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Univariate and multivariate sex differences and similarities in gray matter volume within essential language-processing areas 基本语言处理区灰质体积的单变量和多变量性别差异与相似性
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-21 DOI: 10.1186/s13293-023-00575-y
Carla Sanchis-Segura, Rand R. Wilcox, Alvaro Javier Cruz-Gómez, Sonia Félix-Esbrí, Alba Sebastián-Tirado, Cristina Forn
Sex differences in language-related abilities have been reported. It is generally assumed that these differences stem from a different organization of language in the brains of females and males. However, research in this area has been relatively scarce, methodologically heterogeneous and has yielded conflicting results. Univariate and multivariate sex differences and similarities in gray matter volume (GMVOL) within 18 essential language-processing brain areas were assessed in a sex-balanced sample (N = 588) of right-handed young adults. Univariate analyses involved location, spread, and shape comparisons of the females’ and males’ distributions and were conducted with several robust statistical methods able to quantify the size of sex differences and similarities in a complementary way. Multivariate sex differences and similarities were estimated by the same methods in the continuous scores provided by two distinct multivariate procedures (logistic regression and a multivariate analog of the Wilcoxon–Mann–Whitney test). Additional analyses were addressed to compare the outcomes of these two multivariate analytical strategies and described their structure (that is, the relative contribution of each brain area to the multivariate effects). When not adjusted for total intracranial volume (TIV) variation, “large” univariate sex differences (males > females) were found in all 18 brain areas considered. In contrast, “small” differences (females > males) in just two of these brain areas were found when controlling for TIV. The two multivariate methods tested provided very similar results. Multivariate sex differences surpassed univariate differences, yielding "large" differences indicative of larger volumes in males when calculated from raw GMVOL estimates. Conversely, when calculated from TIV-adjusted GMVOL, multivariate differences were "medium" and indicative of larger volumes in females. Despite their distinct size and direction, multivariate sex differences in raw and TIV-adjusted GMVOL shared a similar structure and allowed us to identify the components of the SENT_CORE network which more likely contribute to the observed effects. Our results confirm and extend previous findings about univariate sex differences in language-processing areas, offering unprecedented evidence at the multivariate level. We also observed that the size and direction of these differences vary quite substantially depending on whether they are estimated from raw or TIV-adjusted GMVOL measurements. While it is generally assumed that there is a distinct organization of language in the brains of females and males, studies investigating potential sex-based differences in language-related neural circuits have been characterized by their methodological heterogeneity and yielded inconclusive results. In this study, we explored how the brains of men and women differ in a well-defined network of brain areas essential for basic language functions. We found that there are indeed dif
据报道,语言相关能力存在性别差异。一般认为,这些差异源于女性和男性大脑中不同的语言组织结构。然而,这方面的研究相对较少,方法也不尽相同,得出的结果也相互矛盾。本研究以性别均衡的右手型青壮年样本(588 人)为研究对象,评估了 18 个重要语言处理脑区灰质体积(GMVOL)的单变量和多变量性别差异和相似性。单变量分析涉及女性和男性分布的位置、扩散和形状比较,并采用了几种稳健的统计方法,能够以互补的方式量化性别差异和相似性的大小。多变量性别差异和相似性是通过两种不同的多变量程序(Logistic 回归和 Wilcoxon-Mann-Whitney 检验的多变量类似方法)以同样的方法对连续得分进行估计的。附加分析旨在比较这两种多元分析策略的结果,并描述其结构(即每个脑区对多元效应的相对贡献)。在未对颅内总容积(TIV)变化进行调整的情况下,在所有 18 个脑区都发现了 "大 "的单变量性别差异(男性>女性)。相反,在控制 TIV 后,仅在其中两个脑区发现了 "小 "差异(女性>男性)。所测试的两种多元方法得出的结果非常相似。多变量性别差异超过了单变量差异,根据原始 GMVOL 估计值计算得出的 "大 "差异表明男性的体积更大。相反,根据 TIV 调整后的 GMVOL 计算,多变量差异为 "中等",表明女性的体积更大。尽管原始 GMVOL 和 TIV 调整后 GMVOL 的多变量性别差异在大小和方向上各不相同,但它们具有相似的结构,使我们能够确定 SENT_CORE 网络中更有可能对观察到的效应做出贡献的成分。我们的研究结果证实并扩展了之前关于语言处理领域单变量性别差异的发现,在多变量水平上提供了前所未有的证据。我们还观察到,这些差异的大小和方向有很大的不同,这取决于它们是根据原始的还是经过 TIV 调整的 GMVOL 测量结果估算出来的。虽然人们普遍认为女性和男性的大脑中存在着不同的语言组织,但对语言相关神经回路中潜在的性别差异进行调查的研究却因其方法上的不一致性而产生了不确定的结果。在这项研究中,我们探讨了男女大脑在一个明确定义的、对基本语言功能至关重要的脑区网络中的差异。我们发现,与语言有关的某些脑区的大小确实存在差异,男性和女性在这些差异方面表现出不同的模式。有趣的是,观察这些差异的方式取决于是对整个网络还是对单个脑区进行评估。此外,当考虑到这些脑区的大小与整体颅骨体积的关系时,差异也发生了变化。因此,这项研究强调,要理解这些大脑差异,需要考虑不同的因素,如颅骨大小的现有性别差异,不仅要研究局部效应,还要研究它们在更广泛的大脑功能网络背景下的相互作用和关系。
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引用次数: 0
Sex and interspecies differences in ESR2-expressing cell distributions in mouse and rat brains 小鼠和大鼠大脑中 ESR2 表达细胞分布的性别和种间差异
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-18 DOI: 10.1186/s13293-023-00574-z
Masahiro Morishita, Shimpei Higo, Kinuyo Iwata, Hirotaka Ishii
