社会退缩和性别差异临床表型和生物学基础步骤3.docx

Social withdrawal and gender differences: Clinical phenotypes and biological bases
社交退缩和性别差异：临床表型和生物学基础

Abstract
抽象

Evidence from everyday life suggests that differences in social behaviors between males and females exist, both in animal and in humans. These differences can be related to socio-cultural determinants, but also to specialized portions of the brain (the social brain), from the neurotransmitter to the neural network level. The high vulnerability of this system is expressed by the wide range of neuropsychiatric disorders associated with social dysfunctions, particularly social withdrawal. The principal psychiatric disorders with prominent social withdrawal are described, in-cluding hikikomori-like syndromes, and anxiety, depressive, autistic, schizophrenic, and personality disorders. It is hypothesized that social withdrawal can be partially independent from other symptoms and likely reflect alterations in the social brain itself, leading to a similar, transdiagnostic social dysfunction, reflecting defects in the social brain across a variety of psychopathological conditions. An overview is provided of gender effects in the biological determinants of social behavior, includ-ing: the anatomical structures of the social brain; the dimorphic brain structures, and the modulation of their development by sex steroids; gender differences in “social” neurotransmitters (vasopressin and oxytocin), and in their response to social stress. A better comprehension of gender differences in the phenotypes of social disorders and in the neural bases of social behaviors may provide new insights for timely, fo-cused, innovative, and gender-specific treatments.
日常生活的证据表明，雄性和雌性之间的社会行为存在差异，无论是在动物还是人类中。这些差异可能与社会文化决定因素有关，但也与大脑的特殊部分（社会大脑）有关，从神经递质到神经网络水平。该系统的高度脆弱性表现为与社交功能障碍相关的各种神经精神疾病，尤其是社交退缩。描述了具有显着社交退缩的主要精神障碍，包括 hikikomori 样综合征，以及焦虑、抑郁、自闭症、精神分裂症和人格障碍。据推测，社交退缩可以部分独立于其他症状，并且可能反映了社交大脑本身的改变，导致类似的、跨诊断的社交功能障碍，反映了各种精神病理学条件下的社交大脑缺陷。概述了社会行为的生物学决定因素中的性别影响，包括：社会大脑的解剖结构;二态性大脑结构，以及性类固醇对其发育的调节;“社会”神经递质（加压素和催产素）及其对社会压力的反应的性别差异。更好地理解社交障碍表型和社会行为神经基础的性别差异可能为及时、集中、创新和性别特异性的治疗提供新的见解。

KEYWORDS
关键字

gender differences, psychopathology, social behavior, social brain, social withdrawal
性别差异，精神病理学，社会行为，社交大脑，社交退缩

1 | GENDER DIFFERENCES IN CLINICAL
1 |临床性别差异

PHENOTYPES OF SOCIAL WITHDRAWAL
社交退缩的表型

1.1 | Clinical features of social withdrawal
1.1 |社交退缩的临床特征

Social withdrawal can be defined as a long-term (at least 6 months) social isolation and self-exclusion, including non-attendance at school or work, minimal social contact, and persistent staying at home. Social isolation is a psychopathological dimension, with a continuum between normal and pathological extremes. While the forms on the border can be hardly distinguished from temperamen-tal social inhibition, with excessive interest for isolated activities, se-vere and impairing withdrawal has negative consequences in school or occupation, with severe social and economic impact, especially when the course is chronic, leading to poor functional outcomes.
社交退缩可定义为长期（至少 6 个月）的社交孤立和自我排斥，包括不上学或不上班、很少的社交接触和持续待在家里。社会孤立是一个精神病理学维度，介于正常和病态极端之间。虽然边境上的形式很难与喜怒无常的社会抑制区分开来，但对孤立活动过度感兴趣，连续和损害性的戒断对学校或职业产生负面影响，具有严重的社会和经济影响，特别是当课程是慢性的时，导致不良的功能结果。

The high complexity of social functioning can explain the ele-vated vulnerability to different internal and external pathogenic in-fluences, which can result in a wide range of psychiatric disorders
社会功能的高度复杂性可以解释对不同内部和外部致病因素影响的高度脆弱性，这可能导致广泛的精神疾病

associated with social withdrawal, such as anxiety disorders (Plana et al., 2014), post-traumatic stress disorder (PTSD) (Sipper et al., 2020), major depressive disorder (Bora & Berk, 2016; Kupferberg et al., 2016), autism spectrum disorders (ASDs) (Barlati et al., 2020), and schizophrenia (Rocca et al., 2016). Social withdrawal can be the first sign of these disorders, sometimes years before the full- blown symptomatology and diagnosis, and independent from other symptoms, and is associated with negative prognostic implications, in terms of poorer outcome and more frequent treatment refrac-toriness. Other forms of social withdrawal seemingly do not meet the criteria for any existing psychiatric disorder. A prototypical form of “primary” social withdrawal, strongly related to a specific social context, is the so-called Japanese “Hikikomori,” which has become, in the last years, a model for similar hikikomori-like clinical presen-tations in other countries, with diverse cross-cultural perceptions of the phenomenon (Kato et al., 2012). However, although apparently “primary,” most of the hikikomori-like conditions are associated with other mental disorders, not correctly recognized for the lack of a proper assessment (Koyama et al., 2010). Some forms of social with-drawal can follow the exposure to life adversities and/or traumatic experiences, that is, within the context of a PTSD. Furthermore, other social and environmental influences have strongly influenced the phenomenology of social withdrawal in the last two decades, especially the availability of electronic devices (personal computers, smartphones), and of social networks (Facebook, Instagram, etc.), within the context of the so-called Internet addiction or pathological gaming disorder (Durkee et al., 2012; Kato et al., 2020; Masi et al., 2020).
与社交退缩有关，如焦虑症（Plana等人，2014年）、创伤后应激障碍（PTSD）（Sipper等人，2020年）、重度抑郁症（Bora和Berk，2016年;Kupferberg 等人，2016 年）、自闭症谱系障碍（ASD）（Barlati 等人，2020 年）和精神分裂症（Rocca 等人，2016 年）。社交退缩可能是这些疾病的第一个迹象，有时在全面的症状和诊断前数年，并且独立于其他症状，并且与不良预后影响有关，就较差的结果和更频繁的治疗反应而言。其他形式的社交退缩似乎不符合任何现有精神疾病的标准。与特定社会背景密切相关的“原发性”社会退缩的典型形式是所谓的日本“隐居”，在过去几年中，它已成为其他国家类似隐居相似的临床预示的模型，对这种现象有着不同的跨文化认知（Kato et al.， 2012）。然而，尽管表面上是“原发性”，但大多数类似隐居者的疾病与其他精神障碍有关，由于缺乏适当的评估而没有得到正确认识（Koyama et al.， 2010）。某些形式的社交 with-drawal 可以在暴露于生活逆境和/或创伤经历之后发生，即在 PTSD 的背景下。此外，其他社会和环境影响对过去二十年中社交退缩现象学产生了强烈影响，尤其是在所谓的网络成瘾或病态游戏障碍的背景下，电子设备（个人电脑、智能手机）和社交网络（Facebook、Instagram 等）的可用性（Durkee 等人。, 2012;Kato等人，2020 年;Masi et al.， 2020）。

