Clinical Features of 544 Patients With Ruptured Aortic Aneurysm　- A Report From the Tokyo Acute Aortic Super Network Database.

BACKGROUND: Epidemiological data on ruptured aortic aneurysms from large-scale studies are scarce. The aims of this study were to: clarify the clinical course of ruptured aortic aneurysms; identify aneurysm site-specific therapies and outcomes; and determine the clinical course of patients receiving conservative therapy.Methods and Results: Using the Tokyo Acute Aortic Super Network database, we retrospectively analyzed 544 patients (mean [±SD] age 78±10 years; 70% male) with ruptured non-dissecting aortic aneurysms (AAs) after excluding those with impending rupture. Patient characteristics, status on admission, therapeutic strategy, and outcomes were evaluated. Shock or pulselessness on admission were observed in 45% of all patients. Conservative therapy, endovascular therapy (EVT), and open surgery (OS) accounted for 32%, 23%, and 42% of cases, respectively, with corresponding mortality rates of 93%, 30%, and 29%. The overall in-hospital mortality rate was 50%. The prevalence of pulselessness was highest (48%) in the ruptured ascending AA group, and in-hospital mortality was the highest (70%) in the ruptured thoracoabdominal AA group. Multivariable logistic regression analysis indicated in-hospital mortality was positively associated with pulselessness (odds ratio [OR] 10.12; 95% confidence interval [CI] 4.09-25.07), and negatively associated with invasive therapy (EVT and OS; OR 0.11; 95% CI 0.06-0.20). CONCLUSIONS: The outcomes of ruptured AAs remain poor; emergency invasive therapy is essential to save lives, although it remains challenging to reduce the risk of death.

Outcomes of type A acute aortic dissection with cardiopulmonary arrest: Tokyo Acute Aortic Super-network Registry.

OBJECTIVES: Preventing loss of life in patients with type A acute aortic dissection (AAD) who present with cardiopulmonary arrest (CPA) can be extremely difficult. Thus, we investigated the early outcomes in these patients. METHODS: Patients with type A AAD who were transported to hospitals belonging to the Tokyo Acute Aortic Super-network between January 2015 and December 2019 were considered for this study. We assessed the early mortality of these patients presenting with CPA and also investigated the differences in outcomes between patients with out-of-hospital and in-hospital CPA. RESULTS: A total of 3307 patients with type A AAD were transported, 434 (13.1%) of whom presented with CPA. The overall mortality of patients presenting with CPA was 88.2% (383/434), of which 94.5% (240/254) experienced out-of-hospital CPA and 79.4% (143/180) experienced in-hospital CPA (P < 0.001). Multivariable analysis revealed that aortic surgery [odds ratio (OR), 0.022; 95% confidence interval (CI), 0.008-0.060; P < 0.001] and patient age over 80 years (OR, 2.946; 95% CI, 1.012-8.572; P = 0.047) were related with mortality in patients with type A AAD and CPA. Between in-hospital and out-of-hospital CPA, the proportions of DeBakey type 1 (OR, 2.32; 95% CI, 1.065-5.054; P = 0.034), cerebral malperfusion (OR, 0.188; 95% CI, 0.056-0.629; P = 0.007), aortic surgery (OR, 0.111; 95% CI, 0.045-0.271; P = 0.001), age (OR, 0.969; 95% CI, 0.940-0.998; P = 0.039) and the time from symptom onset to hospital admission (OR, 1.122; 95% CI, 1.025-1.228; P = 0.012) were significantly different. CONCLUSIONS: Patients with type A AAD presenting with CPA exhibited extremely high rates of death. Patient outcomes following in-hospital CPA tended to be better than those following out-of-hospital CPA; however, this difference was not significantly different. To prevent deaths, aortic surgery, when possible, should be considered in patients with type A AAD who sustained CPA.

Sex-Related Differences in Clinical Features and In-Hospital Outcomes of Type B Acute Aortic Dissection: A Registry Study.