ESR2, a nuclear estrogen receptor also known as estrogen receptor β, is expressed in the brain and contributes to the actions of estrogen in various physiological phenomena. However, its expression profiles in the brain have long been debated because of difficulties in detecting ESR2-expressing cells. In the present study, we aimed to determine the distribution of ESR2 in rodent brains, as well as its sex and interspecies differences, using immunohistochemical detection with a well-validated anti-ESR2 antibody (PPZ0506). To determine the expression profiles of ESR2 protein in rodent brains, whole brain sections from mice and rats of both sexes were subjected to immunostaining for ESR2. In addition, to evaluate the effects of circulating estrogen on ESR2 expression profiles, ovariectomized female mice and rats were treated with low or high doses of estrogen, and the resulting numbers of ESR2-immunopositive cells were analyzed. Welch’s t-test was used for comparisons between two groups for sex differences, and one-way analysis of variance followed by the Tukey–Kramer test were used for comparisons among multiple groups with different estrogen treatments. ESR2-immunopositive cells were observed in several subregions of mouse and rat brains, including the preoptic area, extended amygdala, hypothalamus, mesencephalon, and cerebral cortex. Their distribution profiles exhibited sex and interspecies differences. In addition, low-dose estrogen treatment in ovariectomized female mice and rats tended to increase the numbers of ESR2-immunopositive cells, whereas high-dose estrogen treatment tended to decrease these numbers. Immunohistochemistry using the well-validated PPZ0506 antibody revealed a more localized expression of ESR2 protein in rodent brains than has previously been reported. Furthermore, there were marked sex and interspecies differences in its distribution. Our histological analyses also revealed estrogen-dependent changes in ESR2 expression levels in female brains. These findings will be helpful for understanding the ESR2-mediated actions of estrogen in the brain. Although the brain is a major target organ of estrogens, the distribution of estrogen receptors in the brain is not fully understood. ESR2, also known as estrogen receptor β, is an estrogen receptor subtype; its localization in the brain has long been controversial because it has traditionally been difficult to detect. In the present study, we analyzed the expression sites of ESR2 in mouse and rat brains using immunohistochemistry with a well-validated antibody, PPZ0506. The immunohistochemical analysis revealed a more localized expression of ESR2 protein in brain subregions than has previously been reported. Additionally, there were clear sex and interspecies differences in the distribution of this protein. We also observed changes in ESR2 expression in the female brain in response to circulating estrogen levels. Our results, which show the precise expression profiles of ESR2 prote
ESR2是一种核雌激素受体,也称为雌激素受体β,在大脑中表达,并在各种生理现象中参与雌激素的作用。然而,由于很难检测到 ESR2 表达的细胞,其在大脑中的表达谱长期以来一直存在争议。在本研究中,我们使用一种经过验证的抗 ESR2 抗体(PPZ0506)进行免疫组化检测,旨在确定 ESR2 在啮齿动物大脑中的分布及其性别和种间差异。为了确定 ESR2 蛋白在啮齿类动物大脑中的表达情况,对雌雄小鼠和大鼠的整个大脑切片进行了 ESR2 免疫染色。此外,为了评估循环雌激素对 ESR2 表达谱的影响,用低剂量或高剂量的雌激素处理卵巢切除的雌性小鼠和大鼠,并分析由此产生的 ESR2 免疫阳性细胞的数量。两组间性别差异的比较采用韦尔奇 t 检验,不同雌激素处理的多组间比较采用单因素方差分析和 Tukey-Kramer 检验。在小鼠和大鼠大脑的多个亚区,包括视前区、扩展杏仁核、下丘脑、间脑和大脑皮层,都观察到了ESR2-免疫阳性细胞。它们的分布特征表现出性别和种间差异。此外,对卵巢切除的雌性小鼠和大鼠进行低剂量雌激素治疗后,ESR2-免疫阳性细胞的数量呈上升趋势,而高剂量雌激素治疗则呈下降趋势。使用经过充分验证的 PPZ0506 抗体进行免疫组织化学研究发现,ESR2 蛋白在啮齿类动物大脑中的表达比以前报道的更加局部化。此外,其分布还存在明显的性别和种间差异。我们的组织学分析还揭示了雌性大脑中 ESR2 表达水平的雌激素依赖性变化。这些发现将有助于了解 ESR2 在大脑中介导的雌激素作用。虽然大脑是雌激素的一个主要靶器官,但雌激素受体在大脑中的分布还不完全清楚。ESR2又称雌激素受体β,是雌激素受体的一种亚型;由于传统上很难检测到它,因此它在大脑中的定位一直存在争议。在本研究中,我们用一种有效的抗体 PPZ0506 进行免疫组化,分析了 ESR2 在小鼠和大鼠大脑中的表达位点。免疫组化分析表明,ESR2 蛋白在大脑亚区域的表达比以往报道的更加局部化。此外,该蛋白的分布还存在明显的性别和种间差异。我们还观察到 ESR2 在女性大脑中的表达随循环雌激素水平的变化而变化。我们的研究结果显示了ESR2蛋白在啮齿动物大脑中的精确表达谱,这将有助于理解ESR2介导的雌激素作用。
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引用次数: 0
Sex differences in type 2 diabetes: an opportunity for personalized medicine 2 型糖尿病的性别差异:个性化医疗的机遇
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-13 DOI: 10.1186/s13293-023-00571-2
Meredith L. Johnson, Joshua D. Preston, Cetewayo S. Rashid, Kevin J. Pearson, J. Nina Ham
Over the past several decades, substantial ground has been gained in understanding the biology of sex differences. With new mandates to include sex as a biological variable in NIH-funded research, greater knowledge is forthcoming on how sex chromosomes, sex hormones, and social and societal differences between sexes can affect the pathophysiology of health and disease. A detailed picture of how biological sex impacts disease pathophysiology will directly inform clinicians in their treatment approaches and challenge canonical therapeutic strategies. Thus, a profound opportunity to explore sex as a variable in personalized medicine now presents itself. While many sex differences are apparent in humans and have been described at length, we are only beginning to see how such differences impact disease progression, treatment efficacy, and outcomes in obesity, type 2 diabetes, and cardiovascular disease. Here, we briefly present the most salient and convincing evidence of sex differences in type 2 diabetes detection, diagnostics, disease course, and therapeutics. We then offer commentary on how this evidence can inform clinicians on how to approach the clinical workup and management of different patients with diabetes. Finally, we discuss some gaps that remain in the literature and propose several research questions to guide basic and translational researchers as they continue in this growing area of scientific exploration. For decades, most research in the laboratory and clinical settings focused primarily on males. However, more recently, grant-funding agencies, including the National Institutes of Health, have prioritized research that studies both males and females. This has dramatically improved our understanding of how biological sex impacts whether a person is at higher risk for developing a particular disease and what treatment options may be best to achieve the healthiest outcomes. This article offers the perspectives of practicing physicians and scientists on how our knowledge about biological sex may impact disease incidence, progression, treatment options, and outcomes in obesity, diabetes, and heart disease. The piece will offer a broad overview of the current science and personalized medicine approaches in these areas. It then discusses gaps in our knowledge and proposes several questions to guide future research.
