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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.

Additional file 1: Table S1. A list of antibodies used in the present study. Table S2. A list of reagents used in the present study. Table S3. Mean (±SEM) duration of rearing, grooming and non-specific behaviors in males and females during the activation trial. Figure S1. A-B: Mean (±SEM) density of adult-born cells in the dorsal (A) and ventral (B) dentate gyrus. There were no significant sex differences in the density of DCX-ir cells, IdU-ir cells or CldU-ir cells in the dorsal or ventral dentate gyrus. Figure S2. A-C: Mean (±SEM) density of zif268-ir cells in the nucleus accumbens (A), the amygdala (B) and the dorsal striatum (C). The density of zif268-ir cells in the nucleus accumbens shell is greater compared to the nucleus accumbens core (A). Females, compared to males, showed greater density of zif268-ir cells in the amygdala (B). A priori we found that the density of zif268-ir cells was significantly greater in the lDS compared to mDS in males, but not in females. * indicates p < 0.05.

Decision-making is a complex process essential to daily adaptation in many species. Risk is an inherent aspect of decision-making and it is influenced by gonadal hormones. Testosterone and 17β-estradiol may modulate decision making and impact the mesocorticolimbic dopamine pathway. Here, we explored sex differences, the effect of gonadal hormones and the dopamine agonist amphetamine on risk-based decision making. Intact or gonadectomised (GDX) male and female rats underwent to a probabilistic discounting task. High and low doses of testosterone propionate (1.0 or 0.2 mg) and 17β-estradiol benzoate (0.3 µg) were administered to assess acute effects on risk-based decision making. After 3-days of washout period, intact and GDX rats received high or low (0.5 or 0.125 mg/kg) doses of amphetamine and re-tested in the probabilistic discounting task. Results showed that males made more risk-based choices during the probability discounting task than female rats, but GDX did not influence risky choices. The high dose, but not the low dose, of testosterone reduced risky decision making in GDX male rats. However, 17β-estradiol had no significant effect on risk-based decision making regardless GDX status in either sex. Lastly, the high dose of amphetamine enhanced risky decision making in both intact males and females, with no effect in GDX rats. These findings demonstrated sex differences in risk-based decision making, with males making more risky choices. GDX status influenced the effects of amphetamine, suggesting different dopaminergic regulation in risk-based choices among males and females. Highlights Male rats made more risky choices in the probability discounting task than females. Gonadectomy (GDX) did not influence risk-based decision making in both sexes. A high dose of testosterone reduced risky choices in GDX male rats. A high dose of amphetamine enhanced risky choices in intact male and female rats. 17β-estradiol did not affect risk-based decision making in male or female rats.

Sex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused one, two or three weeks after BrdU injection, marking newly dividing cells. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than females. Males had a greater reduction in neurogenesis between one and two weeks after mitosis, while females showed similar levels of neurogenesis throughout. The faster maturation and attrition of new neurons suggests greater potential for neurogenesis to respond to external stimuli in males compared to females and emphasizes the importance of studying sex on adult hippocampal neurogenesis.

Adult neurogenesis in the dentate gyrus (DG) plays a crucial role for pattern separation and there are sex differences in the regulation of neurogenesis. Although sex differences, favoring males, in spatial navigation have been reported, it is not known whether there are sex differences in pattern separation. The current study was designed to determine whether there are sex differences in the ability for separating similar or distinct patterns, learning strategy choice, adult neurogenesis and immediate early gene (IEG) expression in the DG in response to pattern separation training. Male and female Sprague-Dawley rats received a single injection of the DNA synthesis marker, bromodeoxyuridine (BrdU) and were tested for the ability of separating spatial patterns in a spatial pattern separation version of delayed nonmatching to place task using the 8-arm radial arm maze. Twenty eight days following BrdU injection, rats received a probe trial to determine whether they were idiothetic or spatial strategy users. We found that male spatial strategy users outperformed female spatial strategy users only when separating similar, but not distinct, patterns. Furthermore male spatial strategy users had greater neurogenesis in response to pattern separation training than all other groups. Interestingly neurogenesis was positively correlated with performance on similar pattern trials during pattern separation in female spatial strategy users but negatively correlated with performance in male idiothetic strategy users. These results suggest that the survival of new neurons may play an important positive role for pattern separation of similar patterns in females. Furthermore, we found sex and strategy differences in IEG expression in the CA1 and CA3 regions in response to pattern separation. These findings emphasize the importance of studying biological sex on hippocampal function and neural plasticity.

Adult neurogenesis in the dentate gyrus (DG) plays a crucial role for pattern separation and there are sex differences in the regulation of neurogenesis. Although sex differences, favoring males, in spatial navigation have been reported, it is not known whether there are sex differences in pattern separation. The current study was designed to determine whether there are sex differences in the ability for separating similar or distinct patterns, learning strategy choice, adult neurogenesis and immediate early gene (IEG) expression in the DG in response to pattern separation training. Male and female Sprague-Dawley rats received a single injection of the DNA synthesis marker, bromodeoxyuridine (BrdU) and were tested for spatial pattern separation in a delayed nonmatching to place task using the 8-arm radial arm maze. Twenty eight days following BrdU injection, rats received a probe trial to determine whether they were idiothetic or spatial strategy users. We found that male spatial strategy users outperformed female spatial strategy users only when separating similar, but not distinct, patterns. Furthermore male spatial strategy users had greater neurogenesis in response to pattern separation training than all other groups. Interestingly neurogenesis was positively correlated with performance on similar pattern trials during pattern separation in female spatial strategy users but negatively correlated with performance in male idiothetic strategy users. These results suggest that the survival of new neurons may play an important positive role for pattern separation of similar patterns in females. Furthermore, we found sex and strategy differences in IEG expression in the CA1 and CA3 regions in response to pattern separation. These findings emphasize the importance of studying biological sex on hippocampal function and neural plasticity.