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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.

Both natural estrogens and progesterone influence synaptic plasticity and neurogenesis within the female hippocampus. However, less is known of the impact of synthetic hormones on hippocampus structure and function. There is some evidence that administration of the synthetic progestin, medroxyprogesterone acetate (MPA) is not as beneficial as natural progesterone and can attenuate estrogen-induced neuroprotection. Although estradiol’s effects have been well studied, little is known about the effects of natural and synthetic progestins alone and in combination with estradiol on adult neurogenesis in the female. In the present study, we investigated the effects of chronic estradiol, progesterone, MPA, and a co-administration of each progestin with estradiol on neurogenesis within the dentate gyrus of adult ovariectomized female rats. Twenty-four hours following a bromodeoxyuridine (BrdU; 200mg/kg) injection, female rats were repeatedly administered with either progesterone (1 or 4 mg), MPA (1 or 4 mg), estradiol benzoate (EB), progesterone or MPA in combination with EB (10