Background The association between female sex and poor outcomes following surgery for type A acute aortic dissection has been reported; however, sex-related differences in clinical features and in-hospital outcomes of type B acute aortic dissection, including classic aortic dissection and intramural hematoma, remain to be elucidated. Methods and Results We studied 2372 patients with type B acute aortic dissection who were enrolled in the Tokyo Acute Aortic Super-Network Registry. There were fewer and older women than men (median age [interquartile range]: 76 years [66-84 years], n=695 versus 68 years [57-77 years], n=1677; P<0.001). Women presented to the aortic centers later than men. Women had a higher proportion of intramural hematoma (63.7% versus 53.7%, P<0.001), were medically managed more frequently (90.9% versus 86.3%, P=0.002), and had less end-organ malperfusion (2.4% versus 5.7%, P<0.001) and higher in-hospital mortality (5.3% versus 2.7%, P=0.002) than men. In multivariable analysis, age (per year, odds ratio [OR], 1.06 [95% CI, 1.03-1.08]; P<0.001), hyperlipidemia (OR, 2.09 [95% CI, 1.13-3.88]; P=0.019), painlessness (OR, 2.59 [95% CI, 1.14-5.89]; P=0.023), shock/hypotension (OR, 2.93 [95% CI, 1.21-7.11]; P=0.017), non-intramural hematoma (OR, 2.31 [95% CI, 1.32-4.05]; P=0.004), aortic rupture (OR, 26.6 [95% CI, 14.1-50.0]; P<0.001), and end-organ malperfusion (OR, 4.61 [95% CI, 2.11-10.1]; P<0.001) were associated with higher in-hospital mortality, but was not female sex (OR, 1.67 [95% CI, 0.96-2.91]; P=0.072). Conclusions Women affected with type B acute aortic dissection were older and had more intramural hematoma, a lower incidence of end-organ malperfusion, and higher in-hospital mortality than men. However, female sex was not associated with in-hospital mortality after multivariable adjustment.

Perforation of the right atrial appendage during implantation of a leadless pacemaker.

We report a case of perforation of the right atrial appendage during implantation of a leadless pacemaker in a 94 years old woman. We performed emergency surgery to repair the perforation site. To our konwledge, there are few reports of right atrial perforation during a leadless pacemaker indwelling.

Estrogens influence female itch sensitivity via the spinal gastrin-releasing peptide receptor neurons.

There are sex differences in somatosensory sensitivity. Circulating estrogens appear to have a pronociceptive effect that explains why females are reported to be more sensitive to pain than males. Although itch symptoms develop during pregnancy in many women, the underlying mechanism of female-specific pruritus is unknown. Here, we demonstrate that estradiol, but not progesterone, enhances histamine-evoked scratching behavior indicative of itch in female rats. Estradiol increased the expression of the spinal itch mediator, gastrin-releasing peptide (GRP), and increased the histamine-evoked activity of itch-processing neurons that express the GRP receptor (GRPR) in the spinal dorsal horn. The enhancement of itch behavior by estradiol was suppressed by intrathecal administration of a GRPR blocker. In vivo electrophysiological analysis showed that estradiol increased the histamine-evoked firing frequency and prolonged the response of spinal GRP-sensitive neurons in female rats. On the other hand, estradiol did not affect the threshold of noxious thermal pain and decreased touch sensitivity, indicating that estradiol separately affects itch, pain, and touch modalities. Thus, estrogens selectively enhance histamine-evoked itch in females via the spinal GRP/GRPR system. This may explain why itch sensation varies with estrogen levels and provides a basis for treating itch in females by targeting GRPR.

Subcellular dynamics of estrogen-related receptors involved in transrepression through interactions with scaffold attachment factor B1.

Estrogen-related receptor (ERR), a member of the nuclear receptor superfamily, consists of three subtypes (α, ß, γ) and has strong homology with estrogen receptor. No endogenous ligands have been identified for ERRs, but they play key roles in metabolic, hormonal, and developmental processes as transcription factors without ligand binding. Although subnuclear dynamics are essential for nuclear events including nuclear receptor-mediated transcriptional regulation, the dynamics of ERRs are poorly understood. Here, we report that ERRs show subcellular kinetic changes in response to diethylstilbestrol (DES), a synthetic estrogen that represses the transactivity of all three ERR subtypes, using live-cell imaging with fluorescent protein labeling. Upon DES treatment, all ERR subtypes formed discrete clusters in the nucleus, with ERRγ also displaying nuclear export. Fluorescence recovery after photobleaching analyses revealed significant reductions in the intranuclear mobility of DES-bound ERRα and ERRß, and a slight reduction in the intranuclear mobility of DES-bound ERRγ. After DES treatment, colocalization of all ERR subtypes with scaffold attachment factor B1 (SAFB1), a nuclear matrix-associated protein, was observed in dot-like subnuclear clusters, suggesting interactions of the ERRs with the nuclear matrix. Consistently, co-immunoprecipitation analyses confirmed enhanced interactions between ERRs and SAFB1 in the presence of DES. SAFB1 was clarified to repress the transactivity of all ERR subtypes through the ERR-response element. These results demonstrate ligand-dependent cluster formation of ERRs in the nucleus that is closely associated with SAFB1-mediated transrepression. Taken together, the present findings provide a new understanding of the pathophysiology regulated by ERR/SAFB1 signaling pathways and their subcellular dynamics.

