RNAi-mediated silencing of estrogen receptor {alpha} in the ventromedial nucleus of hypothalamus abolishes female sexual behaviors.
Estrogen receptor alpha (ERalpha) plays a major role in the regulation of neuroendocrine functions and behaviors by estrogens. Although the generation of ERalpha knockout mice advanced our knowledge of ERalpha functions, gene deletion using this method is global and potentially confounded by developmental consequences. To achieve a site-specific knockdown of ERalpha in the normally developed adult brain, we have generated an adeno-associated virus vector expressing a small hairpin RNA targeting ERalpha. After bilateral injection of this vector into the hypothalamic ventromedial nucleus in ovariectomized female mice, expression levels of ERalpha as well as the estrogen-inducible progesterone receptor were profoundly reduced despite the continued presence of this receptor elsewhere in the brain. Functionally, silencing of ERalpha in the ventromedial nucleus abolished female proceptive and receptive sexual behaviors while enhancing rejection behavior. These results provide evidence that adeno-associated virus-mediated long-term knockdown of genes can be used to delineate their effects on complex behaviors in discrete brain regions.
Musatov
Sergei
S
*Neurologix, Inc., Fort Lee, NJ 07024.|Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10021.|Laboratory of Molecular Neurosurgery, Weill Medical College of Cornell University, New York, NY 10021; and.
Chen
Walter
W
Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10021.
Pfaff
Donald W
DW
Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10021; pfaff@rockefeller.edu.
Kaplitt
Michael G
MG
Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10021.|Laboratory of Molecular Neurosurgery, Weill Medical College of Cornell University, New York, NY 10021; and.
Ogawa
Sonoko
S
Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10021; ogawa@mail.rockefeller.edu.|Kansei, Behavioral, and Brain Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
D000230:Adenocarcinoma / Q000235:genetics; D000818:Animals; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D012725:Sexual Behavior / Q000502:physiology*; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism*
D047628:Estrogen Receptor alpha