The goal of this new research program is to determine how the classic estrogen receptor (ERalpha, or ERa) controls expression of motivated behaviors. Although often considered a """"""""female"""""""" hormone, estrogen has numerous effects on male physiology and behavior. One highly influential hypothesis on the control of male sexual behavior, the so-called aromatization theory, states that estrogen is required both during development and in adulthood to organize and activate male sexual behaviors. The actions of early estrogens are thought to cause permanent neuronal changes, which dictate expression of behavior in adulthood. Many hormone and drug studies have shown that exposure to estrogen in female neonates increases their potential to display masculine behavior in adulthood. In contrast, males deprived of estrogen are less apt to select female partners and engage in sexual interactions. In addition, recent studies have linked the aromatase system to catecholamines, particularly dopamine, which is well known to play a role in male sexual motivation. For this proposal, genetically engineered knockout mice will be utilized. Use of this model yields an adult that has been completely deprived, during development and adulthood, of estrogens' actions via just one of its genomic estrogen receptors. The recent discovery that estrogen has multiple receptor subtypes makes this mouse, which lacks functional ERa, yet has the newly characterized ERbeta (ERb) in brain, invaluable for distinguishing the actions of estrogen on its receptor subtypes. There are no pharmacological tools that distinguish between the various ERs. Given the data reviewed above, it was predicted that the disruption of ERa would cause a deficit in male sexual motivation. However, data collected by this lab and others suggest that sexual motivation and behavior in male mice with the ERa disruption (referred to as ERaKOs) can be modified by experience and/or steroid hormone level. Experiments will be conducted to critically evaluate and quantify the sexual motivation and performance of the ERaKO mice. In particular, the hypotheses that deprivation of ERa alters neuronal sensitivity to androgens, and that elevated levels of testosterone (T) can compensate for the lack of ERa, will be tested. If T can produce normal masculine behavior, either the ERb is essential for estrogen's actions on normal masculine development, or the lack of ERa during development can be overcome in the adult. Alternatively, if T replacement does not reinstate normal behavior in ERaKOs, this proves that lack of this gene permanently alters the neurocircuitry which regulates these motivated behaviors. To test the hypothesis that the ERb is essential during development for expression of male sexual behaviors, neonates will be treated with an aromatase inhibitor, which blocks the conversion of T to estradiol. This will eliminate any potential actions of the ERb during the critical period in both ERaKO and WT mice. To assess the hypothesis that loss of ERa during development causes irreversible alterations in the basic neural circuitry that underlies male copulatory behaviors, fos immuno- cytochemistry will be used to detect neural responses to specifics in wildtype and ERaKO males. Dopamine is highly sensitive to the effects of estrogen during development and may regulate aromatase enzyme. Moreover, this monoamine plays a pronounced role in male rat sexual motivation and copulation. Thus, to test the hypothesis that ERa disruption affects masculine behavior by its actions on dopamine, both neuroanatomical and behavioral studies will be employed. These studies critically evaluate the role of the ERa on motivated behaviors. Moreover, the studies examine the possibility that compensatory mechanisms can act on the adult nervous system long after well established critical periods of neuronal development have passed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH057759-04
Application #
6538807
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Project Start
1999-04-01
Project End
2003-09-28
Budget Start
2002-04-01
Budget End
2003-09-28
Support Year
4
Fiscal Year
2002
Total Cost
$183,056
Indirect Cost
Name
University of Virginia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Quinnies, Kayla M; Cox, Kimberly H; Rissman, Emilie F (2015) Immune deficiency influences juvenile social behavior and maternal behavior. Behav Neurosci 129:331-8
Cox, Kimberly H; Quinnies, Kayla M; Eschendroeder, Alex et al. (2015) Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice. Psychoneuroendocrinology 51:271-81
Cox, Kimberly H; Bonthuis, Paul J; Rissman, Emilie F (2014) Mouse model systems to study sex chromosome genes and behavior: relevance to humans. Front Neuroendocrinol 35:405-19
Stolzenberg, Danielle S; Stevens, Jacqueline S; Rissman, Emilie F (2014) Histone deacetylase inhibition induces long-lasting changes in maternal behavior and gene expression in female mice. Endocrinology 155:3674-83
Cox, Kimberly H; So, Nina L T; Rissman, Emilie F (2013) Foster dams rear fighters: strain-specific effects of within-strain fostering on aggressive behavior in male mice. PLoS One 8:e75037
Bharadwaj, Pranay; McInnis, Christine; Madden, Amanda M K et al. (2013) Increased dendritic spine density and tau expression are associated with individual differences in steroidal regulation of male sexual behavior. PLoS One 8:e69672
Wolstenholme, J T; Rissman, E F; Bekiranov, S (2013) Sexual differentiation in the developing mouse brain: contributions of sex chromosome genes. Genes Brain Behav 12:166-80
Wolstenholme, Jennifer T; Goldsby, Jessica A; Rissman, Emilie F (2013) Transgenerational effects of prenatal bisphenol A on social recognition. Horm Behav 64:833-9
Abel, Jean LeBeau; Rissman, Emilie F (2013) Running-induced epigenetic and gene expression changes in the adolescent brain. Int J Dev Neurosci 31:382-90
Bonthuis, Paul J; Rissman, Emilie F (2013) Neural growth hormone implicated in body weight sex differences. Endocrinology 154:3826-35

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