过去几十年来,人们在了解性别差异的生物学方面取得了长足的进步。在美国国立卫生研究院(NIH)资助的研究中,性别作为一个生物变量被纳入了新的研究任务,人们即将获得更多关于性染色体、性激素以及社会和社会性别差异如何影响健康和疾病病理生理学的知识。详细了解生物性别如何影响疾病的病理生理学,将直接指导临床医生的治疗方法,并对传统的治疗策略提出挑战。因此,将性别作为个性化医疗中的一个变量进行探索的大好时机已经到来。虽然许多性别差异在人类身上显而易见,并且已经有了详细的描述,但我们才刚刚开始了解这些差异如何影响肥胖症、2 型糖尿病和心血管疾病的疾病进展、治疗效果和预后。在此,我们简要介绍了在 2 型糖尿病检测、诊断、病程和治疗方面性别差异最突出和最有说服力的证据。然后,我们就这些证据如何指导临床医生对不同的糖尿病患者进行临床检查和管理发表评论。最后,我们讨论了文献中仍然存在的一些空白,并提出了几个研究问题,以指导基础研究人员和转化研究人员继续在这一不断发展的科学领域进行探索。几十年来,实验室和临床环境中的大多数研究主要集中在男性身上。但最近,包括美国国立卫生研究院在内的拨款机构已将研究男性和女性的研究列为优先事项。这极大地提高了我们对生理性别如何影响一个人罹患某种疾病的风险,以及什么样的治疗方案是实现最健康结果的最佳选择的认识。本文从执业医生和科学家的角度,阐述了我们对生理性别的了解可能会如何影响肥胖症、糖尿病和心脏病的发病率、病情发展、治疗方案和治疗效果。文章将对这些领域的现有科学和个性化医疗方法进行广泛概述。然后讨论我们的知识差距,并提出几个问题以指导未来的研究。
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引用次数: 0
Sex bias in celiac disease: XWAS and monocyte eQTLs in women identify TMEM187 as a functional candidate gene 乳糜泻的性别偏见:女性的 XWAS 和单核细胞 eQTL 确定 TMEM187 为功能性候选基因
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-11 DOI: 10.1186/s13293-023-00572-1
Alba Hernangomez-Laderas, Ariadna Cilleros-Portet, Silvia Martínez Velasco, Sergi Marí, María Legarda, Bárbara Paola González-García, Carlos Tutau, Iraia García-Santisteban, Iñaki Irastorza, Nora Fernandez-Jimenez, Jose Ramon Bilbao
Celiac disease (CeD) is an immune-mediated disorder that develops in genetically predisposed individuals upon gluten consumption. HLA risk alleles explain 40% of the genetic component of CeD, so there have been continuing efforts to uncover non-HLA loci that can explain the remaining heritability. As in most autoimmune disorders, the prevalence of CeD is significantly higher in women. Here, we investigated the possible involvement of the X chromosome on the sex bias of CeD. We performed a X chromosome-wide association study (XWAS) and a gene-based association study in women from the CeD Immunochip (7062 cases, 5446 controls). We also constructed a database of X chromosome cis-expression quantitative trait loci (eQTLs) in monocytes from unstimulated (n = 226) and lipopolysaccharide (LPS)-stimulated (n = 130) female donors and performed a Summary-data-based MR (SMR) analysis to integrate XWAS and eQTL information. We interrogated the expression of the potentially causal gene (TMEM187) in peripheral blood mononuclear cells (PBMCs) from celiac patients at onset, on a gluten-free diet, potential celiac patients and non-celiac controls. The XWAS and gene-based analyses identified 13 SNPs and 25 genes, respectively, 22 of which had not been previously associated with CeD. The X chromosome cis-eQTL analysis found 18 genes with at least one cis-eQTL in naïve female monocytes and 8 genes in LPS-stimulated female monocytes, 2 of which were common to both situations and 6 were unique to LPS stimulation. SMR identified a potentially causal association of TMEM187 expression in naïve monocytes with CeD in women, regulated by CeD-associated, eQTL-SNPs rs7350355 and rs5945386. The CeD-risk alleles were correlated with lower TMEM187 expression. These results were replicated using eQTLs from LPS-stimulated monocytes. We observed higher levels of TMEM187 expression in PBMCs from female CeD patients at onset compared to female non-celiac controls, but not in male CeD individuals. Using X chromosome genotypes and gene expression data from female monocytes, SMR has identified TMEM187 as a potentially causal candidate in CeD. Further studies are needed to understand the implication of the X chromosome in the higher prevalence of CeD in women. Celiac disease (CeD) is an immune-related condition triggered by gluten consumption in genetically susceptible individuals. Women present higher prevalence of CeD than men, but the biological explanation of such difference has not been elucidated. In this study, we investigated whether specific genetic variations on the X chromosome were associated with CeD in each sex. Surprisingly, we found 13 genetic variants and 25 genes significantly linked to CeD in women, but not in men. Additionally, we identified genetic variants on the X chromosome associated with gene expression of monocytes, a type of immune cells that is activated in CeD after gluten intake. Integrating these data with our previous findings, we found that lower express
