Molecular mechanisms of estrogen action in the brain: Possible role of CREB signaling

Estrogen has been shown to have effects on cognitive and affective behaviors. However, the molecular mechanisms underlying these behaviors are still unclear. The amygdala and hippocampus are limbic brain regions key to the circuitry for cognition and affect. The gene transcription factor cyclic AMP response element-binding protein (CREB) is a molecular target of antidepressants and implicated in synaptic plasticity. We tested the hypotheses that long-term estrogen (E2) treatment: (1) alters components of the CREB signaling cascade in the amygdala and hippocampus of ovariectomized (OVX) rats; (2) has an anxiolytic effect in the elevated plus maze (EPM); (3) ameliorates alcohol-related anxiety in the EPM; and (4) increases protein levels of components of the CREB pathway. E2 increased protein levels of components of CREB pathway and protein and mRNA levels of the CREB-related gene product brain-derived neurotrophic factor (BDNF) in the medial and basomedial amygdala and CA1 and CA3 regions of the hippocampus. Components of the CREB pathway examined include: calcium/calmodulin-dependent protein kinase IV (CaMK IV), CREB, and phosphorylated CREB (pCREB). No changes in CREB protein levels were seen in hippocampus. E2 decreased levels of calcineurin, which is capable of dephosphorylating CREB, in the medial and basomedial amygdala and CA1 region of the hippocampus.; E2 had an anxiolytic effect in the EPM. During ethanol withdrawal, rats were anxiogenic in the EPM and components of the CREB pathway were down-regulated in the medial and central amygdala. Ethanol withdrawn rats pretreated with E2 for 15 days showed an increase in anxiolytic behavior in the EPM relative to the vehicle-treated controls. In these rats, levels of CaMK IV, pCREB, CREB and BDNF protein and BDNF mRNA were increased relative to vehicle-treated ethanol withdrawn rats; no effect of E2 was observed in the central amygdala. Therefore, the positive effect of E2 on anxiety is associated with an increase in levels of components of the CREB pathway and BDNF in the medial amygdala. We identify a neuroanatomically novel molecular pathway in the limbic brain that is regulated by E2 and which provides a basis for interventional strategies for the amelioration of female-related mood disorders, including those associated with alcohol abuse.