Neonatal Estrogen Decreases Neural Density of the Septum–Midbrain Central Gray Connection Underlying the Lordosis-Inhibiting System in Female Rats

Tsukahara, Shinji; Ezawa, Naoki; Yamanouchi, Korehito

doi:10.1159/000073706

Cited by 16 publications

(9 citation statements)

References 45 publications

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“…The strength of inhibition in the intermediate part of the lateral septum [5], where its projections to the midbrain central gray are sexually dimorphic [54], is thought to be caused by neonatal injection with estrogen in a dose-dependent manner [55]. In the lateral septum, ERα exists only in the ventral part and not in the intermediate part in adult rats [56].…”

Section: Discussionmentioning

confidence: 99%

Defeminization of Brain Functions by a Single Injection of Estrogen Receptor α or β Agonist in Neonatal Female Rats

Kanaya

Yamanouchi²

2012

Neuroendocrinology

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Sexual differentiation of brain function is regulated by estrogen in the perinatal period of rodents. However, the role of the estrogen receptor subtypes ERα and ERβ is still in question. Accordingly, the effects of neonatal treatment with the ERα agonist propyl pyrazole triol (PPT) or the ERβ agonist diarylpropionitrile (DPN) on female reproductive functions were investigated in rats. Female rats were injected subcutaneously with 100–500 µg/10 g body weight (b.w.) PPT or DPN, 100 µg/10 g b.w. estradiol (E₂), or saline at day 5 (birth day = day 1), and then vaginal opening and vaginal smears were examined. On day 60, their ovaries were removed and lordosis behavior was observed after subcutaneous implantation of a silicon tube containing E₂. As a result, in most PPT and all E₂ rats, vaginal opening was advanced and an irregular estrous cycle was observed. In contrast, in most rats of the DPN groups, vaginal opening was comparable to that of the control and there was a regular estrous cycle. Lordosis tests revealed that the mean lordosis quotients (LQs) in the 250- and 500-µg PPT groups was lower than in the saline group, but higher than in the E₂ group. Mean LQs in all DPN groups were comparable to those in the saline group. These results suggest that ERα plays a major role in masculinization of the system regulating the estrous cycle in the rat brain. In behavioral defeminization of the lordosis-regulation system, ERα was also found to be the main target of estrogen.

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Section: Discussionmentioning

confidence: 99%

Defeminization of Brain Functions by a Single Injection of Estrogen Receptor α or β Agonist in Neonatal Female Rats

Kanaya

Yamanouchi²

2012

Neuroendocrinology

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“…Neural projections from the LSi to MCG, which are involved in the inhibition of lordosis (Tsukahara and Yamanouchi, 2001), are sexually dimorphic. The number of LSi neurons that were labeled by FG, a retrograde neurotracer, injected into the MCG is greater in female rats than male rats (Tsukahara and Yamanouchi, 2002; Tsukahara et al, 2003) (Figures 4A,B). The sex difference in the neural connectivity between the LSi and MCG is presumably related to the sex difference in inhibitory regulation of lordosis.…”

Section: Lordosis-inhibiting System In the Lsmentioning

confidence: 99%

Neuroanatomy and sex differences of the lordosis-inhibiting system in the lateral septum

2014

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Female sexual behavior in rodents, termed lordosis, is controlled by facilitatory and inhibitory systems in the brain. It has been well demonstrated that a neural pathway from the ventromedial hypothalamic nucleus (VMN) to the midbrain central gray (MCG) is essential for facilitatory regulation of lordosis. The neural pathway from the arcuate nucleus to the VMN, via the medial preoptic nucleus, in female rats mediates transient suppression of lordosis, until female sexual receptivity is induced. In addition to this pathway, other regions are involved in inhibitory regulation of lordosis in female rats. The lordosis-inhibiting systems exist not only in the female brain but also in the male brain. The systems contribute to suppression of heterotypical sexual behavior in male rats, although they have the potential ability to display lordosis. The lateral septum (LS) exerts an inhibitory influence on lordosis in both female and male rats. This review focuses on the neuroanatomy and sex differences of the lordosis-inhibiting system in the LS. The LS functionally and anatomically links to the MCG to exert suppression of lordosis. Neurons of the intermediate part of the LS (LSi) serve as lordosis-inhibiting neurons and project axons to the MCG. The LSi-MCG neural connection is sexually dimorphic, and formation of the male-like LSi-MCG neural connection is affected by aromatized testosterone originating from the testes in the postnatal period. The sexually dimorphic LSi-MCG neural connection may reflect the morphological basis of sex differences in the inhibitory regulation of lordosis in rats.