乳糜泻(Celiac disease,CeD)是一种免疫介导的疾病,易感基因携带者在食用麸质食品后发病。HLA 风险等位基因可解释乳糜泻 40% 的遗传因素,因此人们一直在努力发掘可解释剩余遗传性的非 HLA 基因位点。与大多数自身免疫性疾病一样,女性的 CeD 患病率明显更高。在此,我们研究了 X 染色体对 CeD 性别偏向的可能影响。我们对 CeD 免疫片段(7062 例病例,5446 例对照)中的女性进行了全 X 染色体关联研究(XWAS)和基于基因的关联研究。我们还在未受刺激(n = 226)和受脂多糖(LPS)刺激(n = 130)的女性供体单核细胞中构建了一个 X 染色体顺式表达定量性状位点(eQTL)数据库,并进行了基于摘要数据的 MR(SMR)分析,以整合 XWAS 和 eQTL 信息。我们检测了乳糜泻患者发病时、无麸质饮食时、潜在乳糜泻患者和非乳糜泻对照组的外周血单核细胞(PBMC)中潜在致病基因(TMEM187)的表达情况。基于 XWAS 和基因的分析分别发现了 13 个 SNP 和 25 个基因,其中 22 个基因以前从未与乳糜泻相关联。X染色体顺式-eQTL分析发现,在天真雌性单核细胞中有18个基因具有至少一个顺式-eQTL,在LPS刺激的雌性单核细胞中有8个基因具有至少一个顺式-eQTL,其中2个基因在两种情况下都有,6个基因在LPS刺激下特有。SMR确定了TMEM187在女性幼稚单核细胞中的表达与CeD的潜在因果关系,该关系受CeD相关的eQTL-SNPs rs7350355和rs5945386调节。CeD 风险等位基因与较低的 TMEM187 表达相关。我们利用 LPS 刺激单核细胞的 eQTLs 复制了这些结果。我们观察到,与女性非糜烂性对照组相比,女性糜烂性结肠炎患者发病时的 PBMC 中 TMEM187 表达水平较高,而男性糜烂性结肠炎患者则没有。利用来自女性单核细胞的 X 染色体基因型和基因表达数据,SMR 发现 TMEM187 可能是 CeD 的致病候选基因。要了解 X 染色体对女性糜烂性胃炎发病率较高的影响,还需要进一步的研究。乳糜泻(Celiac disease,CeD)是一种与免疫相关的疾病,由基因易感者食用麸质引发。女性的乳糜泻发病率高于男性,但这种差异的生物学解释尚未阐明。在这项研究中,我们调查了 X 染色体上的特定基因变异是否与不同性别的 CeD 相关。令人惊讶的是,我们发现女性中有 13 个基因变异和 25 个基因与 CeD 有显著关联,而男性则没有。此外,我们还发现了与单核细胞基因表达相关的 X 染色体遗传变异,单核细胞是一种免疫细胞,摄入麸质后会激活 CeD。将这些数据与我们之前的研究结果相结合,我们发现名为 TMEM187 的基因表达较低可能与女性 CeD 风险的潜在增加有关。最后,验证实验证实,与非乳糜泻女性患者相比,女性乳糜泻患者血细胞中的 TMEM187 水平较高,而男性则没有这种差异。总之,我们的研究表明,X 染色体基因 TMEM187 可能在 CeD 的发展过程中起着关键作用,为女性 CeD 的高发病率提供了启示。
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引用次数: 0
Sex differences in mouse infralimbic cortex projections to the nucleus accumbens shell 小鼠下边缘皮层投射到伏隔核外壳的性别差异
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-11 DOI: 10.1186/s13293-023-00570-3
Caroline S. Johnson, Andrew D. Chapp, Erin B. Lind, Mark J. Thomas, Paul G. Mermelstein
The nucleus accumbens (NAc) is an important region in motivation and reward. Glutamatergic inputs from the infralimbic cortex (ILC) to the shell region of the NAc (NAcSh) have been implicated in driving the motivation to seek reward through repeated action-based behavior. While this has primarily been studied in males, observed sex differences in motivational circuitry and behavior suggest that females may be more sensitive to rewarding stimuli. These differences have been implicated for the observed vulnerability in women to substance use disorders. We used an optogenetic self-stimulation task in addition to ex vivo electrophysiological recordings of NAcSh neurons in mouse brain slices to investigate potential sex differences in ILC-NAcSh circuitry in reward-seeking behavior. Glutamatergic neurons in the ILC were infected with an AAV delivering DNA encoding for channelrhodopsin. Entering the designated active corner of an open field arena resulted in photostimulation of the ILC terminals in the NAcSh. Self-stimulation occurred during two consecutive days of testing over three consecutive weeks: first for 10 Hz, then 20 Hz, then 30 Hz. Whole-cell recordings of medium spiny neurons in the NAcSh assessed both optogenetically evoked local field potentials and intrinsic excitability. Although both sexes learned to seek the active zone, within the first day, females entered the zone more than males, resulting in a greater amount of photostimulation. Increasing the frequency of optogenetic stimulation amplified female reward-seeking behavior. Males were less sensitive to ILC stimulation, with higher frequencies and repeated days required to increase male reward-seeking behavior. Unexpectedly, ex vivo optogenetic local field potentials in the NAcSh were greater in slices from male animals. In contrast, female medium-spiny neurons (MSNs) displayed significantly greater intrinsic neuronal excitability. Taken together, these data indicate that there are sex differences in the motivated behavior driven by glutamate within the ILC-NAcSh circuit. Though glutamatergic signaling was greater in males, heightened intrinsic excitability in females appears to drive this sex difference. The shell region of the nucleus accumbens (NAcSh) is involved in motivation and reward. It receives excitatory glutamatergic inputs from multiple brain regions. One specific region is the infralimbic cortex (ILC), which when activated, influences reward-seeking behavior. While previous research has focused on males, there are inherent sex differences in reward circuitry and reward-seeking behavior. Using an optogenetic self-stimulation task, in addition to ex vivo electrophysiological recordings, we found inherent sex differences in the ILC-NAcSh circuit in behavioral output, synaptic strength, and intrinsic neurophysiology. Female mice showed more robust reward-seeking behavior. Increasing the frequency of stimulation intensified this behavior in females, while males required higher
纳氏核(Narc)是动机和奖赏的重要区域。从下边缘皮层(ILC)到 NAc 壳区(NAcSh)的谷氨酸能输入被认为与通过重复动作行为寻求奖赏的动机有关。虽然这项研究主要针对男性,但观察到的动机回路和行为的性别差异表明,女性可能对奖赏刺激更加敏感。这些差异被认为是女性易患药物使用障碍的原因。除了对小鼠脑片中的NAcSh神经元进行体外电生理记录外,我们还使用了光遗传自刺激任务来研究ILC-NAcSh回路在奖赏寻求行为中的潜在性别差异。ILC中的谷氨酸能神经元感染了一种AAV,该AAV可提供编码channelrhodopsin的DNA。在连续三周进行的连续两天的测试中都会出现自我刺激:首先是10赫兹,然后是20赫兹,最后是30赫兹。对NarcSh中刺神经元的全细胞记录评估了光诱发的局部场电位和内在兴奋性。尽管雌雄动物都学会了寻找活跃区,但在第一天内,雌性动物进入活跃区的次数多于雄性动物,从而导致光刺激量增加。增加光遗传刺激的频率会放大雌性寻求奖赏的行为。雄性对ILC刺激的敏感性较低,需要更高的频率和重复的天数才能增加雄性寻求奖赏的行为。意想不到的是,雄性动物的切片在NarcSh中的体外光遗传局部场电位更高。相比之下,雌性中刺神经元(MSN)的内在神经元兴奋性明显更高。综上所述,这些数据表明,ILC-NAcSh回路中谷氨酸驱动的动机行为存在性别差异。虽然谷氨酸能信号在雄性中更强,但雌性中更强的内在兴奋性似乎是这种性别差异的驱动因素。伏隔核的外壳区(NAcSh)与动机和奖赏有关。它接受来自多个脑区的兴奋性谷氨酸能输入。其中一个特定区域是下边缘皮层(ILC),该区域被激活后会影响寻求奖赏的行为。以往的研究主要集中在男性身上,但奖赏回路和奖赏寻求行为存在固有的性别差异。除了体内外电生理记录外,我们还利用光遗传自刺激任务发现了 ILC-NAcSh 电路在行为输出、突触强度和内在神经生理学方面的固有性别差异。雌性小鼠表现出更强烈的奖赏寻求行为。增加刺激频率可强化雌性小鼠的这种行为,而雄性小鼠则需要更高的频率和重复测试天数才能增加其寻求奖赏的行为。令人惊讶的是,通过光遗传刺激脑片中NAcSh的ILC末端,雄性会产生更强烈的反应。与行为数据更加一致的是,雌性MSN显示出更高的内在兴奋性。我们的研究结果表明,在ILC-NAc回路的谷氨酸能信号驱动下,动机行为存在性别差异。尽管男性基于 ILC 的谷氨酸能信号更强,但女性 MSNs 内在兴奋性的提高似乎是这种寻求奖赏行为性别差异背后的驱动力。这些发现有助于我们了解基于性别的动机差异背后的神经机制及其对药物使用障碍的潜在影响。
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引用次数: 0
Sex differences in the rapid detection of neutral faces associated with emotional value. 快速识别中性面孔与情感价值的性别差异。
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-14 DOI: 10.1186/s13293-023-00567-y
Akie Saito, Wataru Sato, Sakiko Yoshikawa