Risk analysis for early mortality in emergency acute type A aortic dissection surgery: experience of Tokyo Acute Aortic Super-network.

OBJECTIVES: We investigated the various pre- and postoperative complications related to early (30-day) mortality after open surgery for acute type A aortic dissection. METHODS: Data from the Tokyo Acute Aortic Super-network database spanning January 2015 to December 2017 were retrospectively reviewed. Pre- and postoperative factors related to early postoperative mortality were assessed in 1504 of 2058 (73.0%) consecutive patients [age: 66.6 (SD: 13.5) years, male: 52.9%] who underwent acute type A aortic dissection repair. RESULTS: The early mortality rate following surgical repair was 8.9%. According to multivariable analysis, male sex [odds ratio (OR) 1.670, 95% confidence interval (CI) 1.063-2.624, P = 0.026], use of percutaneous circulatory assist devices (n = 116, 7.7%) including extracorporeal membrane oxygenators or intra-aortic balloon pumps (OR 4.857, 95% CI 2.867-8.228, P < 0.001), shock (n = 162, 10.8%) (OR 3.06, 95% CI 1.741-5.387, P < 0.001), cardiopulmonary arrest (n = 41, 2.7%) (OR 7.534, 95% CI 3.407-16.661, P < 0.001), coronary ischaemia (n = 36, 2.3%) (OR 2.583, 95% CI 1.042-6.404, P = 0.041) and cerebral ischaemia (n = 59, 3.9%) (OR 2.904, 95% CI 1.347-6.261, P = 0.007) were independent preoperative risk factors for early mortality, while cardiac tamponade (n = 34, 2.3%) (OR 10.282, 95% CI 4.640-22.785, P < 0.001), cerebral ischaemia (n = 80, 5.3%) (OR 2.409, 95% CI 1.179-4.923, P = 0.016) and mesenteric ischaemia (n = 15, 1.0%) (OR 44.763, 95% CI 13.027-153.808, P < 0.001) were independent postoperative risk factors. CONCLUSIONS: Not only critical preoperative conditions but also postoperative cardiac tamponade and vital organ ischaemia are risk factors for early mortality after acute type A aortic dissection repair.

Scaffold attachment factor B: distribution and interaction with ERα in the rat brain.

Scaffold attachment factor (SAFB) 1 and its homologue SAFB2 are multifunctional proteins that are involved in various cellular mechanisms, including chromatin organization and transcriptional regulation, and are also corepressors of estrogen receptor alpha (ERα). Both SAFBs are expressed at high levels in the brain. However, the distributions of SAFB1 and SAFB2 have yet to be characterized in detail and it is unclear whether both proteins interact with ERα in the brain. In this study, we investigated the expression and distribution of both SAFBs and their interaction with ERα in adult male rat brain. Immunohistochemical staining showed that SAFB1 and SAFB2 have a similar distribution pattern and are widely expressed throughout the brain. Double-fluorescence immunohistochemical and immunocytochemical analyses in primary cultures showed that the two SAFB proteins are localized in nuclei of neurons, astrocytes, and oligodendrocytes. Of note, SAFB2 was also found in cytoplasmic regions in these cell lineages. Both SAFB proteins were also expressed in ERα-positive cells in the medial preoptic area (MPOA) and arcuate and ventromedial hypothalamic nuclei. Co-immunoprecipitation experiments revealed that both SAFB proteins from the MPOA reciprocally interact with endogenous ERα. These results indicate that, in addition to a role in basal cellular function in the brain, the SAFB proteins may serve as ERα corepressors in hormone-sensitive regions.

Intranuclear Mobility of Estrogen Receptor: Implication for Transcriptional Regulation.

The estrogen receptor (ER) is a ligand-dependent transcription factor that has two subtypes: ERα and ERß. ERs regulate transcription of estrogen-responsive genes through interactions with multiple intranuclear components, such as cofactors and the nuclear matrix. Live cell imaging using fluorescent protein-labeled ERs has revealed that ligand-activated ERs are highly mobile in the nucleus, with transient association with the DNA and nuclear matrix. Scaffold attachment factor B (SAFB) 1 and its paralogue, SAFB2, are nuclear matrix-binding proteins that negatively modulate ERα-mediated transcription. Expression of SAFB1 and SAFB2 reduces the mobility of ERα in the presence of ligand. This regulatory machinery is emerging as an epigenetic-like mechanism that alters transcriptional activity through control of intranuclear molecular mobility.

