Sexually Dimorphic Formation of the Preoptic Area and the Bed Nucleus of the Stria Terminalis by Neuroestrogens

Abstract

Testicular androgens during the perinatal period play an important role in the sexual differentiation of the brain of rodents. Testicular androgens transported into the brain act via androgen receptors or are the substrate of aromatase, which synthesizes neuroestrogens that act via estrogen receptors. The latter that occurs in the perinatal period significantly contributes to the sexual differentiation of the brain. The preoptic area (POA) and the bed nucleus of the stria terminalis (BNST) are sexually dimorphic brain regions that are involved in the regulation of sex-specific social behaviors and the reproductive neuroendocrine system. Here, we discuss how neuroestrogens of testicular origin act in the perinatal period to organize the sexually dimorphic structures of the POA and BNST. Accumulating data from rodent studies suggest that neuroestrogens induce the sex differences in glial and immune cells, which play an important role in the sexually dimorphic formation of the dendritic synapse patterning in the POA, and induce the sex differences in the cell number of specific neuronal cell groups in the POA and BNST, which may be established by controlling the number of cells dying by apoptosis or the phenotypic organization of living cells. Testicular androgens in the peripubertal period also contribute to the sexual differentiation of the POA and BNST, and thus their aromatization to estrogens may be unnecessary. Additionally, we discuss the notion that testicular androgens that do not aromatize to estrogens can also induce significant effects on the sexually dimorphic formation of the POA and BNST.

Keywords: androgens; bed nucleus of the stria terminalis; estrogens; preoptic area; sex difference; sexual differentiation of the brain; sexually dimorphic nucleus.

FIGURE 1

Morphological sex differences in the POA and BNST of rats and mice. The AVPV exhibits female-biased sex differences in volume and neuron number. Compared with males, females have a greater number of kisspeptin neurons, dopamine neurons, and GABA/glutamate neurons in the AVPV. The SDN-POA exhibits male-biased sex differences in volume and neuron number. The SDN-POA contains a cluster of Calb neurons termed CALB-SDN. The CALB-SDN is larger in volume and contains a larger number of Calb neurons in males than in females. The POA shows a sex difference in the dendritic synapse pattern. POA neurons in males have more dendritic spines compared with POA neurons in females. The BNST contains a male-biased sexually dimorphic nucleus (BNSTp), which is composed of a sexually dimorphic subregion that is larger in volume and number of Calb neurons in males (CALB-BNSTp) and a sexually dimorphic subregion that is larger in volume and number of non-Calb neurons in females (BNSTpv).

FIGURE 2

Possible mechanisms for organizing the sexually dimorphic structures of the POA and BNST of rats and mice. (A) The mechanism responsible for the sexual differentiation of dendritic synapse patterning in the POA, which was proposed by McCarthy and colleagues (see reviews Arambula and McCarthy, 2020; McCarthy, 2020). Estradiol (E), which is synthetized in the brain from testicular testosterone (T) during the perinatal period, stimulates histamine release from mast cells, which then stimulates prostaglandin E2 (PGE2) to increase dendritic spines. (B) The mechanism for organizing the sexually dimorphic structures of the SDN-POA/CALB-SDN and CALB-BNSTp. E originating from testicular T in the perinatal period protects a population of neurons from apoptotic cell death, although the neurochemical properties of the cell population have not been identified. Additionally, E may upregulate Calb expression, followed by induction of a male-biased sex difference in the number of Calb neurons. (C) The mechanisms for inducing a female-biased sex difference in the number of cells in the specific neuronal cell groups in the AVPV. E originating from testicular T in the perinatal period induces the death of GABA neurons by apoptosis to reduce their number. E may also reduce the number of kisspeptin neurons and dopamine neurons by a mechanism other than apoptosis, although the mechanism remains unknown. (D) The roles of T and E during the perinatal period in the sexual differentiation of the BNSTpv. T and E reduce the number of BNSTpv neurons that do not express Calb. However, identification of the neurochemical properties and the mechanism responsible for inducing the sex difference require further investigation.