Background: Rapid detection of faces with emotional meaning is essential for understanding the emotions of others, possibly promoting successful interpersonal relationships. Although few studies have examined sex differences in the ability to detect emotional faces, it remains unclear whether faces with emotional meaning capture the attention of females and males differently, because emotional faces have visual saliency that modulates visual attention. To overcome this issue, we tested the rapid detection of the neutral faces associated with and without learned emotional value, which are all regarded as free from visual saliency. We examined sex differences in the rapid detection of the neutral female and male faces associated with emotional value.

Methods: First, young adult female and male participants completed an associative learning task in which neutral faces were associated with either monetary rewards, monetary punishments, or no monetary outcomes, such that the neutral faces acquired positive, negative, and no emotional value, respectively. Then, they engaged in a visual search task in which previously learned neutral faces were presented as discrepant faces among newly presented neutral distractor faces. During the visual search task, the participants were required to rapidly identify discrepant faces.

Results: Female and male participants exhibited comparable learning abilities. The visual search results demonstrated that female participants achieved rapid detection of neutral faces associated with emotional value irrespective of the sex of the faces presented, whereas male participants showed this ability only for male faces.

Conclusions: Our results demonstrated that sex differences in the ability to rapidly detect neutral faces with emotional value were modulated by the sex of those faces. The results suggest greater sensitivity to faces with emotional significance in females, which might enrich interpersonal communication, regardless of sex.

