual behavior. Similar to humans, sheep possess a sexual dimorphic preoptic nucleus (SDN) that is larger in males that are attracted to females than in males that are attracted to other males. The ovine SDN (oSDN) develops prior to birth and is enlarged by testosterone exposure during a prenatal critical period that occurs after the external genitals have sexually differentiated. Recently we found that exposure to testosterone prior to the oSDN critical period (Early T) paradoxically reduces the size of the oSDN, suggesting that testosterone exerts opposite effects on masculine oSDN development depending on when it is elevated during gestation. The cellular and molecular mechanisms acting to suppress oSDN development and the impact this has on sexual partner preference are not yet known. Preliminary data show that the hypothalamus-pituitary-gonadal (HPG) axis is sensitive to negative feedback during the oSDN critical period making it possible that Early T could consequently suppress testosterone secretion at the time it is required for oSDN masculinization. Thus, we will test the hypothesis that Early T exposure triggers lasting effects on endocrine feedback and neuronal development that disrupt masculinization of the oSDN later in gestation, producing rams that prefer to mate with other rams but still possess other male-typical neuroendocrine and behavioral traits. My laboratory and collaborators have extensive expertise with the ram model and with the methods needed to elucidate the mechanisms involved in programming the functions of the brain that control sexual attraction.
Our specific aims i nclude: 1) Studies in adult rams to determine whether Early T exposure feminizes their sexual partner preferences without affecting other masculine behaviors and neuroendocrine responses; 2) Physiological evaluation of the HPG axis and gene expression to determine how Early T disrupts the masculinization program in lamb fetuses; 3) Cellular and molecular studies of dissociated fetal neuronal cultures to determine the morphological basis for anatomical differences in oSDN size. The project is conceptually innovative because it will test a novel mechanism by which male-typical sexual partner preference and oSDN structure can be demasculinized/ feminized without globally affecting the masculinization program. The project is significant because it will contribute to our understanding of the biological origins of sexual orientation. Finally, advancing the sheep model will provide a valuable animal resource for research bridging the interests of NICHD, NIMH and NINDS.

Public Health Relevance

The long term goal of the proposed research is to further characterize, expand and improve the usefulness of a unique ram model to study the neuroendocrine determinants of sexual partner preference. We will test the novel hypothesis that individual variations in adult mate selection depend on prenatal developmental events that determine the timing of brain exposure to testosterone. The project is significant because it will contribute to our understanding of the biological origins of sexual orientation and provide a scientific foundation for counseling individuals who have questions and concerns about their sexuality.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Research Project (R01)
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Vonkollmar, Desiree
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Oregon Health and Science University
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Heck, A L; Crestani, C C; Fernández-Guasti, A et al. (2018) Neuropeptide and steroid hormone mediators of neuroendocrine regulation. J Neuroendocrinol 30:e12599
Scully, C M; Estill, C T; Amodei, R et al. (2018) Early prenatal androgen exposure reduces testes size and sperm concentration in sheep without altering neuroendocrine differentiation and masculine sexual behavior. Domest Anim Endocrinol 62:1-9
Mirto, A J; Austin, K J; Uthlaut, V A et al. (2017) Fos Expression in the Olfactory Pathway of High- and Low-Sexually Performing Rams Exposed to Urine from Estrous or Ovariectomized Ewes. Appl Anim Behav Sci 186:22-28
Roselli, C E; Meaker, M; Stormshak, F et al. (2016) Effects of Long-Term Flutamide Treatment During Development on Sexual Behaviour and Hormone Responsiveness in Rams. J Neuroendocrinol 28:
Roselli, Charles E; Amodei, Rebecka; Gribbin, Kyle P et al. (2016) Excess Testosterone Exposure Alters Hypothalamic-Pituitary-Testicular Axis Dynamics and Gene Expression in Sheep Fetuses. Endocrinology 157:4234-4245
Zubeldia-Brenner, L; Roselli, C E; Recabarren, S E et al. (2016) Developmental and Functional Effects of Steroid Hormones on the Neuroendocrine Axis and Spinal Cord. J Neuroendocrinol 28:
Reddy, Radhika C; Amodei, Rebecka; Estill, Charles T et al. (2015) Effect of Testosterone on Neuronal Morphology and Neuritic Growth of Fetal Lamb Hypothalamus-Preoptic Area and Cerebral Cortex in Primary Culture. PLoS One 10:e0129521
Roselli, Charles E; Reddy, Radhika C; Estill, Charles T et al. (2014) Prenatal influence of an androgen agonist and antagonist on the differentiation of the ovine sexually dimorphic nucleus in male and female lamb fetuses. Endocrinology 155:5000-10
Reddy, Radhika C; Scheldrup, Melissa; Meaker, Mary et al. (2014) Cell death in the central division of the medial preoptic nucleus of male and female lamb fetuses. Brain Res 1554:21-8
Reddy, R C; Estill, C T; Meaker, M et al. (2014) Sex differences in expression of oestrogen receptor ? but not androgen receptor mRNAs in the foetal lamb brain. J Neuroendocrinol 26:321-8

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