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“…Moreover, approximately 60% of genes showing male or female-biased expression demonstrated altered levels with EB in females, pointing to an involvement of genes necessary for normal processes of male-or female-type brain sexual differentiation in its disruptive effects. It is well known that the perinatal/neonatal treatment of animals with estrogenic compounds can affect sexual development of both sexes, resulting in reproductive dysfunction (Nagao et al, 1999;Odum et al, 2002;Tsukahara et al, 2003;Shibutani et al, 2005). With regard to the effects of antiandrogens, disruption of sexual development has generally been apparent in males, but the situation is largely unclear for females (Gray and Kelce, 1996;Wolf et al, 2004).…”

Section: Figurementioning

confidence: 99%

“…For instance, both and estrogen receptors (ERs) are strongly expressed in the hypothalamus during neonatal development, showing region-specific distributions (Orikasa et al, 2002), and neonatal hormonal manipulations can affect their expression levels and/or locations (TenaSempere et al, 2001;Orikasa et al, 2002), resulting in organizational changes in the brain structure and reproductive function in later life (Nagao et al, 1999;Tsukahara et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Hypothalamus region‐specific global gene expression profiling in early stages of central endocrine disruption in rat neonates injected with estradiol benzoate or flutamide

Shibutani

Lee

Igarashi

et al. 2007

Developmental Neurobiology

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To identify genes linked to early stages of disruption of brain sexual differentiation, hypothalamic region-specific microarray analyses were performed using a microdissection technique with neonatal rats exposed to endocrine-acting drugs. To validate the methodology, the expression fidelity of microarrays was first examined with two-round amplified antisense RNAs (aRNAs) from methacarn-fixed paraffin-embedded tissue (PET) in comparison with expression in unfixed frozen tissue (UFT). Decline of expression fidelity when compared with the 1x-amplified aRNAs from UFTs was found as a result of the preferential amplification of the 3' side of mRNAs in the second round in vitro transcription. However, expression patterns for the 2x-amplified aRNAs were mostly identical between methacarn-fixed PET and UFT, suggesting no obvious influence of methacarn fixation and subsequent paraffin embedding on expression levels. Next, in the main experiment, neonatal rats at birth were treated subcutaneously either with estradiol benzoate (EB; 10 microg/pup) or flutamide (FA; 250 microg/pup), and medial preoptic area (MPOA)-specific microarray analysis was performed 24 h later using 2x-amplified aRNAs from methacarn-fixed PET. Numbers of genes showing constitutively high expression in the MPOA predominated in males, implying a link with male-type growth supported by perinatal testosterone. Around 60% of genes showing sex differences in expression demonstrated altered levels after EB treatment in females, suggesting an involvement of genes necessary for brain sexual differentiation. When compared with EB, FA affected a rather small number of genes, but fluctuation was mostly observed in females, as with EB. Moreover, many selected genes common to EB and FA showed down-regulation in females with both drugs, suggesting a common mechanism for endocrine center disruption in females, at least at early stages of post-natal development.

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Neonatal Estrogen Decreases Neural Density of the Septum–Midbrain Central Gray Connection Underlying the Lordosis-Inhibiting System in Female Rats

Cited by 16 publications

References 45 publications

Defeminization of Brain Functions by a Single Injection of Estrogen Receptor α or β Agonist in Neonatal Female Rats

Defeminization of Brain Functions by a Single Injection of Estrogen Receptor α or β Agonist in Neonatal Female Rats

Neuroanatomy and sex differences of the lordosis-inhibiting system in the lateral septum

Hypothalamus region‐specific global gene expression profiling in early stages of central endocrine disruption in rat neonates injected with estradiol benzoate or flutamide

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