The Development of Kisspeptin Circuits in the Mammalian Brain - Kisspeptin Signaling in Reproductive Biology - page 224

Likewise, in the developing rat hippocampus, higher levels of postnatal sex steroids in
males increase the number of new cells, leading to more neurons present in males than
in females [ 75 ]. However, because the AVPV/PeN as a whole does not undergo dif-
ferential neurogenesis during the postnatal critical period [ 32 ], differential neurogen-
esis between males and females may not be a major contributor to the sexual
differentiation of specifi c subpopulations within the AVPV/PeN, such as the kisspeptin
neurons. However, this assertion has not yet been directly tested.
One of the primary mechanisms implicated in the sexual differentiation of a num-
ber of sexually dimorphic brain populations is programmed cell death (apoptosis)
[ 76 - 78 ]. In fact, in rodents, sex differences in the overall size and total cell number
of the AVPV region, as well as other brain regions such as the BNST, are induced
by apoptosis. Most of these apoptosis-induced sex differences are dependent on the
pro-apoptotic gene, Bax [ 77 - 79 ]. BAX is a protein located primarily in the cytosol
in a healthy cell. In response to cell death signals, BAX translocates to the mito-
chondria where it precipitates the release of cytochrome c, thereby triggering cas-
pase pathways that culminate in cell death [ 80 ]. Interestingly, in the developing rat
AVPV, postnatal males have higher Bax expression than postnatal females, which
possibly initiates more cell death in the former sex [ 81 ]. Higher Bax expression in
postnatal males than females therefore correlates with the presence of fewer AVPV
cells in adult males. The sexually dimorphic postnatal Bax levels also coincide with
higher sex steroid levels in postnatal males than females, suggesting that sex ste-
roids might affect postnatal Bax expression [ 81 ]. Supporting this prediction, E 2
treatment of neonatal female rats increases the number of apoptotic AVPV neurons
[ 82 ]. Importantly, a recent study determined that the sex difference in total number
of AVPV neurons is eliminated in Bax knockout mice [ 76 ]. Thus, total cell number
in the AVPV is sexually differentiated via Bax -dependent apoptotic mechanisms.
Despite these fi ndings, the sexual differentiation of Kiss1 neurons in the AVPV/PeN
is surprisingly unaltered in Bax knockout mice [ 40 ]. When Kiss1 cell numbers are
compared between adult male and female Bax KO mice, the Kiss1 sex difference
was still incredibly robust [ 40 ]. Thus, the Kiss1 population is sexually differentiated
either by other apoptotic pathways, such as tumor necrosis -dependent or -inde-

pendent mechanisms (as may be the case for AVPV GABA-ergic neurons [ 78 ]) or,
by non-apoptosis-related mechanisms (Fig. 11.4 ).
It is likely that the sexual differentiation of AVPV/PeN Kiss1 cells is not induced
by mechanisms that affect the physical existence of cells (like apoptosis). Rather,
sex differences in Kiss1 cell number may be induced by developmental mechanisms
affecting transcriptional activity of the Kiss1 gene (Fig. 11.4 ) [ 5 , 83 ]. In fact, epi-
genetic changes, such as histone modifi cations and DNA methylation, precipitated
by postnatal sex steroids are emerging as critical contributors to alterations in neu-
ronal cell number and gene expression between the sexes [ 73 , 84 - 88 ]. Histones are
proteins that allow for the packaging of DNA into chromatin. When histones are
modifi ed, such as by acetylation, transcriptional activity is altered [ 89 ]. Histone
acetylation, which is generally associated with increased transcriptional activity,
has recently been implicated in the sex steroid-induced sexual differentiation of the
BNST [ 73 ]. For example, inhibiting histone deacetylase (HDAC) during the early

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