Effects of Sex Steroids on the Spinal Gastrin-Releasing Peptide System Controlling Male Sexual Function in Rats.

The gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord controls male sexual function in rats. In contrast, in female rats, GRP neurons could scarcely be detected around puberty when circulating ovarian steroid hormones such as estradiol and progesterone levels are increasing. However, little information is available on feminizing or demasculinizing effects of ovarian steroids on the central nervous system in female puberty and adulthood. In this study, to visualize the spinal GRP neurons in vivo, we generated a GRP-promoter-Venus transgenic (Tg) rat line and studied the effects of the sex steroid hormones on GRP expression in the rat lumbar cord by examining the Venus fluorescence. In these Tg rats, the sexually dimorphic spinal GRP neurons controlling male sexual function were clearly labeled with Venus fluorescence. As expected, Venus fluorescence in the male lumbar cord was markedly decreased after castration and restored by chronic androgen replacement. Furthermore, androgen-induced Venus expression in the spinal cord of adult Tg males was significantly attenuated by chronic treatment with progesterone but not with estradiol. A luciferase assay using a human GRP-promoter construct showed that androgens enhance the spinal GRP system, and more strikingly, that progesterone acts to inhibit the GRP system via an androgen receptor-mediated mechanism. These results demonstrate that circulating androgens may play an important role in the spinal GRP system controlling male sexual function not only in rats but also in humans and that progesterone could be an important feminizing factor in the spinal GRP system in females during pubertal development.

Effect of Footprint Preparation on Tendon-to-Bone Healing: A Histologic and Biomechanical Study in a Rat Rotator Cuff Repair Model.

PURPOSE: To compare the histologic and biomechanical effects of 3 different footprint preparations for repair of tendon-to-bone insertions and to assess the behavior of bone marrow-derived cells in each method of insertion repair. METHODS: We randomized 81 male Sprague-Dawley rats and green fluorescent protein-bone marrow chimeric rats into 3 groups. In group A, we performed rotator cuff repair after separating the supraspinatus tendon from the greater tuberosity and removing the residual tendon tissue. In group B, we also drilled 3 holes into the footprint. The native fibrocartilage was preserved in groups A and B. In group C, we excavated the footprint until the cancellous bone was exposed. Histologic repair of the tendon-to-bone insertion, behavior of the bone marrow-derived cells, and ultimate force to failure were examined postoperatively. RESULTS: The areas of metachromasia in groups A, B, and C were 0.033 ± 0.019, 0.089 ± 0.022, and 0.002 ± 0.001 mm2/mm2, respectively, at 4 weeks and 0.029 ± 0.022, 0.090 ± 0.039, and 0.003 ± 0.001 mm2/mm2, respectively, at 8 weeks. At 4 and 8 weeks postoperatively, significantly higher cartilage matrix production was observed in group B than in group C (4 weeks, P = .002; 8 weeks, P < .001). In green fluorescent protein-bone marrow chimeric rats in group B, bone marrow-derived chondrogenic cells infiltrated the fibrocartilage layer. Ultimate force to failure was significantly higher in group B (19.7 ± 3.4 N) than in group C (16.7 ± 2.0 N) at 8 weeks (P = .031). CONCLUSIONS: Drilling into the footprint and preserving the fibrocartilage improved the quality of repair tissue and biomechanical strength at the tendon-to-bone insertion after rotator cuff repair in an animal model. CLINICAL RELEVANCE: Drilling into the footprint and preserving the fibrocartilage can enhance repair of tendon-to-bone insertions. This method may be clinically useful in rotator cuff repair.

The Arcuate Nucleus: A Site of Fast Negative Feedback for Corticosterone Secretion in Male Rats.

