Figure 4. Cell genesis may become a new fundamental principle of sexual differentiation of the brain.

There are almost twice as many future neurons being born in the developing hippocampus of male rat pups compared to their female littermates. Treating females with estradiol increases the rate of neurogenesis to that of males, while treating males with either an estrogen receptor antagonist or aromatase inhibitor decreases the rate to that of females [97]. This sex difference is notably different than the well established fundamental principle of sex differences in cell death in select nuclei during the perinatal period. A second example of a sex difference in cell genesis is illustrated here and is unusual in several ways. First is that a sex difference in the overall tone of endocannabinoids mediates the sex difference. Females have higher levels of the degradation enzymes, FAAH and MAGL, and as a result have lower resting levels of the endocannabinoids, 2-AG and anandamide. There is also a higher rate of cell proliferation in the medial amygdala of females during the early neonatal period. Raising the endocannabinoid tone by either inhibiting FAAH and MAGL or supplying exogenous endocannabinoids, reduces the rate of proliferation in females to that of males, but has no effect on males. Lastly, most of the new cells being born during the perinatal period will differentiate into neurons, but a small population that accounts for the observed sex difference will become astrocytes, and as a result females have more astrocytes in the medial amygdala compared to males [89].