Mapping of neural and signal transduction pathways for lordosis in the search for estrogen actions on the central nervous system

Abstract

Estrogen can act on the brain to regulate various biological functions and behavior. In attempts to elucidate the estrogen action, the rodent female reproductive behavior, lordosis, was used as a model. Lordosis is an estrogen-dependent reflexive behavior and, hence, is mediated by discrete neural pathways that are modulated by estrogen. Therefore, a strategy of mapping the pathways, both neural and biochemical, and examining them for estrogen effect was used to localize and subsequently analyze the central action of estrogen. Using various experimental approaches, an ‘inverted Y-shaped’ neural pathway both sufficient and essential for mediating lordosis was defined. The top portion is a descending pathway conveying the permissive estrogen influence which originated from hypothalamic ventromedial nucleus relayed via midbrain periaqueductal grey down to medullary reticular formation, the top of the spino-bulbo-spinal reflex arc at the bottom. This estrogen influence alters the input–output relationship, shifting the output toward more excitation. With this shift in output, estrogen can enable the otherwise ineffective lordosis-triggering sensory stimuli to elicit lordosis. In the ventromedial nucleus, the origin of the estrogen influence, a multidisciplinary approach was used to map intracellular signaling pathways. A phosphoinositide pathway involving a specific G protein and the activation of protein kinase C was found to be involved in the mediation of lordosis as well as a probable target of the permissive estrogen action. The action of estrogen on this signal transduction pathway, a potentiation, is consistent with and, hence, may be an underlying mechanism for the estrogen influenced shift toward excitation. Thus, further investigation on this specific signal transduction pathway should be helpful in elucidating the action of estrogen on the brain.