Sex differences in adult hippocampal neurogenesis and the influence of estradiol

Sex differences exist in hippocampal plasticity, cognition, and in various brain diseases that target the integrity of the hippocampus. Females are more likely to be diagnosed with stress and anxiety related disorders and have a greater lifetime risk for Alzheimer’s disease than males. Females are more likely to experience greater cognitive decline in Alzheimer’s disease and cognitive symptoms in depression and post-traumatic stress disorders, and these diseases characterized by hippocampal dysfunction. The hippocampus is a highly plastic structure, important for processing higher order information, and is sensitive to intrinsic and extrinsic factors such as gonadal hormones and cognitive training. The hippocampus retains the ability to produce new neurons in the dentate gyrus, and new neurons play an important role in pattern separation, a process of separating similar inputs and making distinct neural representations during memory encoding. This thesis investigated sex differences in and the effects of estrogens on basal characteristics of neurogenesis, and in neural network of activated neurons following pattern separation. In Chapter 2, I found that adult-born neurons matured faster in males compared to females, whereas males showed a greater reduction in neurogenesis between one week and two weeks after mitosis. The faster maturation and greater attrition of new neurons in males compared to females suggests greater potential for neurogenesis to respond to external stimuli in males. In Chapter 3, I found that females showed greater contextual pattern separation compared to males, with females and males employing different brain networks during fear memory retrieval. In Chapter 4, I found that estradiol and estrone initially enhanced production of immature neurons whereas long exposure to estrogens eliminated the enhancing effects on neurogenesis. In Chapter 5, I found that a chronic high dose of estradiol reduced adult neurogenesis in females, but also enhanced functional connectivity in the hippocampus during spatial pattern separation. Overall, these results highlight the importance of studying sex differences and hormonal regulation of hippocampal neuroplasticity and the contribution of adult neurogenesis to hippocampus-dependent cognition. Therefore, attention to these factors in research will lead to a better understanding how sex contributes to the susceptibility to hippocampus-related diseases.Medicine, Faculty ofGraduat