An important differential feature of social withdrawal is between ego-dystonic versus ego-syntonic forms. In the ego-dystonic form, individuals desire and try to escape the prison of their isolation, but consider themselves unable to do it. In the ego-syntonic form, t isolation is seemingly a “free choice” for avoiding a threatening or boring world, or for attending interesting but addicting activities, much more appealing than social interactions. Ego-dystonic forms can include social withdrawal within the context of a depression (low self-esteem, loss of energy, and anhedonia), or of anxiety disorders (namely, social anxiety disorders, agoraphobia with or without panic disorder, separation anxiety disorder). The ego-syntonic forms more often occur within high functioning ASD, where behavioral addic-tions can be included, namely Internet addiction and/or gaming use disorder, or in personality disorders (i.e., schizotypal and schizoid). However, some individuals can present with both ego-syntonic and ego-dystonic features, and these behaviors can change in time, as well as thoughts and emotions regarding social relationships.
社交退缩的一个重要差异特征是自我-肌张力障碍和自我-共张力形式。在自我-肌张力障碍形式中，个体渴望并试图逃离孤立的牢笼，但认为自己无法做到。在自我共调形式中，t 隔离似乎是一种“自由选择”，可以避免一个有威胁或无聊的世界，或者参加有趣但令人上瘾的活动，这比社交互动更有吸引力。自我肌张力障碍形式可包括抑郁（低自尊、精力不足和快感缺乏）或焦虑障碍（即社交焦虑障碍、广场恐惧症伴或不伴恐慌症、分离焦虑障碍）背景下的社交退缩。自我共调形式更常发生在高功能 ASD 中，其中可能包括行为附加性，即网络成瘾和/或游戏使用障碍，或人格障碍（即分裂型和分裂样）。然而，有些人可能同时表现出自我共调和自我肌张力障碍的特征，这些行为会随着时间的推移而改变，关于社会关系的想法和情绪也会发生变化。

Significant gender differences are reported in social withdrawal, in terms of prevalence rate as well as i degree of functional impair-ment, as boys tend to present a much larger functional impact in their lifetime (Coplan et al., 2004). This sex difference is probably attributed to the traditional gender roles (Asendorpf et al., 2008), but growing evidence suggests that gender differences may be af-fected by both neurobiological and endocrinological determinants (Hayashi et al., 2020; Porcelli et al., 2019). In the following sections,a description of gender differences in the different phenotypes of social withdrawal will be provided in clinical and community sam-ples. Then, a summary of available knowledge of gender specificities in the biological foundations of social withdrawal will be proposed. Both of this evidence may help to develop gender specific treat-ments and supports for social withdrawal.
据报道，在社交退缩方面，在患病率和功能损害程度方面存在显着的性别差异，因为男孩在其一生中往往表现出更大的功能影响（Coplan 等人，2004 年）。这种性别差异可能归因于传统的性别角色（Asendorpf et al.， 2008），但越来越多的证据表明，性别差异可能受到神经生物学和内分泌决定因素的影响（Hayashi et al.， 2020;Porcelli et al.， 2019）。在以下部分中，将在临床和社区样本中提供社交退缩不同表型的性别差异的描述。然后，将总结社会退缩的生物学基础中性别特异性的可用知识。这两个证据都可能有助于开发针对性别的治疗和支持社交退缩。

Significance
意义

Differences in social behaviors between genders are re-lated to different social and cultural environments, but also to differences in portions of the brain, developed in animals and humans during the evolution to optimize so-cial functioning, the so-called “social brain.” This complex system is highly vulnerable, as demonstrated by frequent social behavior disorders, particularly social withdrawal, in different psychiatric disorders, including anxiety, depres-sion, autism, and schizophrenia. All these disorders may share a similar trans-diagnostic dysfunction in the social brain, with peculiarities in males and females. A compre-hension of these differences may provide new insights for focused and innovative treatments of social dysfunctions.
性别之间社会行为的差异与不同的社会和文化环境有关，但也与大脑部分的差异有关，这些部分在动物和人类的进化过程中发展起来，以优化社会功能，即所谓的“社会大脑”。这个复杂的系统非常脆弱，正如不同的精神疾病（包括焦虑、抑郁、自闭症和精神分裂症）中频繁的社交行为障碍，尤其是社交退缩所证明的那样。所有这些疾病在社会大脑中可能具有类似的反诊断功能障碍，在男性和女性中都有特点。对这些差异的理解可能会为社交功能障碍的重点和创新治疗提供新的见解。

1.2 | Primary social withdrawal: The “Hikikomori” syndrome
1.2 |原发性社交退缩：“隐居森”综合症

The “Hikikomori” syndrome had once been thought to be a Japanese culture-specific phenomenon, but cases of “Hikikomori” have been reported outside Japan, suggesting that the phenomenon is not necessarily specific to the Japanese culture (Kato et al., 2012; Kato, Kanba, et al., 2019). Milder hikikomori-like conditions, characterized by social disengagement, have been described in different countries, with different names and conceptualizations (Li & Wong, 2015; Teo
“隐居森”综合症曾被认为是日本文化特有的现象，但在日本以外也有“隐居”的案例报道，这表明这种现象不一定是日本文化特有的（Kato et al.， 2012;Kato， Kanba et al.， 2019）。较轻的隐居类疾病，以社交脱离为特征，在不同的国家被描述，有不同的名称和概念化（Li & Wong，2015;张

&Gaw, 2010). The lifetime prevalence of "Hikikomori" in males is approximately five times as high as in females (Koyama et al., 2010), and the onset, or at least the prodromal signs, is during adolescence. Some individuals have friends, but they do not maintain relation-ships with them, while others do not have close friends, but maintain alternative, online relationships. Some of these patients commonly report having few meaningful social relationships and reduced social contacts, but deny avoiding social interaction. This lack of avoid-ance is one of the primary differences between “Hikikomori” and social anxiety disorder, as most of the patients do not show sub-jective distress, and actually feel content in their social withdrawal, particularly in the earlier phase of the condition. When the dura-tion of social withdrawal is protracted, people with “Hikikomori” can begin endorsing distress, such as feelings of loneliness. More than 50% of the patients with “Hikikomori” had also received a specific psychiatric diagnosis in their lifetime (i.e., a 6.1 times higher risk of lifetime comorbidity of a mood disorder compared with those with-out “Hikikomori”) (Koyama et al., 2010).
&Gaw， 2010）。男性 “Hikikomori” 的终生患病率大约是女性的五倍（Koyama et al.， 2010），并且发病或至少是前驱症状，发生在青春期。有些人有朋友，但他们不与他们保持关系，而另一些人没有亲密的朋友，但保持着另类的在线关系。其中一些患者通常报告几乎没有有意义的社交关系和减少的社交接触，但否认避免社交互动。这种缺乏回避是 “隐居 ”和社交焦虑症之间的主要区别之一，因为大多数患者没有表现出潜意识的痛苦，而是真正在他们的社交退缩中感到满足，特别是在病情的早期阶段。当社交退缩的持久性旷日持久时，患有 “隐居 ”的人可以开始认可痛苦，例如孤独感。超过 50% 的“Hikikomori”患者在其一生中还接受过特定的精神病学诊断（即，与没有“Hikikomori”的患者相比，终生患有情绪障碍的风险高 6.1 倍）（Koyama 等人，2010 年）。

1.3 | Social withdrawal in anxiety disorders
1.3 |焦虑障碍中的社交退缩

Anxiety disorders are the most prevalent psychiatric diagnoses, with an estimated prevalence ranging from 9.9% to 16.7% worldwide (American Psychiatric Association, 2013; Kessler, 2007), and are the most frequent reason for social isolation.
焦虑症是最普遍的精神病学诊断，估计全球患病率为 9.9% 至 16.7%（美国精神病学协会，2013 年;Kessler，2007 年），并且是社会孤立的最常见原因。

