A primary goal of the proposed studies is the identification of androgen regulated gene products which are essential for the neuromodulation of male sexual behavior (MSB). This project will address two key aspects of androgen action. First, we will challenge the hypothesis that gradual changes in protein synthesis occurring in certain androgen-concentrating brain nuclei underlie the long lag time required for the postcastration decline of MSB as well as the long testosterone (T) exposure required for the restoration of behavior. We have shown that implants of the protein synthesis inhibitor, anisomycin (ANI), into the medial preoptic area (MPOA) prevent restoration of MSB.
Specific Aim 1 will extend this finding to establish whether ANI implants into other androgen- concentrating areas, the hypothalamic ventromedial nucleus (VMN), medial amygdala (AME) and lateral septum (SEPT) also prevent restoration of MSB.
In Specific Aim 2 we will implant ANI into sites where restoration of MSB was inhibited to determine if maintenance of MSB is also inhibited.
Specific Aim 3 will use 2-dimensional gel electrophoresis (2DE) to extend our finding that 5 MPOA proteins are increased by T, and establish whether these same proteins are induced by T in VMN, AME and SEPT.
Specific Aim 4 will use 2DE to determine if these proteins gradually disappear after castration and reappear following T exposure.
Specific Aim 5 is to identify the cellular and subcellular localization of these proteins by immunocytochemistry. The results of these experiments will: 1) identify brain nuclei essential for mediating the genomic effects of T on the restoration and maintenance of male sexual behavior, 2) single out a small population of proteins uniquely expressed by T and demonstrate if there is site specificity in their induction, and if their disappearance/reappearance coincides with the decline and restoration of MSB, and 3) identify potential functional sites of action for these proteins. The second basic question is how specific are the efects of T? Specific Aim 6 will use Northern blots and in situ hybridization to establish whether androgen receptor (AR) and estrogen receptor (ER) mRNA are colocalized in the same neurons, and whether T, and estradiol (E2) are similar or different in inducing the message for these receptors in MPOA, VMN, AME and SEPT.
Specific Aim 7 will employ 2DE of micropunched MPOA, VMN, AME and SEPT to detect local similarities and differences in the profiles of proteins uniquely expressed by T, E2 and DHT. These results should answer whether aromatization of T to E2 is in fact an essential step in evoking MSB, and point to salient differences in the actions of T vs its metabolites that could account for differences in their behavioral effects. The results of these studies will make it possible to devise a molecular approach to understanding reproductive behavior and yield insight into the treatment of hormone dependent tumors, neurologic diseases and injuries influenced by androgens, androgen resistance syndromes, and sexual dysfunctions such as impotence.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD027727-04
Application #
2200615
Study Section
Biopsychology Study Section (BPO)
Project Start
1992-02-01
Project End
1997-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Cunningham, Rebecca L; Lumia, Augustus R; McGinnis, Marilyn Y (2013) Androgenic anabolic steroid exposure during adolescence: ramifications for brain development and behavior. Horm Behav 64:350-6
Harding, Shannon M; McGinnis, Marilyn Y (2004) Androgen receptor blockade in the MPOA or VMN: effects on male sociosexual behaviors. Physiol Behav 81:671-80
McGinnis, Marilyn Y; Vakulenko, M (2003) Characterization of 50-kHz ultrasonic vocalizations in male and female rats. Physiol Behav 80:81-8
Harding, Shannon M; McGinnis, Marilyn Y (2003) Effects of testosterone in the VMN on copulation, partner preference, and vocalizations in male rats. Horm Behav 43:327-35
McGinnis, Marilyn Y; Montana, Robert C; Lumia, Augustus R (2002) Effects of hydroxyflutamide in the medial preoptic area or lateral septum on reproductive behaviors in male rats. Brain Res Bull 59:227-34
Yu, W H; McGinnis, M Y (2001) Androgen receptors in cranial nerve motor nuclei of male and female rats. J Neurobiol 46:1-10
Vagell, M E; McGinnis, M Y (1998) The role of gonadal steroid receptor activation in the restoration of sociosexual behavior in adult male rats. Horm Behav 33:163-79
Vagell, M E; McGinnis, M Y (1997) The role of aromatization in the restoration of male rat reproductive behavior. J Neuroendocrinol 9:415-21
Vagell, M E; McGinnis, M Y (1997) Inhibition of brain oestrogen receptors by RU 58668. J Neuroendocrinol 9:797-800
McGinnis, M Y; Kahn, D F (1997) Inhibition of male sexual behavior by intracranial implants of the protein synthesis inhibitor anisomycin into the medial preoptic area of the rat. Horm Behav 31:15-23

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