背景:快速识别具有情感意义的面孔对于理解他人的情绪至关重要,可能促进成功的人际关系。尽管很少有研究考察性别在识别情绪面孔能力上的差异,但目前尚不清楚具有情绪含义的面孔是否能以不同的方式吸引女性和男性的注意力,因为情绪面孔具有调节视觉注意力的视觉显著性。为了克服这个问题,我们测试了对有或没有习得情感价值的中性面孔的快速检测,这些面孔都被认为没有视觉显著性。我们研究了在快速识别与情感价值相关的中性女性和男性面孔方面的性别差异。方法:首先,年轻的成年女性和男性参与者完成了一个联想学习任务,在这个任务中,中性面孔与金钱奖励、金钱惩罚或没有金钱结果相关联,这样中性面孔分别获得了积极、消极和没有情感价值。然后,他们参与了一个视觉搜索任务,在这个任务中,先前学习过的中性面孔被呈现为新呈现的中性分心面孔中的差异面孔。在视觉搜索任务中,参与者被要求快速识别不一致的面孔。结果:女性和男性参与者表现出相当的学习能力。视觉搜索结果表明,女性参与者能够快速识别出与情感价值相关的中性面孔,而男性参与者只对男性面孔有这种能力。结论:我们的研究结果表明,快速识别具有情感价值的中性面孔的能力的性别差异受到这些面孔的性别的调节。研究结果表明,女性对具有情感意义的面孔更敏感,这可能会丰富男女之间的人际交流。
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引用次数: 0
Sex-based differences in natural killer T cell-mediated protection against diet-induced steatohepatitis in Balb/c mice. Balb/c小鼠中自然杀伤T细胞介导的抗饮食性脂肪性肝炎保护的性别差异
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-14 DOI: 10.1186/s13293-023-00569-w
Carlos Cuño-Gómiz, Estefanía de Gregorio, Anna Tutusaus, Patricia Rider, Nuria Andrés-Sánchez, Anna Colell, Albert Morales, Montserrat Marí

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in Western countries, evolving into metabolic dysfunction-associated steatohepatitis (MASH) with a sexual dimorphism. Fertile women exhibit lower MASLD risk than men, which diminishes post-menopause. While NKT-cell involvement in steatohepatitis is debated, discrepancies may stem from varied mouse strains used, predominantly C57BL6/J with Th1-dominant responses. Exploration of steatohepatitis, encompassing both genders, using Balb/c background, with Th2-dominant immune response, and CD1d-deficient mice in the Balb/c background (lacking Type I and Type II NKT cells) can clarify gender disparities and NKT-cell influence on MASH progression.

Methods: A high fat and choline-deficient (HFCD) diet was used in male and female mice, Balb/c mice or CD1d-/- mice in the Balb/c background that exhibit a Th2-dominant immune response. Liver fibrosis and inflammatory gene expression were measured by qPCR, and histology assessment. NKT cells, T cells, macrophages and neutrophils were assessed by flow cytometry.

Results: Female mice displayed milder steatohepatitis after 6 weeks of HFCD, showing reduced liver damage, inflammation, and fibrosis compared to males. Male Balb/c mice exhibited NKT-cell protection against steatohepatitis whereas CD1d-/- males on HFCD presented decreased hepatoprotection, increased liver fibrosis, inflammation, neutrophilic infiltration, and inflammatory macrophages. In contrast, the NKT-cell role was negligible in early steatohepatitis development in both female mice, as fibrosis and inflammation were similar despite augmented liver damage in CD1d-/- females. Relevant, hepatic type I NKT levels in female Balb/c mice were significantly lower than in male.

Conclusions: NKT cells exert a protective role against experimental steatohepatitis as HFCD-treated CD1d-/- males had more severe fibrosis and inflammation than male Balb/c mice. In females, the HFCD-induced hepatocellular damage and the immune response are less affected by NKT cells on early steatohepatitis progression, underscoring sex-specific NKT-cell influence in MASH development.

背景:代谢功能障碍相关的脂肪性肝病(MASLD)在西方国家很普遍,并演变为代谢功能障碍相关的脂肪性肝炎(MASH)伴性别二态性。有生育能力的女性比男性表现出更低的MASLD风险,这在绝经后会减少。虽然nkt细胞参与脂肪性肝炎仍有争议,但差异可能源于使用的不同小鼠品系,主要是C57BL6/J与th1主导应答。研究包括两性在内的脂肪性肝炎,使用Balb/c背景,以th2为主的免疫反应,以及Balb/c背景的cd1缺陷小鼠(缺乏I型和II型NKT细胞),可以澄清性别差异和NKT细胞对MASH进展的影响。方法:采用高脂胆碱缺乏(HFCD)饮食,分别饲喂雄性和雌性小鼠、Balb/c小鼠或Balb/c背景下表现出th2显性免疫反应的CD1d-/-小鼠。采用qPCR检测肝纤维化和炎症基因表达,并进行组织学评估。流式细胞术检测NKT细胞、T细胞、巨噬细胞和中性粒细胞。结果:与雄性小鼠相比,雌性小鼠在HFCD治疗6周后表现出较轻的脂肪性肝炎,表现出较轻的肝损伤、炎症和纤维化。雄性Balb/c小鼠对脂肪性肝炎表现出nkt细胞保护作用,而CD1d-/-雄性HFCD小鼠的肝保护作用降低,肝纤维化、炎症、中性粒细胞浸润和炎症性巨噬细胞增加。相比之下,在两种雌性小鼠中,nkt细胞在早期脂肪性肝炎发展中的作用可以忽略不计,因为尽管CD1d-/-雌性小鼠的肝损伤增强,但纤维化和炎症相似。与此相关,雌性Balb/c小鼠肝脏I型NKT水平显著低于雄性。结论:NKT细胞对实验性脂肪性肝炎具有保护作用,CD1d-/-雄性小鼠比Balb/c雄性小鼠有更严重的纤维化和炎症。在女性中,hfcd诱导的肝细胞损伤和免疫应答在早期脂肪性肝炎进展中较少受到NKT细胞的影响,这强调了NKT细胞在MASH发展中的性别特异性影响。
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引用次数: 0
Sex differences in binge alcohol drinking and the behavioral consequences of protracted abstinence in C57BL/6J mice. C57BL/6J小鼠狂欢饮酒的性别差异和长期戒酒的行为后果
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-13 DOI: 10.1186/s13293-023-00565-0
Jean K Rivera-Irizarry, Lia J Zallar, Olivia B Levine, Mary Jane Skelly, Jared E Boyce, Thaddeus Barney, Ruth Kopyto, Kristen E Pleil

Background: Binge alcohol drinking is a risk factor linked to numerous disease states including alcohol use disorder (AUD). While men binge drink more alcohol than women, this demographic gap is quickly shrinking, and preclinical studies demonstrate that females consistently consume more alcohol than males. Further, women are at increased risk for the co-expression of AUD with neuropsychiatric diseases such as anxiety and mood disorders. However, little is understood about chronic voluntary alcohol drinking and its long-term effects on behavior. Here, we sought to characterize sex differences in chronic binge drinking and the effects of protracted alcohol abstinence on anxiety- and affective-related behaviors in males and females.