Social anxiety disorder is characterized by intense and persistent fear about social situations, particularly with unfamiliar people, as-sociated with intense distress and avoidance of social interactions and/or performance situations. Social anxiety can start in childhood, often in continuity with previous marked shyness, can be stable over time, and increases developmental risk for further psychopathology during adolescence, when the oversensitivity to trivial social situa-tions amplifies the impact of these experiences over their lifetime (Masi et al., 2012). These individuals always live longer at home, and in the most severe forms, they remain there during their lifetime, sometimes presenting with delusional-like components, that is, par-anoid thoughts or body dysmorphic features (Pisano et al., 2016). Gender differences are negligible, with slight prevalence for males in some epidemiological studies, even if females may be more rarely diagnosed, as social anxiety is more consistent with the expected gender roles. Phenomenology can be different between genders, as females report more fears and more frequent comorbidities (other forms of anxiety, depression, and alcohol abuse), while males more often present with disruptive behavior disorders and behavioral ad-dictions (American Psychiatric Association, 2013; Masi et al., 2012).
社交焦虑障碍的特征是对社交场合的强烈和持续的恐惧，尤其是与不熟悉的人在一起，并伴有强烈的痛苦和回避社交互动和/或表演场合。社交焦虑可以从童年开始，通常与以前明显的害羞相延续，随着时间的推移可以稳定下来，并增加青春期进一步精神病理学的发展风险，此时对琐碎的社会环境过度敏感会放大这些经历对他们一生的影响（Masi 等人，2012 年）。这些人总是在家里活得更久，而且在最严重的情况下，他们一生都会留在那里，有时会出现类似妄想的成分，即阳极念或身体畸形特征（Pisano et al.， 2016）。性别差异可以忽略不计，在一些流行病学研究中，男性的患病率略低，即使女性可能更罕见地被诊断出来，因为社交焦虑与预期的性别角色更一致。现象学可能因性别而异，因为女性报告了更多的恐惧和更频繁的合并症（其他形式的焦虑、抑郁和酗酒），而男性更经常出现破坏性行为障碍和行为用语（美国精神病学协会，2013 年;Masi et al.， 2012）。

Separation anxiety disorder, with avoidance of situations imply-ing separation from attachment figures, is firstly evident towards school attendance (school refusal), but rapidly it can extend to every life and social activity (Masi et al., 2001). It can persist through ado-lescence and adulthood, with dependent relationships with closest relatives, over-concern about activities away from home, negative impacts on sociality, work or leisure, and high risk of panic attacks and/or depressive episodes (Pini et al., 2014). Gender differences have been reported, but not consistently, as girls are usually more reluctant to attend school, while males may manifest with limited independent activity, more dependent relationships, and reluctance to move away from home.
分离焦虑症，回避意味着与依恋人物分离的情况，首先在学校出勤（拒绝上学）中很明显，但很快它可以扩展到每一个生活和社会活动（Masi et al.， 2001）。它可以持续到青春期和成年期，与最亲近的亲属建立依赖关系，过度关注离家活动，对社交、工作或休闲的负面影响，以及惊恐发作和/或抑郁发作的高风险（Pini 等人，2014 年）。有性别差异的报道，但并非始终如一，因为女孩通常更不愿意上学，而男性可能表现为独立活动有限、依赖关系更多以及不愿离开家。

Panic disorder, often preceded by and associated with separation anxiety disorder, can further worsen social withdrawal, with need for staying homebound, and sometimes in a room, to counteract fears of new abrupt attacks and their consequences (American Psychiatric Association, 2013; Masi et al., 2000, 2004). Agoraphobia, the most frequent complication of a panic disorder, usually starts from ad-olescence, with high persistence in adulthood, and is complicated with other disorders during the lifetime (other anxiety disorders, depression, substance abuse, and behavioral addictions). The con-sequence is to stay home, with extreme fear of going out, being de-pendent on others and unable to study or work. Panic attacks and agoraphobia are prevalent in females, since adolescence (American Psychiatric Association, 2013). Females with panic disorder report more frequent stressful life events including separation experiences, lower levels of confrontation and coping strategies and more severe agoraphobia than males, suggesting that the patient's gender may be relevant to the assessment and the treatment (Kim et al., 2017).
恐慌症，通常在分离焦虑症之前并与之相关，会进一步恶化社交退缩，需要呆在家里，有时在房间里，以抵消对新的突然发作及其后果的恐惧（美国精神病学协会，2013 年;Masi et al.， 2000， 2004）。广场恐惧症是惊恐障碍最常见的并发症，通常始于发作期，在成年期具有高度持续性，并在一生中与其他疾病（其他焦虑障碍、抑郁症、药物滥用和行为成瘾）并发。其结果是呆在家里，极度害怕外出，不敢依赖他人，无法学习或工作。自青春期以来，惊恐发作和广场恐惧症在女性中普遍存在（美国精神病学协会，2013 年）。与男性相比，患有恐慌症的女性报告了更频繁的压力生活事件，包括分离经历、较低水平的对抗和应对策略以及更严重的广场恐惧症，这表明患者的性别可能与评估和治疗有关（Kim et al.， 2017）。

1.4 | Depression
1.4 |抑郁症

Social withdrawal is a possible feature of depression, episodic and related to the depressive symptomatology, but sometimes with chronic course, resistance to antidepressants, and residual functional impairment (Gur & Gur, 2016; Kupferberg et al., 2016; Rhebergen et al., 2010: Rizvi et al., 2015). More recently, a new presentation of chronic depression called “modern type depression” (MTD), has been described in Japanese samples, with the main presentation not being disordered mood and cognition, but social isolation (Kato, Katsuki, et al., 2019). These patients are particularly sensitive to so-cial defeat, experienced as a trauma, easily falling into social with-drawal (Kato & Kanba, 2017). Their personological features include both avoidance and narcissism/omnipotence, attachment to oneself, but not to social structures, with distress and disregard about social order and rules, and avoidance of activities requiring perseverance and cognitive effort (Kato et al., 2016; Kato & Kanba, 2017). Further studies are needed in other countries and social environments, since, being hypersensitivity the prominent feature, MTD is often recog-nized elsewhere as clinically impairing, but diagnosed as an adjust-ment disorder.
社交退缩是抑郁症的一个可能特征，是偶发性的，与抑郁症状有关，但有时伴有慢性病程、对抗抑郁药的抵抗和残留功能障碍（Gur & Gur，2016;Kupferberg 等人，2016 年;Rhebergen et al.， 2010： Rizvi et al.， 2015）。最近，在日本样本中描述了一种称为“现代型抑郁症”（MTD）的慢性抑郁症的新表现，主要表现不是情绪和认知障碍，而是社会孤立（Kato、Katsuki 等人，2019 年）。这些患者对社会的失败特别敏感，经历过创伤，容易陷入社交困境（Kato & Kanba，2017）。他们的人格特征包括回避和自恋/无所不能，依恋自我但不依恋社会结构，对社会秩序和规则感到痛苦和无视，以及回避需要毅力和认知努力的活动（Kato et al.， 2016;Kato & Kanba，2017 年）。其他国家和社会环境需要进一步的研究，因为 MTD 是超敏反应的突出特征，通常在其他地方被认为是临床损害，但被诊断为一种适应障碍。

