Symposium
Recent Progress in Gonadal Steroid Action on the Modulation of Multiple Brain Functions and Behaviors
シンポジウム
ステロイドホルモンによる多様な脳機能と行動の調節に関する研究の最前線 |
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| 7月25日（木）16:55～17:20 第5会場（朱鷺メッセ 3F 302）
1S05e-1
Latent Sex Differences in Acute Estradiol Modulation of Excitatory Synapses in the Hippocampus
Catherine S Woolley（Woolley Catherine S）
Northwestern University
The hippocampus of both sexes synthesizes estrogens as neurosteroids that can potentiate excitatory synapses on a time scale of minutes. We have used hippocampal slice electrophysiology and pharmacology to investigate whether and how molecular mechanisms that underlie acute estradiol (E2)-induced synaptic potentiation differ between the sexes. These studies showed that despite apparently identical E2-induced potentiation in males and females, the roles of three estrogen receptor (ER) subtypes (ERα, ERβ, GPER1), cAMP-regulated protein kinase, internal calcium stores, and L-type calcium channels differ between the sexes. Other kinases, including Src, Erk, ROCK, and CaMKII, appear to be similarly involved in each sex. The results of these experiments demonstrate latent sex differences in which the same functional outcome in males and females is achieved through distinct underlying mechanisms in each sex. The existence of latent sex differences suggests that while males and females respond similarly to an endogenous neuromodulator, E2, they might respond differently to perturbations directed at specific components of the molecular pathway linking E2 to synaptic potentiation. We tested this using acute intra-hippocampal infusion of an ERβ agonist and found that this produced opposite effects on anxiety-like behavior in females and males. Together, these results indicate that molecular mechanisms targeted for drug development may differ between the sexes even in the absence of an overt sex difference in disease. | | 7月25日（木）17:20～17:45 第5会場（朱鷺メッセ 3F 302）
1S05e-2
視索前野におけるカルビンディンニューロンの性分化
Shinji Tsukahara（塚原 伸治）
埼玉大院理工生命科学
Nuclei exhibiting morphological sex differences are called sexually dimorphic nuclei. The first sexually dimorphic nucleus was discovered in the preoptic area of rats. This nucleus is known to express calbindin, a calcium binding protein. The nucleus of male rats contains more calbindin neurons compared with female rats, and it is therefore called the calbindin-sexually dimorphic nucleus (CALB-SDN). The CALB-SDN have been found in other species including mice, musk shrews, common marmosets, suggesting the sex differences in this nucleus are conserved across species. In rodents, it is classically documented that testicular testosterone in the perinatal period acts to masculinize and defeminize the brain after testosterone is converted to estradiol by aromatase. The CALB-SDN in mice is masculinized by aromatized testosterone, but not by non-aromatized testosterone. The classic view of the sexual differentiation of the brain is revised by studies for the last few decades. Testicular testosterone in the peripubertal period also contribute to the sexual differentiation of the brain. We recently found that calbindin neuron number of the CALB-SDN in adult male mice are decreased by prepubertal orchidectomy. Additionally, the decreased calbindin neuron number in adult male mice by prepubertal orchidectomy are recovered by testosterone replacement in the peripubertal period, but not by estradiol replacement. These findings suggest a difference in the mode of actions of testicular testosterone between the perinatal and peripubertal periods for masculinization of the CALB-SDN. As many researchers studied, calbindin is a useful marker to determine the morphological sex differences in the preoptic area, although the physiological roles of calbindin require further investigation. The preoptic area is known to be involved in the control of sexual behavior. In the result of our study for testing the effects of knockdown of calbindin in the preoptic area, we found that knockdown of calbindin had no effect on sexual behavior in male rats. In contrast, the performance to display lordosis, a female sexual behavior, in female rats decreased with knockdown of calbindin, suggesting that calbindin in the preoptic area is involved in the regulation of female sexual behavior. | | 7月25日（木）17:45～18:05 第5会場（朱鷺メッセ 3F 302）
1S05e-3
雌雄の社会行動発現の制御におけるエストロゲン受容体の役割
Kazuhiro Sano（佐野 一広），Tetsu Hatsukano（初鹿野 徹），Sonoko Ogawa（小川 園子）
筑波大学行動神経内分泌研究室
Gonadal steroids such as testosterone (T) and estradiol (E2) play a crucial role in the regulation of social behaviors and the development of their neural bases in both male and female mice. In males, T is secreted from testis. It can act not only through androgen receptors (AR), but also through estrogen receptors - both α (ERα) and β (ERβ) - after being aromatized to E2 in the brain. In females, E2 is secreted from ovaries and acts through ERα and ERβ. Studies using knockout models have shown that the absence of ERα results in a great reduction of social behaviors in both sexes while the effect of ERβ deletion was context dependent. Thus, the presence of ERα is suggested to be essential whereas the role of ERβ may be modulatory for the expression of social behaviors. However, it is not fully understood of `when' and `where' the activation of these receptors by gonadal steroid is important for the expression of social behaviors or the development of their neural basis. We have been working on this issue mainly by using virally mediated RNAi methods and have elucidated several `site-specific' and `time-specific' roles of ERα and ERβ in both male and female mice. For example, activation of ERα in the medial preoptic area (MPOA) at the time of testing is required for the facilitation of sexual but not aggressive behaviors while in the ventromedial nucleus of the hypothalamus (VMH) it is required for both behaviors in adult males. In the medial amygdala (MeA), activation of ERα during pubertal period is absolutely necessary for a full expression of male sexual and aggressive behaviors, although activation at the time of testing is not required. In females, expression of ERβ in the dorsal raphe nucleus (DRN) is required for the inhibition of lordosis responses during non-estrous stages. In this talk, we will present these findings and also introduce several on-going studies in our laboratory. | | 7月25日（木）18:05～18:30 第5会場（朱鷺メッセ 3F 302）
