Our long term goal is to characterize, expand and improve knowledge of the developmental and neurobiological determinants of sexual partner preferences/orientation using domestic sheep as the experimental model. The sheep is an exceptional model because variations in male-typical sexual partner preference occur spontaneously, with as much as 8% of the ram population exhibiting mating preferences for the same-sex. Sheep have a long period of gestation making them an ideal experimental model for the study of possible links between fetal neuroendocrine programming and adult sexual behavior. Similar to humans, sheep possess a sexually 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 develops prior to birth and is enlarged by testosterone (T) exposure during a prenatal critical period that occurs after the external genitals have sexually differentiated. We recently discovered that the hypothalamic-pituitary-gonadal (HPG) axis is active during the critical period suggesting that variations of T exposure in males could be centrally mediated through control of gonadotropin releasing hormone (GnRH) secretion. In adults, GnRH neuron activity is regulated by inputs from afferent neurons that co-express kisspeptin (KP), neurokinin B (NKB) and dynorphin (DYN) and are referred to as KNDY neurons. KNDY neurons are reciprocally interconnected and critical to the control of pulsatile GnRH secretion and steroid feedback. We reported that KP, NKB, DYN and their receptors are expressed in the fetal lamb hypothalamus. However, whether a functional circuit is established among KNDY neurons and GnRH neurons in the fetal lamb brain is not yet known. The goal of this proposal is to test the hypothesis that KNDY-GnRH signaling plays a pivotal role in the activation/regulation of the reproductive axis during fetal development and is responsible for masculinizing sexual partner preferences by controlling T secretion by the fetal testes. 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 neuroendocrine functions and sexual attraction.
Our specific aims i nclude: 1) Behavioral studies of rams prenatally treated with a GnRH antagonist to determine if GnRH control mechanisms that regulate fetal T secretion play a direct role in establishing adult male-typical sexual preferences; 2) Physiological studies using chronically catheterized non-anesthetized lamb fetuses to determine if KP, NKB and DYN regulate GnRH neurons and consequently pituitary LH and testicular T secretion during the critical period; 3) Anatomical studies to determine when during early development the neuronal components of the KNDY-GnRH neural circuit are established and how they are regulated. Our sheep model is unique because it allows us to identify mechanisms underlying sexual partner preference without the confound of having subjects that differ in sex as well as in sexual orientation. Advancing the sheep model bridges research interests of NICHD, NIMH and NINDS.

Public Health Relevance

. Fetal development is a time when critical neuroanatomical and physiological components of the reproductive system are established and determine the sexual phenotype and reproductive health of the adult individual. The proposed studies will illuminate essential hormonal, neural and cellular mechanisms that activate the fetal reproductive axis, and will contribute to our understanding of underpinnings of brain sexual differentiation, especially in relation to sexual partner preferences. Advancing the sheep model is an important resource effort to provide a valuable large animal model for research that bridges the priorities of NICHD (basic mechanisms of fetal development); NIMH (define the neural mechanisms of complex behaviors) and NINDS (understand how the normal brain and nervous system develop).

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Project (R01)
Project #
2R01OD011047-19A1
Application #
9734841
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Vonkollmar, Desiree
Project Start
2000-09-15
Project End
2024-07-31
Budget Start
2019-08-15
Budget End
2020-07-31
Support Year
19
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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, 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:
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:
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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