Depression is more prevalent in females, at least after adoles-cence, but without clear difference, between genders, in symptom-atology, developmental course, treatment response and outcome (American Psychiatric Association, 2013). The most consistent dif-ferential feature is the higher risk of suicidal ideation and attempts in females, and completed suicide in males, even though this finding is more consistent in the general population than in clinical samples with depression (Hawton & van Heeringen, 2009). Women are also at significantly greater risk of developing stress-related depres-sion, possibly related to hormonal and inflammation mechanisms (Martinez-Muniz & Wood, 2020). The role of imbalanced inflam-matory mechanisms in the pathophysiology of depression in males versus females is under study, as well as a possible mediator effect of estradiol (Slavich & Sacher, 2019). This issue may be related to the anti-inflammatory effect of older and newer antidepressants, possi-bly affecting gender differences in the response to pharmacological treatments (Martinez-Muniz & Wood, 2020).
抑郁症在女性中更为普遍，至少在青春期之后，但在性别、症状、发育过程、治疗反应和结果方面没有明显差异（美国精神病学协会，2013 年）。最一致的差异特征是女性自杀意念和企图的风险更高，男性自杀的风险更高，尽管这个发现在普通人群中比在患有抑郁症的临床样本中更为一致（Hawton & van Heeringen），2009）。女性患压力相关抑郁症的风险也明显更大，这可能与激素和炎症机制有关（Martinez-Muniz & Wood，2020）。不平衡的炎症机制在男性与女性抑郁症的病理生理学中的作用正在研究中，以及雌二醇可能的中介作用（Slavich & Sacher，2019）。这个问题可能与旧款和新型抗抑郁药的抗炎效果有关，可能会影响对药物治疗反应的性别差异（Martinez-Muniz & Wood， 2020）。

1.5 | Autism spectrum disorder
1.5 |自闭症谱系障碍

Along with repetitive and stereotyped behavior, the prototypi-cal feature of ASD is the early-onset deficit in social relation and communication. The new DSM 5 concept of ASD has lowered the clinical threshold and increased the number of diagnosed individu-als, prevalently without intellectual disability, with lower severity and more subtle social deficits (American Psychiatric Association, 2013). During adolescence and early adulthood, some patients organize their personality and behavior around social isolation, restricted interests and behaviors, and most of these patients receive a misdiagnosis of personality disorder (Ford & Crewther, 2014).
除了重复和刻板的行为外，ASD 的典型特征是社会关系和沟通的早发性缺陷。ASD 的新 DSM 5 概念降低了临床阈值并增加了被诊断出的个体性硬化症的数量，通常没有智力障碍，严重程度较低，社交缺陷更细微（美国精神病学协会，2013 年）。在青少年和早期成年期，一些患者围绕社交孤立、限制的兴趣和行为来组织他们的性格和行为，而这些患者中的大多数都被误诊为人格障碍（Ford & Crewther， 2014）。

ASD is diagnosed more frequently in boys than in girls (American Psychiatric Association, 2013), but females with au-tism are more often under-identified (camouflaging) (Beggiato et al., 2016). Among biological factors supporting gender differ-ences, sex-linked genetic and hormonal factors may enhance risk in males and decrease it in females (Beggiato et al. 2016; Ferri et al. 2018; Lai et al., 2011). High-functioning females with ASD may present with more efficient non-verbal communication (gestures) than boys with autism (Rynkievicz et al., 2016), masking other di-agnostic features. Regarding gender effects on presentation and course, diagnosed females overall show fewer restricted/repeti-tive behaviors/interests or activities (RRBI) than males (Antezana et al., 2019; Lai & Szatmari, 2020). Within specific RRBIs, height-ened stereotyped behaviors and restricted interests are prevalent in boys, while compulsive, sameness, restricted, and self-injurious behaviors are more frequently reported in girls (Antezana et al., 2019), although co-occurring psychopathologies (i.e., anxiety) may also affect these gender differences. Difficulties in adaptive functioning and social challenges, however, may emerge more frequently in females during adolescence (Lai & Szatmari, 2020). However, young girls more likely present improvement of symp-toms over time, namely less intense autistic symptoms, and better cognitive outcomes (Lai et al., 2011). Further research is required to examine these features in females, so as to possibly improve gender-specific diagnostic work-ups.
ASD 在男孩中比在女孩中更常见（美国精神病学协会，2013 年），但患有自闭症的女性更经常被低估（伪装）（Beggiato 等人，2016 年）。在支持性别差异的生物因素中，与性别相关的遗传和荷尔蒙因素可能会增加男性的风险并降低女性的风险（Beggiato 等人，2016 年;Ferri 等人，2018 年;Lai et al.， 2011）。与自闭症男孩相比，患有 ASD 的高功能女性可能表现出更有效的非语言交流（手势）（Rynkievicz 等人，2016 年），掩盖了其他不可知的特征。关于性别对表现和病程的影响，被诊断为女性总体上表现出比男性更少的限制/重复行为/兴趣或活动（RRBI）（Antezana 等人，2019 年;Lai & Szatmari，2020 年）。在特定的 RRBI 中，身高刻板的行为和限制的兴趣在男孩中普遍存在，而强迫性、相同性、限制性和自残行为在女孩中更常见（Antezana 等人，2019 年），尽管同时发生的精神病理学（即焦虑）也可能影响这些性别差异。然而，在青春期的女性中，适应性功能的困难和社交挑战可能会更频繁地出现（Lai & Szatmari，2020）。然而，随着时间的推移，年轻女孩更有可能表现出症状的改善，即自闭症症状不那么严重，认知结果更好（Lai et al.， 2011）。需要进一步的研究来检查女性的这些特征，以便可能改善性别特异性诊断检查。

1.6 | Schizophrenic spectrum disorders
1.6 |精神分裂症谱系障碍

Dysfunctions in social functioning can sometimes emerge years be-fore the full onset of schizophrenia, with solitary play in pre-school years and, in early adolescence, with lower social confidence and so-cial anxiety (Keskinen et al., 2015). Adolescents can present solitary, eccentric and esoteric interests, frequently mediated by electronic devices, oddities, and peculiarities in social relationships, vague, metaphoric language, magical thinking, and partial insight, years before presenting overt hallucinations, delusions and disorganized language, thought and behavior. According to the social deafferen-tation hypothesis (Hoffman, 2007), social dysfunctions may cause early social withdrawal, which further worsens alterations in the social brain through deprivation, leading to more severe social with-drawal deprivation, facilitating the onset of psychotic symptoms (Howes & Murray, 2014). An Attenuated Psychotic Syndrome has been proposed in the DSM 5 (American Psychiatric Association, 2013) among the conditions for further studies, characterized by suspiciousness or attenuated persecutory delusions, distrustful at-titude, altered sensory perceptions, disruption in sleep-wake cycle, and frequent social isolation, with conversion to psychosis in a mi-nority of affected individuals (Fusar Poli et al., 2016).
社会功能功能障碍有时会在精神分裂症完全发作前几年出现，在学龄前阶段独自玩耍，在青春期早期，社交信心较低和社会焦虑（Keskinen 等人，2015 年）。青少年可以表现出孤独、古怪和深奥的兴趣，通常由电子设备、社会关系中的奇特和特殊性、模糊、隐喻的语言、神奇的思维和部分洞察力介导，然后几年才表现出明显的幻觉、妄想和杂乱无章的语言、思想和行为。根据社交去情感假说（Hoffman，2007），社交功能障碍可能导致早期社交退缩，这进一步恶化了社交大脑通过剥夺的改变，导致更严重的社交剥夺，促进了精神病症状的发作（Howes & Murray，2014）。DSM 5（美国精神病学协会，2013 年）在进一步研究的条件中提出了一种减轻的精神病综合症，其特征是可疑或减轻的迫害妄想、不信任的态度、感官知觉改变、睡眠-觉醒周期的中断和频繁的社会孤立，并在受影响的个体中转化为精神病（Fusar Poli 等人，2016 年）。

