Turning sex inside-out: Peripheral contributions to sexual differentiation of the central nervous system

2018

Although gonadal testosterone is the principal endocrine factor that promotes masculine traits in mammals, the development of a male phenotype requires local production of both androgenic and oestrogenic signals within target tissues. Much of our knowledge concerning androgenic components of testosterone signalling in sexual differentiation comes from studies of androgen receptor (Ar) loss of function mutants. Here, we review these studies of loss of Ar function and of AR overexpression either globally or selectively in the nervous system of mice. Global and neural mutations affect sociosexual behaviour and the neuroanatomy of these mice in a sexually differentiated manner. Some masculine traits are affected by both global and neural mutation, indica- is remarkable, and it is fair to say that this stems largely from the apt discussion of the findings, which captured the key questions that drive research in this field even today. One of the key conclusions of these studies was that testosterone promotes masculine behavioural traits and removes feminine behavioural traits likely by affecting the nervous system. This is the beginning of the site of action question concerning the action of testosterone in sexual differentiation of brain and behaviour. The assumption that behavioural change was the result of brain change was criticised at the time as being unwarranted because, logically, it was equally likely that sexually differentiated sexual responses could be driven, for example, by sexually differentiated genitalia. A wealth of experimental data has subsequently left no doubt that testosterone sexually differentiates the nervous system structurally, functionally and biochemically, and the field has increasingly focused on the brain as the site of testosterone action in producing masculine behavioural phenotypes. 4 Nonetheless, there is reason to

Section: Neural‐specific Models Of Loss Of Functionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Non‐neural androgen receptors affect sexual differentiation of brain and behaviour

Monks

2018

“…Although AR has been implicated in androgenic regulation of survival of new neurones in the hippocampus, it is unclear where it acts to do so. Although a local androgenic mechanism within the hippocampus is the most straightforward hypothesis, indirect effects of AR on neural structures are common . Similarly, both a neural activation hypothesis and peripheral/non‐neural hypothesis have been proposed to explain environmental effects on adult neurogenesis in the hippocampus.…”

Section: Introductionmentioning

confidence: 99%

Neural androgen receptors affect the number of surviving new neurones in the adult dentate gyrus of male mice

Duarte‐Guterman

Hamson

et al. 2018

Adult hippocampal neurogenesis occurs in many mammalian species. In rats, the survival of new neurones within the hippocampus is modulated by the action of androgen via the androgen receptor (AR); however, it is not known whether this holds true in mice. Furthermore, the evidence is mixed regarding whether androgens act in neural tissue or via peripheral non-neural targets to promote new neurone survival in the hippocampus. We evaluated whether the action of androgen via AR underlies the survival of new neurones in mice, and investigated whether increasing AR selectively in neural tissue would increase new neurone survival in the hippocampus. We used the cre-loxP system to overexpress AR only in neural tissues (Nestin-AR). These males were compared with wild-type males, as well as control males with 1 of the 2 mutations required for overexpression. Mice were gonadectomised and injected with the DNA synthesis marker, bromodeoxyuridine (BrdU) and for 37 days (following BrdU injection), mice were treated with oil or dihydrotestosterone (DHT). Using immunohistochemistry, proliferation (Ki67) and survival (BrdU) of new neurones were both evaluated in the dorsal and ventral dentate gyrus. Dihydrotestosterone treatment increased the survival of new neurones in the entire hippocampus in wild-type mice and control mice that only have 1 of 2 necessary mutations for transgenic expression. However, DHT treatment did not increase the survival of new neurones in mice that overexpressed AR in neural tissue. Cell proliferation (Ki67) and cell death (pyknotic cells) were not affected by DHT treatment in wild-type or transgenic males. These results suggest that androgens act via neural AR to affect hippocampal neurogenesis by promoting cell survival; however, the relationship between androgen dose and new neurone survival is nonlinear.

“…The evidence used to formulate and test the hypothesised sites of androgen action with respect to masculinising the SNB system has come from experiments using local pharmacological and surgical approaches, as well as studies of loss of AR function mutants . For example, in agreement with the results of selective ablation of neonatal spinal cord containing the SNB and local delivery of AR antagonist to the perineum, testosterone increases survival of rat SNB motoneurones regardless of whether they express functional AR .…”

Section: Introductionmentioning

confidence: 99%

Neural androgen receptor overexpression affects cell number in the spinal nucleus of the bulbocavernosus

Coome

Ramzan

et al. 2017

The spinal nucleus of the bulbocavernosus (SNB) is a sexually dimorphic neuromuscular system in which the masculinisation of cell number is assumed to depend on the action of perinatal androgen in non-neural targets, whereas the masculinisation of cell size is assumed to depend primarily on the action of adult androgen on SNB cells themselves. To test these hypotheses, we characterised the SNB of Cre/loxP transgenic mice that overexpress androgen receptor (AR) throughout the body (CMV-AR) or in neural tissue only (Nestin-AR). Additionally, we examined the effects of androgen manipulation in male mutants and wild-type (WT) controls. We reproduced the expected sex differences in both motoneurone number and size, as well as the expected adult androgen dependence of SNB size. We found effects of genotype such that both Nestin-AR and CMV-AR have more SNB motoneurones than WT littermates and also that CMV-AR females have larger SNB motoneurones than Nes-AR or WT females. These results raise the possibility that AR can act in neurones and/or glia to rescue SNB motoneurones, as well as on non-neural AR to increase SNB cell size.