Variations in circulating corticosterone (Cort) are driven by the paraventricular nucleus of the hypothalamus (PVN), mainly via the sympathetic autonomic nervous system (ANS) directly stimulating Cort release from the adrenal gland and via corticotropin-releasing hormone targeting the adenohypophysis to release adrenocorticotropic hormone (ACTH). Cort feeds back through glucocorticoid receptors (GRs). Here we show in male Wistar rats that PVN neurons projecting to the adrenal gland do not express GRs, leaving the question of how the ANS in the PVN gets information about circulating Cort levels to control the adrenal. Since the arcuate nucleus (ARC) shows a less restrictive blood-brain barrier, expresses GRs, and projects to the PVN, we investigated whether the ARC can detect and produce fast adjustments of circulating Cort. In low Cort conditions (morning), local microdialysis in the ARC with type I GR antagonist produced a fast and sustained increase of Cort. This was not observed with a type II antagonist. At the circadian peak levels of Cort (afternoon), a type II GR antagonist, but not a type I antagonist, increased Cort levels but not ACTH levels. Antagonist infusions in the PVN did not modify circulating Cort levels, demonstrating the specificity of the ARC to give Cort negative feedback. Furthermore, type I and II GR agonists in the ARC prevented the increase of Cort after stress, demonstrating the role of the ARC as sensor to modulate Cort release. Our findings show that the ARC may be essential to sense blood levels of Cort and adapt Cort secretion depending on such conditions as stress or time of day.

Immunohistochemical profiling of estrogen-related receptor gamma in rat brain and colocalization with estrogen receptor alpha in the preoptic area.

Estrogen-related receptor (ERR) is a member of the nuclear receptor superfamily that has strong homology with estrogen receptor (ER) α. Despite the lack of endogenous ligands, ERR serves as transcription factors through their constitutively active structure with or without interaction with ERα. Among the three subtypes of ERR (α, ß, and γ), ERRγ is highly expressed in brain, but the distribution of ERRγ is poorly characterized. Therefore, we investigated ERRγ immunoreactivity throughout the rostro-caudal axis in rat brain. Immunohistochemistry revealed localization of ERRγ protein in the cell nucleus, and a ubiquitous distribution of ERRγ in brain regions including the olfactory bulb, cerebrum, brain stem, and cerebellum. Selective intense immunoreactivity was observed in the reticular thalamic nucleus, zona incerta, circular nucleus, interpeduncular nucleus, pontine nucleus, and parasolitary nucleus. Most ERRγ-immunoreactive (ir) regions were also positive for ERα and/or ERß, which suggests that ERRγ is involved in modulation of estrogen signaling in adult rat brain. Double immunofluorescence demonstrated colocalization of ERRγ with ERα within the anteroventral periventricular nucleus of the preoptic area (AVPV) and medial preoptic nucleus (MPO), which are major target sites for estrogen action. The results of this study suggest that ERRγ function in the brain is affected by estrogens through an interaction with ERα. The findings also provide basic information on brain region-specific ERRγ function.

A Sexually Dimorphic Area of the Dorsal Hypothalamus in Mice and Common Marmosets.

We found a novel sexually dimorphic area (SDA) in the dorsal hypothalamus (DH) of mice. The SDA-DH was sandwiched between 2 known male-biased sexually dimorphic nuclei, the principal nucleus of the bed nucleus of the stria terminalis and the calbindin-sexually dimorphic nucleus, and exhibited a female-biased sex difference in neuronal cell density. The density of neurons in the SDA-DH was increased in male mice by orchidectomy on the day of birth and decreased in female mice by treatment with testosterone, dihydrotestosterone, or estradiol within 5 days after birth. These findings indicate that the SDA-DH is defeminized under the influence of testicular testosterone, which acts via both directly by binding to the androgen receptor, and indirectly by binding to the estrogen receptor after aromatization. We measured the activity of SDA-DH neurons with c-Fos, a neuronal activity marker, in female mice during maternal and sexual behaviors. The number of c-Fos-expressing neurons in the SDA-DH of female mice was negatively correlated with maternal behavior performance. However, the number of c-Fos-expressing neurons did not change during female sexual behavior. These findings suggest that the SDA-DH contains a neuronal cell population, the activity of which decreases in females exhibiting higher performance of maternal behavior, but it may contribute less to female sexual behavior. Additionally, we examined the brain of common marmosets and found an area that appears to be homologous with the mouse SDA-DH. The sexually dimorphic structure identified in this study is not specific to mice and may be found in other species.

Expression of Sex Steroid Hormone Receptors in Vagal Motor Neurons Innervating the Trachea and Esophagus in Mouse.

The medullary vagal motor nuclei, the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMV), innervate the respiratory and gastrointestinal tracts. We conducted immunohistochemical analysis of expression of the androgen receptor (AR) and estrogen receptor α (ERα), in relation to innervation of the trachea and esophagus via vagal motor nuclei in mice. AR and ERα were expressed in the rostral NA and in part of the DMV. Tracing experiments using cholera toxin B subunit demonstrated that neurons of vagal motor nuclei that innervate the trachea and esophagus express AR and ERα. There was no difference in expression of sex steroid hormone receptors between trachea- and esophagus-innervating neurons. These results suggest that sex steroid hormones may act on vagal motor nuclei via their receptors, thereby regulating functions of the trachea and esophagus.