The incidence of both schizophrenia and Attenuated Psychotic Syndrome is slightly higher in males, at least in those receiving treatment, while the onset is reported later in females (American Psychiatric Association, 2013). Males usually present with worse premorbid adjustment, more prevalent negative symptoms (namely social isolation) and disorganization, and with greater cognitive impairment and worse response to treatments (Seeman, 2019). However, the advantages in females can vary, depending on the age of the patients and their social and cultural background, thus few definitive answers are available. Better knowledge on gender differ-ences may focus research on critical elements for positive outcome, with more effective and timely interventions (Seeman, 2019).
精神分裂症和减轻精神病综合征的发病率在男性中略高，至少在接受治疗的患者中是这样，而女性的发病报告较晚（美国精神病学协会，2013 年）。男性通常表现为更差的病前适应、更普遍的阴性症状（即社会孤立）和混乱，以及更大的认知障碍和更差的治疗反应（Seeman，2019）。然而，女性的优势可能会有所不同，具体取决于患者的年龄及其社会和文化背景，因此很少有明确的答案。更好地了解性别差异可能会将研究重点放在获得积极结果的关键要素上，并采取更有效和及时的干预措施（Seeman，2019 年）。

1.7 | Social withdrawal in personality disorders
1.7 |人格障碍中的社交退缩

Among the different personality disorders, avoidant, schizotypal, and schizoid personality disorders are mostly associated with so-cial withdrawal (American Psychiatric Association, 2013). Avoidant personality disorder is characterized by enduring and pervasive avoidance of interpersonal contact, hypersensitivity to criticism or evaluation, feelings of social ineptitude, fear of rejection, and severe distress, especially when social pressure is out of control.
在不同的人格障碍中，回避型、分裂型和分裂样人格障碍主要与社会退缩有关（美国精神病学协会，2013 年）。回避型人格障碍的特征是持久和普遍地回避人际接触、对批评或评价过敏、社交无能感、害怕被拒绝和严重的痛苦，尤其是当社会压力失控时。

Distress is usually lacking in schizotypal and schizoid person-ality disorders, both characterized by decreased desire for social contacts. In schizotypal patients, social isolation, often related to paranoid thoughts, can be the earliest manifestation, followed by eccentricities, odd behaviors and beliefs, unusual perceptual experi-ences, magical thinking, inappropriate affects. In schizoid personal-ity disorder, the absence of interest in social contacts is associated with narrow range of emotions and low emotional reactivity and re-duced emotional expressions, associated often with addictive tech-nological interests.
分裂型和分裂样人格障碍通常缺乏痛苦，两者的特征都是对社交接触的渴望降低。在分裂型患者中，通常与偏执思想有关的社会孤立可能是最早的表现，其次是怪癖、古怪的行为和信念、不寻常的感知体验、神奇的思维、不适当的情感。在精神分裂样人格障碍中，对社交交往缺乏兴趣与情绪范围狭窄和情绪反应性低以及情绪表达减少有关，这通常与令人上瘾的技术兴趣有关。

Regarding gender differences, both schizotypal and schizoid per-sonality disorders are slightly more prevalent in males, while avoid-ant personality disorder is equally distributed between genders (American Psychiatric Association, 2013).
关于性别差异，分裂型和分裂样个体性障碍在男性中略为普遍，而回避型人格障碍在性别之间分布均匀（美国精神病学协会，2013 年）。

1.8 | Gender differences in the development of social behaviors in community samples
1.8 |社区样本中社会行为发展的性别差异

Most of the studies fail to report significant gender differences in the prevalence of inhibition, shyness, or socially withdrawn behavior, as assessed by multiple measures, at least during child-hood and early adolescence (Coplan et al., 2001; Doey et al., 2014; Thijs et al. 2004). According to some evidence from young ado-lescents’ self-reports (10.5-to-14.5 year olds), these phenomena do not appear to increase with age (Rubin et al., 2010). However,other studies suggest that early shy-withdrawn behaviors in the transition from late childhood to adolescence are more stable for females than males (Eisenberg et al., 1998; Pihlakoski et al., 2006). Sex hormone activity may account for these differences in the different developmental stages (Hayashi et al., 2020; Peper et al., 2011), affecting vulnerability to social anxiety and social with-drawal (Miskovic & Schmidt, 2012). However, social norms should be carefully considered, when examining gender differences in so-cial withdrawal.
通过多种措施评估，大多数研究未能报告抑制、害羞或社交退缩行为的普遍性存在显着的性别差异，至少在儿童期和青春期早期是这样（Coplan 等人，2001 年;Doey等人，2014 年;Thijs 等人，2004 年）。根据年轻青少年自我报告（10.5 至 14.5 岁）的一些证据，这些现象似乎不会随着年龄的增长而增加（Rubin 等人，2010 年）。然而，其他研究表明，在从童年晚期到青春期的过渡中，女性的早期害羞退缩行为比男性更稳定（Eisenberg et al.， 1998;Pihlakoski et al.， 2006）。性激素活性可能是不同发育阶段的这些差异的原因（Hayashi et al.， 2020;Peper et al.， 2011），影响对社交焦虑和社交吸引力的脆弱性（Miskovic & Schmidt，2012）。然而，在检查社会退缩的性别差异时，应仔细考虑社会规范。

Strong evidence suggests that boys with shyness-withdrawal experience greater stress in social situations compared to girls, as a consequence of violating gender norms and social expec-tations in their social interactions (Doey et al., 2014). However, most of these studies considered shyness much more than so-cial withdrawal (Rubin & Barstead, 2014). Since early childhood, shy-withdrawn boys are more likely to be excluded, rejected or victimized by peers than are shy-withdrawn girls (Coplan et al., 2004, Gazelle & Ladd, 2003). During development, socially inhib-ited boys but not girls describe themselves as more lonely, with poorer social skills, subjective distress and lower self-esteem than their peers (Nelson et al., 2005). These intrapersonal difficulties can longitudinally predict negative self-esteem and internalizing problems, more likely in withdrawn males than withdrawn females (Coplan & Weeks, 2009; Morison & Masten, 1991). Caspi and col-leagues (1988) found that males who were shy in childhood, mar-ried, became fathers, and established careers at a later age than their non-shy peers. In contrast, females who were shy in child-hood did not marry or start families later than other women in the same cohort.
强有力的证据表明，与女孩相比，害羞退缩的男孩在社交场合承受的压力更大，这是由于在社交互动中违反了性别规范和社会表现（Doey et al.， 2014）。然而，这些研究中的大多数更多地考虑了羞怯，而不是社交退缩（Rubin & Barstead，2014）。从小孩时期开始，害羞性孤僻的男孩比害羞的女孩更容易被同龄人排斥、拒绝或成为受害者（Coplan等人，2004年，Gazelle & Ladd，2003年）。在发育过程中，社交抑制的男孩而不是女孩描述自己比同龄人更孤独，社交技能更差，主观痛苦和自尊心更低（Nelson et al.， 2005）。这些个人内在的困难可以纵向预测消极的自尊和内化问题，在孤僻的男性中比在孤僻的女性中更可能（Coplan & Weeks，2009;Morison & Masten，1991年）。Caspi 和 col-leagues （1988）发现，童年时害羞、结婚、成为父亲并在比不害羞的同龄人更晚建立事业的男性。相比之下，童年时害羞的女性并不比同一群体中的其他女性晚结婚或组建家庭。

