RNAi-mediated silencing of estrogen receptor α in the ventromedial nucleus of hypothalamus abolishes female sexual behaviors

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Abstract
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.