1S05e-4
Non-genomic signaling by estrogens via the G-protein coupled estrogen receptor 1 (GPER1) are important for social behaviours
Nandini Vasudevan（Vasudevan Nandini），DeAsia Davis（Davis DeAsia），Ruby Vajaria（Vajaria Ruby），Evangelos Delivopoulos（Delivopoulos Evangelos）
University of Reading, UK
Estrogens are required for the display of sex-typical social behaviours in rodents by acting on nuclei of the social behaviour network. These include nuclei in the hypothalamus, lateral septum, amygdala and the bed nucleus of the stria terminalis. Estrogens like 17&beta-estradiol signal via both genomic and the lesser understood nongenomic pathway. In the genomic pathway, estrogens regulate transcription by binding to classical, intracellular nuclear receptors such as the estrogen receptor (ER)&alpha and ER&beta. In the non-genomic pathway, a membrane estrogen receptors (mERs) whose identity is unknown binds 17&beta-E and signals rapidly and non-genomically to activate kinases and calcium flux. Previously, our laboratory demonstrated that a third pathway that we termed coupled or integrated signalling exists where rapid non-genomic signaling by 17&beta-E potentiates transcription via the phosphorylation of the ER. How this interactive pathway drives social behaviours is still unclear.
Although ER&alpha and ER&beta are themselves present on the cell membrane, novel candidate mERs include the GPER1/GPR30 that appear to be present in several brain nuclei involved in social behaviours, presumably along with ER&alpha and ER&beta. The identity and function of this mER remains controversial. Recently, we demonstrated that GPER1 activation is sufficient for lordosis behaviour and regulates spinogenesis in hypothalamic nuclei, suggesting that this is a receptor capable of initiating the non-genomic signalling part of the coupled signalling pathway. We suggest that GPER1 upregulation of spinogenesis is important for lordosis behaviour. What is the role of GPER1 in males? Contrary to the need for transcription for lordosis behaviour, in the male mouse GPER1 activation can rapidly decrease anxiety. It can also increase the levels of a dendritic spine marker, PSD-95 in the hypothalamus. We also show localization of GPER1 in a novel system of differentiated neurons and astrocytes from mouse embryonic stem cells; the implications of this localization and signalling pathways initiated by GPER1 will be discussed. | | 7月25日（木）18:30～18:50 第5会場（朱鷺メッセ 3F 302）
1S05e-5
Innate immune cells are crucial regulators of hormonally-driven sexual differentiation of brain and motivated behavior
Kathryn M Lenz（Lenz Kathryn M）
Dept. Psychology, Dept. Neuroscience, The Ohio State University, Columbus, Ohio, USA
Steroid hormones control sex-specific brain development by shaping the trajectory of normal developmental processes in the brain, including cell genesis, cell death, migration, and synaptic patterning. Recent attention has been directed at the role of the immune system in normal brain development, particularly on the role of the brain-resident macrophages, called microglia. Yet few studies have assessed the intersection of these fields, namely whether innate immune cells contribute to sex-specific brain development. We have recently found robust, hormonally-determined sex differences in innate immune cells in the rat brain, both microglia as well as the less studied mast cell, both in terms of their number and signaling. We have found that crosstalk between these cell types during brain development programs sex specific synaptic patterning and lifelong behavioral sex differences. Mast cells in the neonatal brain are directly responsive to estrogens, whereas microglia are not. Sex-typical hormone exposure in the male brain during the perinatal period activates mast cells within the developing preoptic area (POA) to jump start the process of masculinizing synaptic connectivity, via mediating effects on microglia and their pro-inflammatory signaling. We have identified the neurotransmitter, histamine, as a key immune-derived mediator of this masculinization process in the POA. Activating mast cells or microglia in females, either pharmacologically or via allergic immune challenge, leads to masculinization of brain and behavior, including sexual and social preference behaviors. Conversely, inhibiting mast cell or microglia function downstream of steroid hormones disrupts male-typical development, including reproductive behavior. Interestingly, in response to early life allergic inflammation or immune challenge, males show dysmasculinization of juvenile rough and tumble play behavior. Together, these studies suggest that males and females show significant differences in immune cell function in the developing brain in response to hormone action, that impact both normal development as well as the brain's response to early life perturbations. | | | |
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