These different outcomes may be partly attributable to socie-tal or cultural expectations (Rubin et al., 2009). According to these stereotypes, the dimensions of masculinity and individualism are stronger in Western than in Eastern (i.e., China, Japan) countries, with males expected to be more assertive, competitive and self- reliant (Casiglia et al., 1998), while females are expected to be more communal, caring, nurturant, and sympathetic (Gebauer et al., 2013). Thus, in Western countries, shyness-withdrawal appears to be less acceptable for boys than for girls, that is, in the interactions between parents and social withdrawn sons and daughters (Rubin et al., 2009). Chen and colleagues demonstrated that in early '90s, shy and reserved behavior in the People’s Republic of China was encouraged by mothers, teachers and peers, being associated with social com-petence and academic success (Chen et al., 1995). Ten years later, Chen et al. (2005) found that, over the years, shy behavior among urban Chinese elementary school children had become associated with negative peer reputations, suggesting that changing cultural, economic, and political climate in China was associated with prefer-ences for more assertive social behavior.
这些不同的结果可能部分归因于社会或文化期望（Rubin et al.， 2009）。根据这些刻板印象，西方国家的男子气概和个人主义的维度比东方（即中国、日本）国家更强，男性被期望更加自信、竞争和自力更生（Casiglia et al.， 1998），而女性被期望更具有公共性、关怀、养育和同情心（Gebauer et al.， 2013）。因此，在西方国家，男孩似乎比女孩更难接受害羞退缩，也就是说，在父母与社交孤僻的儿子和女儿之间的互动中（Rubin et al.， 2009）。Chen 及其同事证明，在 90 年代初，中华人民共和国的害羞和矜持行为受到母亲、老师和同龄人的鼓励，这与社交能力和学业成功有关（Chen et al.， 1995）。十年后，Chen 等人（2005 年）发现，多年来，中国城市小学生的害羞行为已经与负面的同龄人声誉有关，这表明中国不断变化的文化、经济和政治气候与对更自信的社会行为的偏好有关。

In summary, inhibited, withdrawn boys experience different so-cial histories compared to shy females, as the social and psycholog-ical meaning attributed to any social behavior is a function of the sociocultural context (Chen & French, 2008). All these findings sug-gest the relevance of a cross-cultural approach to social withdrawal,that is, considering parenting and peer relationships, but, at the same time the need for integrating this approach with research on biolog-ical markers (Rubin et al., 2009) (Table 1).
总的来说，与害羞的女性相比，抑制、孤僻的男孩经历不同的社会历史，因为任何社会行为的社会和心理意义都是社会文化背景的一个功能（Chen & French，2008）。所有这些发现都表明了跨文化方法与社交退缩的相关性，即考虑养育子女和同伴关系，但与此同时需要将这种方法与生物学标志物的研究相结合（Rubin 等人，2009 年）（表 1）。

TA B L E 1 Social withdrawal: Main issues
TA B L E 1 社交退缩：主要问题

Social withdrawal can be a primary disorder: that is, hikikomori-like disorders (Kato et al., 2012, Kato, Katsuki, et al., 2019); Internet Addiction (Durkee et al., 2012; Kato et al., 2020)
社交退缩可能是一种原发性疾病：即隐居森样疾病（Kato et al.， 2012， Kato， Katsuki， et al.， 2019）;网络成瘾（Durkee 等人，2012 年;Kato等人，2020 年）

Social withdrawal can be a symptom in different psychiatric disorders (Anxiety Disorders, Major Depressive Disorder, Autism Spectrum Disorders, Schizophrenia and Attenuated Psychosis Syndrome, Personality Disorders) (Porcelli et al., 2019)
社交退缩可能是不同精神疾病（焦虑症、重度抑郁症、自闭症谱系障碍、精神分裂症和减轻精神病综合症、人格障碍）的症状（Porcelli 等人，2019 年）

Social withdrawal can be considered, according to a dimensional perspective, a common trans-diagnostic endophenotype shared by different neuropsychiatric disorders, in line with the National Institute of Mental Health Research Domain Criteria (RDoC) project (Cuthbert, 2015; Cuthbert & Insel, 2013; Porcelli et al., 2019)
根据美国国家心理健康研究所领域标准（RDoC）项目（Cuthbert，2015 年;Cuthbert & Insel， 2013;Porcelli等人，2019 年）

Social withdrawal’s impact in real life may be affected by how social inhibition is read in gender role and cultural norms in different geographic areas and in a changing world (Chen et al., 2005; Chen & French, 2008)
社交退缩对现实生活的影响可能会受到不同地理区域和不断变化的世界中的性别角色和文化规范如何解读社会抑制的影响（Chen et al.， 2005;Chen & French， 2008）

2 | GENDER DIFFERENCES IN THE BIOLOGICAL BASES OF SOCIAL BEHAVIOR
2 |社会行为生物学基础的性别差异

2.1 | From neurobiology to clinical phenotypes: A dimensional approach to social withdrawal
2.1 |从神经生物学到临床表型：社交退缩的维度方法

Social behavior includes the capacity to integrate behavioral, cognitive and affective skills to adapt to diverse contexts and demands (Porcelli et al., 2019). The term social cognition includes all the operations re-lated to social behavior, such as perceiving, interpreting, and respond-ing to the intentions, dispositions and behaviors of others (Cacioppo&Hawkley, 2009; Cacioppo et al., 2014; Porcelli et al., 2019). During evolution, social stimuli processing has been developed in parallel to the specialization of specific portions of the human brain, from the neu-rotransmitter to the neural network level, resulting in a “social brain” (Porcelli et al., 2019). Included among the qualitative alterations of the social brain is empathy dysregulation (Milone et al., 2019). Our knowl-edge about social behavior disorders, particularly social withdrawal and their gender differences, strongly depends on the information regard-ing its neurobiological substrates, from pre-clinical to clinical models (Porcelli et al., 2019). The relationship between brain and behavior is bi-directional, as if social behavior depends on social brain, social (dys) function in turn affects neurobiological substrates, in normal develop-ment as well as in mental disorders (Cinini et al., 2014; Robbins, 2016).
社会行为包括整合行为、认知和情感技能以适应不同环境和需求的能力（Porcelli et al.， 2019）。社会认知一词包括与社会行为相关的所有操作，例如感知、解释和回应他人的意图、性格和行为（Cacioppo&Hawkley，2009 年;Cacioppo et al.， 2014;Porcelli et al.， 2019）。在进化过程中，社会刺激处理与人脑特定部分的专业化并行发展，从新传递者到神经网络水平，从而产生了“社交大脑”（Porcelli et al.， 2019）。社交大脑的质改变包括同理心失调（Milone et al.， 2019）。我们对社交行为障碍的了解，尤其是社交退缩及其性别差异，在很大程度上取决于从临床前到临床模型的神经生物学基础信息（Porcelli et al.， 2019）。大脑和行为之间的关系是双向的，就好像社会行为取决于社会大脑一样，社会（障碍）功能反过来会影响神经生物学基质，在正常发育和精神障碍中（Cinini 等人，2014 年;Robbins，2016 年）。