Hepatocyte growth factor/c-met promotes proliferation, suppresses apoptosis, and improves matrix metabolism in rabbit nucleus pulposus cells in vitro.

The etiology of intervertebral disc (IVD) degeneration is closely related to apoptosis and extracellular matrix degradation in nucleus pulposus (NP) cells. These defects in NP cells are induced by excessive external stressors such as reactive oxygen species (ROS) and inflammatory cytokines. Recently, hepatocyte growth factor (HGF) has been shown to repair damage in various diseases through anti-apoptotic and anti-inflammatory activity. In this study, we investigated the effects of HGF on NP cell abnormality caused by ROS and inflammatory cytokines by using primary NP cells isolated from rabbit IVD. HGF significantly enhanced the proliferation of NP cells. Apoptosis of NP cells induced by H2 O2 or TNF-α was significantly inhibited by HGF. Induction of mRNA expression of the inflammation mediators cyclooxygenase-2 and matrix metalloproteinase-3 and -9 by TNF-α was significantly suppressed by HGF treatment. Expression of c-Met, a specific receptor for HGF, was confirmed in NP cells and was increased by TNF-α, suggesting that inflammatory cytokines increase sensitivity to HGF. These findings demonstrate that activation of HGF/c-Met signaling suppresses damage caused by ROS and inflammation in NP cells through multiple pathways. We further suggest the clinical potential of HGF for counteracting IVD degradation involved in NP cell abnormalities.

Metabotropic Glutamate Receptor Subtype 7 in the Bed Nucleus of the Stria Terminalis is Essential for Intermale Aggression.

Metabotropic glutamate receptor subtype 7 (mGluR7) is a member of group III mGluRs, which localize to the presynaptic active zones of the mammalian central nervous system. Although histological, genetic, and electrophysiological studies ensure the importance of mGluR7, its roles in behavior and physiology remain largely unknown. Using a resident-intruder paradigm, we found a severe reduction in intermale aggressive behavior in mGluR7 knockout (KO) mice. We also found alterations in other social behaviors in male mGluR7 KO mice, including sexual behavior toward male intruders. Because olfaction is critical for rodent social behavior, including aggression, we performed an olfaction test, finding that mGluR7 KO mice failed to show interest in the smell of male urine. To clarify the olfactory deficit, we then exposed mice to urine and analyzed c-Fos-immunoreactivity, discovering a remarkable reduction in neural activity in the bed nucleus of the stria terminalis (BNST) of mGluR7 KO mice. Finally, intra-BNST administration of the mGluR7-selective antagonist 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) also reproduced the phenotype of mGluR7 KO mice, including reduced aggression and altered social interaction. Thus mGluR7 may work as an 'enhancer of neural activity' in the BNST and is important for intermale aggression. Our findings demonstrate that mGluR7 is essential for social behavior and innate behavior. Our study on mGluR7 in the BNST will shed light on future therapies for emotional disorders in humans.

Critical role of androgen receptor in the postnatal period in male sexual behavior in rats.

Gonadal hormones have a developmental role in organization of the nervous system that regulates sexually dimorphic behavior. It is well known that androgen secreted from testes in the perinatal period is converted to estrogen by aromatase in rodent brain, and that estrogen and its receptor play a pivotal role in masculinization of brain structure and function. Treatment with flutamide, an androgen receptor (AR) antagonist, during the perinatal period inhibits development of malespecific brain structure and function, suggesting that androgen signaling via AR also influences brain masculinization. In this study, we investigated which stage during the postnatal period is critical for androgen signaling in brain masculinization. The postnatal period was designated as postnatal days (PD) 0-22, and divided into stages I (PD 0-7), II (PD 8-14), and III (PD 15-22). Newborn male rats were given flutamide subcutaneously in each stage. After adulthood, the effects of postnatal flutamide treatment on brain masculinization were evaluated byanalysis of male sexual behavior. Continuous inhibition of AR throughout stages I and II caused a robust reduction of the intromission ratio and ejaculation frequency compared with other groups. AR inhibition in stage I, II, or III did not cause any change. AR inhibition had no effect onmount behavior. These results show that stage-specific AR activation in the first two postnatal weeks may contribute to brain masculinization mediating male sexual behavior in adulthood.