Methods: We assessed binge alcohol drinking patterns in male and female C57BL/6J mice using a modified Drinking in the Dark (DID) paradigm in which mice received home cage access to one bottle of 10% or 20% alcohol (EtOH) or water for 2 h per day on Days 1-3 and to two bottles (EtOH/H2O + H2O) for 24 h on Day 4 for 8 weekly cycles. Mice were then tested for the effects of protracted abstinence on avoidance, affective, and compulsive behaviors.

Results: Female mice consumed more alcohol than males consistently across cycles of DID and at 2, 4, and 24-h timepoints within the day, with a more robust sex difference for 20% than 10% EtOH. Females also consumed more water than males, an effect that emerged at the later time points; this water consumption bias diminished when alcohol was available. Further, while increased alcohol consumption was correlated with decreased water consumption in males, there was no relationship between these two measures in females. Alcohol preference was higher in 10% vs. 20% EtOH for both sexes. During protracted abstinence following chronic binge drinking, mice displayed decreased avoidance behavior (elevated plus maze, open field, novelty suppressed feeding) and increased compulsive behavior (marble burying) that was especially robust in females. There was no effect of alcohol history on stress coping and negative affective behaviors (sucrose preference, forced swim test, tail suspension) in either sex.

Conclusion: Female mice engaged in higher volume binge drinking than their male counterparts. Although females also consumed more water than males, their higher alcohol consumption was not driven by increased total fluid intake. Further, the effects of protracted abstinence following chronic binge drinking was driven by behavioral disinhibition that was more pronounced in females. Given the reciprocal relationship between risk-taking and alcohol use in neuropsychiatric disease states, these results have implications for sex-dependent alcohol drinking patterns and their long-term negative neuropsychiatric/physiological health outcomes in humans.

背景:酗酒是与包括酒精使用障碍(AUD)在内的许多疾病相关的危险因素。虽然男性酗酒比女性多,但这一人口差距正在迅速缩小,临床前研究表明,女性的饮酒量一直比男性多。此外,女性与神经精神疾病(如焦虑和情绪障碍)共同表达AUD的风险增加。然而,人们对长期自愿饮酒及其对行为的长期影响知之甚少。在这里,我们试图描述慢性酗酒的性别差异,以及长期戒酒对男性和女性焦虑和情感相关行为的影响。方法:我们使用改进的黑暗中饮酒(DID)范式评估了雄性和雌性C57BL/6J小鼠的狂饮模式,在第1-3天,小鼠在家里的笼子里每天喝一瓶10%或20%的酒精(EtOH)或水2小时,在第4天,喝两瓶(EtOH/H2O + H2O) 24小时,为期8周。然后对小鼠进行了长期禁欲对回避、情感和强迫行为的影响测试。结果:雌性小鼠在DID周期内以及一天中的2、4和24小时时间点比雄性小鼠消耗更多的酒精,在20%的EtOH比10%的EtOH时性别差异更明显。女性也比男性消耗更多的水,这一效应在较晚的时间点出现;当有酒精时,这种水消耗偏差就会减弱。此外,在男性中,饮酒增加与饮水减少相关,但在女性中,这两项指标之间没有关系。酒精偏好在10% EtOH高于20% EtOH的两性。在长期酗酒后的长期禁欲期间,小鼠表现出减少的回避行为(升高加上迷宫,开阔场地,抑制新奇的喂养)和增加的强迫行为(大理石埋葬),尤其是在雌性中。酒精史对应激应对和负性情感行为(蔗糖偏好、强迫游泳试验、悬尾)均无影响。结论:雌性小鼠比雄性小鼠更容易酗酒。虽然女性也比男性摄入更多的水,但她们更高的饮酒量并不是由总液体摄入量增加引起的。此外,长期酗酒后长期戒酒的影响是由行为去抑制驱动的,这在女性中更为明显。考虑到神经精神疾病状态下的冒险行为和饮酒之间的相互关系,这些结果对性别依赖的饮酒模式及其对人类神经精神/生理健康的长期负面影响具有启示意义。
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引用次数: 0
Correction: Variability of temperature measurements recorded by a wearable device by biological sex. 校正:由可穿戴设备按生物性别记录的温度测量的可变性。
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-13 DOI: 10.1186/s13293-023-00568-x
Lauryn Keeler Bruce, Patrick Kasl, Severine Soltani, Varun K Viswanath, Wendy Hartogensis, Stephan Dilchert, Frederick M Hecht, Anoushka Chowdhary, Claudine Anglo, Leena Pandya, Subhasis Dasgupta, Ilkay Altintas, Amarnath Gupta, Ashley E Mason, Benjamin L Smarr
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引用次数: 0
Sex and age differences in social and cognitive function in offspring exposed to late gestational hypoxia. 妊娠晚期缺氧暴露的后代社会和认知功能的性别和年龄差异。
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-11 DOI: 10.1186/s13293-023-00557-0
Steve Mabry, E Nicole Wilson, Jessica L Bradshaw, Jennifer J Gardner, Oluwadarasimi Fadeyibi, Edward Vera, Oluwatobiloba Osikoya, Spencer C Cushen, Dimitrios Karamichos, Styliani Goulopoulou, Rebecca L Cunningham

Background: Gestational sleep apnea is a hypoxic sleep disorder that affects 8-26% of pregnancies and increases the risk for central nervous system dysfunction in offspring. Specifically, there are sex differences in the sensitivity of the fetal hippocampus to hypoxic insults, and hippocampal impairments are associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. Yet, it is unclear whether gestational sleep apnea impacts these hippocampal-associated functions and if sex and age modify these effects. To examine the relationship between gestational sleep apnea and hippocampal-associated behaviors, we used chronic intermittent hypoxia (CIH) to model late gestational sleep apnea in pregnant rats. We hypothesized that late gestational CIH would produce sex- and age-specific social, anxiety-like, repetitive, and cognitive impairments in offspring.