The complexity of the neurobiological substrates of social func-tioning is parallel to their vulnerability, expressed by the wide range of neuropsychiatric disorders associated with social dysfunction and social withdrawal, as described above. In a dimensional per-spective, different neuropsychiatric disorders may share common a trans-diagnostic endophenotype, that is an impairment in the abil-ity to form/maintain balanced relationships and networks, between individuals and between cortical regions (Bicks et al., 2015; Yizhar et al., 2011). Consistent with this hypothesis, the brain structures and neurotransmitters associated with social deficits may be largely the same across the disorders, reflecting defects in the trans-diagnostic neural networks sustaining social functioning (Bickart et al., 2014).
如上所述，社交功能的神经生物学基础的复杂性与它们的脆弱性平行，由与社交功能障碍和社交退缩相关的广泛神经精神疾病来表达。在维度透视中，不同的神经精神疾病可能具有共同的反式诊断内表型，即在个体之间和皮质区域之间形成/维持平衡关系和网络的能力受损（Bicks et al.， 2015;Yizhar et al.， 2011）。与这一假设一致，与社交缺陷相关的大脑结构和神经递质在疾病中可能大致相同，反映了维持社会功能的反式诊断神经网络的缺陷（Bickart 等人，2014 年）。

2.2 | Social abilities, social brain, and social withdrawal
2.2 |社交能力、社交大脑和社交退缩

The main components of the social brain have been identified in the orbitofrontal cortex, amygdala, and temporal cortex (particularly the superior temporal sulcus), with additional regions, such as the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (Porcelli et al., 2019). This overlapping circuitry is involved both in automated processing (i.e., detection of socially relevant stimuli) and in more complex abilities (i.e., reflecting on one’s own or others’ mental states). Bickart et al. (2014) has described five networks, three centered on the amygdala (social perception network, social affiliation network, and social aversion network), and two other networks, the mirror net-work (Rizzolatti & Craighero, 2004) and the mentalizing network (Frith&Frith, 2006). All these structures are also involved in other mental processes, as suggested by the overlap with other networks.
社交脑的主要组成部分已在眶额叶皮层、杏仁核和颞叶皮层（尤其是颞上沟）中被确定，还有其他区域，例如内侧前额叶皮层（mPFC）和前扣带皮层（Porcelli et al.， 2019）。这种重叠的电路既涉及自动处理（即检测与社会相关的刺激）也涉及更复杂的能力（即反思自己或他人的精神状态）。Bickart et al. （2014）描述了五个网络，其中三个以杏仁核为中心（社会感知网络、社会归属网络和社会厌恶网络），以及另外两个网络，镜像网络（Rizzolatti & Craighero，2004）和心理化网络（Frith&Frith，2006）。所有这些结构也参与其他心理过程，正如与其他网络的重叠所表明的那样。

All the “general” neurotransmitters are implicated in processing social stimuli, such as serotonin (5-HT), dopamine (DA), opioid (OP), and GABA (Porcelli et al., 2019). As an example, social withdrawal has been linked to hyperactivity of the ventral tegmental area (VTA) dopamine neurons (Krishnan et al., 2017). In addition, more specific neurotransmitters, the neuropeptides oxytocin (OT) and vasopres-sin (VP), are specialized in processing and regulating the neural re-sponse in mammals, including humans (Dumais & Veenema, 2016; Lu et al., 2019; Porcelli et al., 2019).
所有“一般”神经递质都与处理社会刺激有关，例如血清素（5-HT）、多巴胺（DA）、阿片类药物（OP）和 GABA（Porcelli 等人，2019 年）。例如，社交退缩与腹侧被盖区（VTA）多巴胺神经元的过度活跃有关（Krishnan et al.， 2017）。此外，更具体的神经递质，即神经肽催产素（OT）和血管蛋白酶（VP），专门处理和调节哺乳动物的神经反应，包括人类（Dumais和Veenema，2016;Lu et al.， 2019;Porcelli et al.， 2019）。

If the social brain is crucial for normal social behaviors, these in turn are crucial for healthy neurobehavioral maturation (Cinini et al., 2014; Robbins, 2016). The exposure to negative social experience in animal models (rodent), alter stress-related neural circuits and neuro-behavioral markers implicated in anxiety, depression, and substance abuse (Burke et al., 2017). In rodents, social isolation in the transi-tion from adolescence to adulthood is associated with a decrease in hippocampal neurogenesis and increased cortisol levels after 1 and 3 weeks of isolation, suggesting that social deprivation contributes to the deleterious consequences of prolonged stressful conditions (Robbins, 2016). Much less is known about the effects of social isola-tion in non-human primates during the transition from adolescence to adulthood (Galvão-Coelho et al., 2017), although some evidence indi-cates that even in primates, social relationships are crucial for the de-velopment and maintenance of normal behavior (Cinini et al., 2014).
如果社交大脑对正常的社会行为至关重要，那么这些反过来又对健康的神经行为成熟至关重要（Cinini 等人，2014 年;Robbins，2016 年）。在动物模型（啮齿动物）中暴露于负面社会经历中，会改变与焦虑、抑郁和药物滥用有关的压力相关神经回路和神经行为标志物（Burke et al.， 2017）。在啮齿动物中，从青春期到成年期的社会孤立与隔离 1 周和 3 周后海马神经发生的减少和皮质醇水平升高有关，这表明社会剥夺导致了长期压力条件的有害后果（Robbins，2016 年）。关于非人类灵长类动物在从青春期到成年期的过渡过程中社会地位的影响知之甚少（Galvão-Coelho et al.， 2017），尽管一些证据表明，即使在灵长类动物中，社会关系对于正常行为的发展和维持也至关重要（Cinini et al.， 2014）。

A major constraint in studying animal models of social interac-tions is the availability of reliable measures to assess sociability. Several behavioral tests have been developed (see for a review Silverman et al., 2010). As an example, to quantitate social tendencies of the experimental mouse, two tasks are measured, the time spent with a novel conspecific, and the preference for a novel versus a familiar conspecific (Kaidanovich-Beilin et al., 2011). The experimen-tal design allows evaluation of two critical aspects of social behavior, such as social affiliation/motivation and social memory and novelty. “Sociability” in this case is defined as propensity to spend time with another mouse, as compared to time spent alone in an identical but empty chamber. “Preference for social novelty” is defined as propen-sity to spend time with a previously unencountered mouse rather than with a familiar mouse (Kaidanovich-Beilin et al., 2011).
研究社会互动动物模型的一个主要制约因素是评估社交能力的可靠措施的可用性。已经开发了几种行为测试（参见Silverman 等人的评论，2010 年）。例如，为了量化实验小鼠的社交倾向，测量了两项任务，与新的同种动物相处的时间，以及对新的同种动物的偏好与熟悉的同种动物的偏好（Kaidanovich-Beilin等人，2011 年）。体验式设计允许评估社会行为的两个关键方面，例如社会归属/动机以及社会记忆和新奇性。在这种情况下，“社交性”被定义为与另一只老鼠共度时光的倾向，与单独在相同但空旷的房间中度过的时间相比。“对社会新奇事物的偏好”被定义为与以前未遇到的老鼠共度时光，而不是与熟悉的老鼠共度时光（Kaidanovich-Beilin et al.， 2011）。

2.3 | Dimorphic brain nuclei, sex steroids and gender differences
2.3 |二态性脑核、性类固醇和性别差异

