Neuroactive steroids

Among the signals that affect brain development and function, neuroactive steroids play an important role. We are investigating the mechanisms of action of neuroactive steroids on neurons and glial cells. Our main emphasis is on the effects of ovarian hormones on neural plasticity and neuroprotection. Different pathologies of the central and peripheral nervous system show sex differences in their incidence, symptomatology and/or neurodegenerative outcome. These include Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, traumatic brain injury, stroke, autism, schizophrenia, drug abuse, depression, anxiety disorders, eating disorders and peripheral neuropathy. Sex differences in the levels or in the action of neuroactive steroids may represent causative factors for sex differences in the incidence or manifestation of pathologies of the nervous system. Neuroactive steroids include hormonal steroids, such as estradiol, and steroids locally synthesized by neural cells. Our general aim is to determine whether brain aromatase, the enzyme that converts testosterone in estradiol, is involved in the sex dimorphic responses to neurodegenerative stimuli and to neuroprotective estrogenic therapies. Our hypothesis is that the increased expression of estrogen receptors induced by the increased aromatase activity in the brain allows exogenous estrogenic therapy to exert neuroprotection. If we block aromatase expression, estrogenic therapy will be impaired. In turn, sex differences in brain aromatase activity may be involved in sex differences in the brain response to injury and in sex dimorphic brain responses to neuroprotective estrogenic therapies. In this regard, the objective of this TFM is to determine the effects of manipulating aromatase expression and activity on the outcome of penetrating cortical injury and the outcome of estrogen therapy in male and female mice.