Methods: Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15-19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine gestational hypoxia-induced behavioral phenotypes, we quantified hippocampal-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal neuronal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, early growth response protein 1, and doublecortin), and circulating hormones in offspring.

Results: Late gestational CIH induced sex- and age-specific differences in social, repetitive, and memory functions in offspring. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, and elevated circulating corticosterone levels but did not impact memory. In contrast, CIH transiently induced spatial memory dysfunction in pubertal male offspring but did not impact social or repetitive functions. Long-term effects of gestational CIH on social behaviors were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating corticosterone levels in young adulthood. No effects of gestational CIH were observed in anxiety-like behaviors, hippocampal neuronal activity, or circulating testosterone and estradiol levels, regardless of sex or age of offspring.

Conclusions: Our results indicate that hypoxia-associated pregnancy complications during late gestation can increase the risk for behavioral and physiological outcomes in offspring, such as social dysfunction, repetitive behaviors, and cognitive impairment, that are dependent on sex and age.

背景:妊娠期睡眠呼吸暂停是一种缺氧睡眠障碍,影响8-26%的妊娠,并增加后代中枢神经系统功能障碍的风险。具体来说,胎儿海马对缺氧损伤的敏感性存在性别差异,海马损伤与社交功能障碍、重复行为、焦虑和认知障碍有关。然而,尚不清楚妊娠期睡眠呼吸暂停是否会影响这些海马相关功能,以及性别和年龄是否会改变这些影响。为了研究妊娠期睡眠呼吸暂停与海马相关行为之间的关系,我们采用慢性间歇缺氧(CIH)对妊娠晚期睡眠呼吸暂停大鼠进行建模。我们假设妊娠晚期CIH会在后代中产生性别和年龄特异性的社交、焦虑样、重复性和认知障碍。方法:定时妊娠的Long-Evans大鼠从妊娠第15 ~ 19天开始暴露于CIH或室内常氧环境。后代的行为测试发生在青春期或青年期。为了研究妊娠缺氧诱导的行为表型,我们量化了海马相关行为(社交功能、重复行为、焦虑样行为、空间记忆和学习)、海马神经元活动(谷氨酸能NMDA受体、多巴胺转运体、单胺氧化酶-a、早期生长反应蛋白1和双皮质素)和后代循环激素。结果:妊娠晚期CIH诱导后代社会、重复和记忆功能的性别和年龄特异性差异。在女性青春期的后代中,CIH损害了社会功能,增加了重复行为,升高了循环皮质酮水平,但不影响记忆。相比之下,CIH短暂地诱导青春期雄性后代的空间记忆功能障碍,但不影响社交或重复功能。妊娠期CIH对社会行为的长期影响仅在雌性后代中观察到,其中CIH诱导社会脱离,并在成年早期抑制循环皮质酮水平。没有观察到妊娠期CIH对焦虑样行为、海马神经元活动或循环睾酮和雌二醇水平的影响,与后代的性别和年龄无关。结论:我们的研究结果表明,妊娠后期与缺氧相关的妊娠并发症会增加后代行为和生理结局的风险,如社交功能障碍、重复行为和认知障碍,这些风险与性别和年龄有关。
{"title":"Sex and age differences in social and cognitive function in offspring exposed to late gestational hypoxia.","authors":"Steve Mabry, E Nicole Wilson, Jessica L Bradshaw, Jennifer J Gardner, Oluwadarasimi Fadeyibi, Edward Vera, Oluwatobiloba Osikoya, Spencer C Cushen, Dimitrios Karamichos, Styliani Goulopoulou, Rebecca L Cunningham","doi":"10.1186/s13293-023-00557-0","DOIUrl":"10.1186/s13293-023-00557-0","url":null,"abstract":"<p><strong>Background: </strong>Gestational sleep apnea is a hypoxic sleep disorder that affects 8-26% of pregnancies and increases the risk for central nervous system dysfunction in offspring. Specifically, there are sex differences in the sensitivity of the fetal hippocampus to hypoxic insults, and hippocampal impairments are associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. Yet, it is unclear whether gestational sleep apnea impacts these hippocampal-associated functions and if sex and age modify these effects. To examine the relationship between gestational sleep apnea and hippocampal-associated behaviors, we used chronic intermittent hypoxia (CIH) to model late gestational sleep apnea in pregnant rats. We hypothesized that late gestational CIH would produce sex- and age-specific social, anxiety-like, repetitive, and cognitive impairments in offspring.</p><p><strong>Methods: </strong>Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15-19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine gestational hypoxia-induced behavioral phenotypes, we quantified hippocampal-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal neuronal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, early growth response protein 1, and doublecortin), and circulating hormones in offspring.</p><p><strong>Results: </strong>Late gestational CIH induced sex- and age-specific differences in social, repetitive, and memory functions in offspring. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, and elevated circulating corticosterone levels but did not impact memory. In contrast, CIH transiently induced spatial memory dysfunction in pubertal male offspring but did not impact social or repetitive functions. Long-term effects of gestational CIH on social behaviors were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating corticosterone levels in young adulthood. No effects of gestational CIH were observed in anxiety-like behaviors, hippocampal neuronal activity, or circulating testosterone and estradiol levels, regardless of sex or age of offspring.</p><p><strong>Conclusions: </strong>Our results indicate that hypoxia-associated pregnancy complications during late gestation can increase the risk for behavioral and physiological outcomes in offspring, such as social dysfunction, repetitive behaviors, and cognitive impairment, that are dependent on sex and age.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"14 1","pages":"81"},"PeriodicalIF":7.9,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10640736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89716833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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Biology of Sex Differences
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