Sex specific effects of estrogen on the neural substrates of episodic and fear memory

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A large body of evidence accumulated showing that the most important estrogen, 17beta-estradiol (E2), modifies plasticity in the animal hippocampus. Behaviourally, E2 impacts on hippocampus-dependent memory. Neuroactive E2 is synthesised locally by hippocampal neurons and acts in a paracrine but also intracellular manner. More recently, the modulation by E2 of other memory-related brain areas, i.e. the perirhinal cortex and the amygdala, has also been described. In addition, E2 affects neuronal plasticity by interacting with the dopaminergic system, which modulates in turn memory formation. With respect to the male brain, similar effects of E2 on the male and female hippocampus have been described in vitro. However, the pattern of data on in vivo effects of E2 is currently inconsistent. The current project aims to translate these findings on central effects of E2 from animals to humans by combining functional magnetic resonance imaging (fMRI) with the pharmacological application of E2. Crucially, an increase in serum E2 levels triggers the central release of Gonadotropin-releasing hormone (GnRH) which in turn regulates E2-synthesis in the brain, resulting in a positive correlation of serum and neuronal E2 levels in both sexes. Hence, a pharmacological increase in serum E2 levels will result in enhanced E2 concentrations in the brain. Moreover, the existing neuroimaging literature shows that fMRI is feasible to detect the neural correlates of brief and subtle fluctuations in hormone levels. To translate the results from animal studies as well as to connect to our own work in the human brain, we will investigate the effect of E2 on three mnestic phenomena and their neural correlates. In particular, we will study the effect of E2 in the amygdala on the consolidation of fear extinction memory. Secondly, we will identify differential modulations of plasticity by E2 in the perirhinal cortex and hippocampus as well as on the specific mnestic processes computed in these areas. Thirdly, the effect of E2 on the dopaminergic modulation of memory formation and also its interaction with reward processing will be determined. In addition, we aim to systemically characterize the sex-specific effects of E2 on the human brain. In particular, E2 levels will be increased pharmacologically in young female but also male volunteers, and the same memory paradigms will be studied in both sexes. Altogether, the current project will be the first systematic and differential characterization of the effects of E2 on human female and male brains and behavior. The results of our experiments are of interest to basic research as they closely connect to findings in animals and will in turn stimulate further animal research. In addition, the experiments are of clinical relevance, since preclinical models of human affective and addictive disorders, i.e. fear conditioning and reward processing, will be studied that show a sex-dependent prevalence consistent with an influence of E2.