Some aspects strongly differentiate social behaviors between males and females, both in animal models and in humans, such as parental attachment and mating, while others are much more similar, such as friendship (Coria-Avila et al., 2014). Biological bases of these differ-ences are far from clear, but it can be hypothesized that gender differ-ences in neural circuitry may contribute to both sexually differentiated social behaviors and their dysfunctions. A better comprehension of gender differences in the neural bases of normal and abnormal social behaviors may provide new insights for innovative and focused treat-ments in males versus females (Arnold, 2009). Current understanding of the neural circuits underlying sexually dimorphic social behaviors is prevalently based on rodent models (Bayless & Shah, 2016).
在动物模型和人类中，某些方面强烈区分了雄性和雌性之间的社会行为，例如父母依恋和交配，而其他方面则更加相似，例如友谊（Coria-Avila et al.， 2014）。这些差异的生物学基础远不清楚，但可以假设神经回路中的性别差异可能导致性别差异化的社会行为及其功能障碍。更好地理解正常和异常社会行为的神经基础的性别差异可能会为男性与女性的创新和集中治疗提供新的见解（Arnold，2009 年）。目前对性二态性社会行为的神经回路的理解主要基于啮齿动物模型（Bayless & Shah，2016）。

Sex hormone-regulated pathways are the predominant internal physiological signals that control these behaviors (Juraska et al., 2013). Estrogens, progesterone, and testosterone bind to nuclear hormone receptors that are also essential for gender-specific social interactions, producing gender differences in gene expression within brain regions most likely to control sexually dimorphic social behav-iors (Bayless & Shah, 2016).
性激素调节途径是控制这些行为的主要内部生理信号（Juraska et al.， 2013）。雌激素、孕激素和睾酮与核激素受体结合，这些受体对于性别特定的社交互动也是必不可少的，在最有可能控制性二态性社交行为的大脑区域内产生基因表达的性别差异（Bayless & Shah，2016）。

In the sexually differentiated brain, there are sex differences in the tissue structures. Sexually dimorphic nuclei present morphologi-cal gender differences (i.e., volume, morphology, number of neurons and glial cells, synaptic number), and can be considered the structural bases for gender differences in brain functions. A number of sexu-ally dimorphic nuclei have been identified in the Central Nervous System of many species, and other novel sexually dimorphic brain structures are still to be explored, as well as their physiological func-tions (Ogawa et al., 2020).
在性别分化的大脑中，组织结构存在性别差异。性二态性细胞核呈现形态学性别差异（即体积、形态、神经元和神经胶质细胞的数量、突触数量），可以被认为是大脑功能性别差异的结构基础。在许多物种的中枢神经系统中已经鉴定出许多性二态性核，其他新的性二态性脑结构及其生理功能仍有待探索（Ogawa et al.， 2020）。

Specific processes of social behavior, such as social recogni-tion and social learning, are probably affected by dimorphic nuclei (Ogawa et al., 2020). Social recognition allows members of a group to distinguish conspecifics, assigning others to specific categories, to adapt their behavior to their social context. Social learning is “learn-ing that is influenced by observation of, or interaction with, another animal, usually a conspecific,” reducing the need for learning through personal, risky experiences (Ogawa et al., 2020).
社会行为的特定过程，例如社会识别和社会学习，可能受到二态核的影响（Ogawa et al.， 2020）。社会认可允许一个群体的成员区分同种生物，将其他生物分配到特定的类别中，以使他们的行为适应他们的社会环境。社会学习是 “受观察另一种动物（通常是同种动物）或与之互动影响的学习”，减少了通过个人、危险经历学习的需求（Ogawa et al.， 2020）。

The roles of sex hormones in the formation of sexually dimorphic nuclei have been extensively explored. The estrogen 17β-Estradiol (17β-E) is a steroid hormone that signals the central nervous sys-tem, via both genomic and non-genomic pathways, to drive behavior,including social behaviors, and anxiety-related behaviors in social contexts (Ogawa et al., 2020). The 17β-E also regulates sexual and aggressive behavior in males, as testosterone secreted from the tes-tes is converted to 17β-E in the brain. Regarding genomic signaling, 17β-E is a ligand for the nuclear receptors, ERα and ERβ, which act as ligand-activated transcription factors, and are more strongly ex-pressed by social behavioral networks in the brain (Nomura et al., 2003). The ventromedial nucleus of the hypothalamus (VMH), the paraventricular nucleus of the hypothalamus (PVN) and the dor-sal raphe nucleus of the midbrain (DRN), the medial preoptic area (mPOA), the medial amygdala (MeA), and the bed nucleus of the stria terminalis (BNST) and the lateral septum (LS) are known to express both ERα and ERβ, even with different ratios in the different portions of the brain (Ogawa et al., 2020). Regarding the respective roles of ERα and ERβ in the estrogenic regulation of social behavior, a re-cently developed transgenic mice tagged for ERβ may contribute to a better understanding of this topic, particularly in the developmen-tal period, and above all of the cross-talk between the different ERs and estrogens and other neurochemical systems in different brain regions (Ogawa et al., 2020).
性激素在性二态性细胞核形成中的作用已被广泛探索。雌激素 17β-雌二醇（17β-E）是一种类固醇激素，通过基因组和非基因组途径向中枢神经系统发出信号，以驱动行为，包括社交行为和社交环境中的焦虑相关行为（Ogawa et al.， 2020）。17β-E 还调节男性的性和攻击性行为，因为 tes-tes 分泌的睾丸激素在大脑中转化为 17β-E。关于基因组信号传导，17β-E 是核受体 ERα 和 ERβ 的配体，它们充当配体激活的转录因子，并且更强烈地受到大脑中社交行为网络的压迫（Nomura et al.， 2003）。已知下丘脑腹内侧核（VMH）、下丘脑室旁核（PVN）和中脑背中缝核（DRN）、内侧视前区（mPOA）、内侧杏仁核（MeA）以及终纹床核（BNST）和外侧隔膜（LS）同时表达 ERα 和 ERβ，即使在大脑的不同部分具有不同的比例（Ogawa 等人， 2020）. 关于 ERα 和 ERβ 在社会行为的雌激素调节中的各自作用，最近开发的标记 ERβ 的转基因小鼠可能有助于更好地理解这个主题，特别是在发育期，尤其是不同 ERs 和雌激素以及不同大脑区域的其他神经化学系统之间的串扰（Ogawa 等人， 2020).

Although animal studies have supported the role of testosterone as a “social hormone,” studies on its influence on human social be-haviors are of relatively more recent vintage (Eisenegger et al., 2011; Hayashi et al., 2020). Testosterone secreted from the testes in the perinatal period is a key molecule in the formation of sexually dimor-phic nuclei, particularly the mPOA and the BNST (Campi et al., 2013). After the effects of testosterone on brain sex differentiation in the perinatal period, the brain is again affected by testicular testosterone in the pubertal period, when the brain is masculinized and defemi-nized, while estrogens secreted from the ovaries during puberty act to feminize and demasculinize the brain (Campi et al., 2013).
尽管动物研究支持睾丸激素作为“社交激素”的作用，但关于其对人类社交行为影响的研究是相对较新的时期（Eisenegger 等人，2011 年;Hayashi et al.， 2020）。围产期睾丸分泌的睾丸激素是形成性二聚细胞核的关键分子，尤其是 mPOA 和 BNST（Campi 等人，2013 年）。在围产期睾酮对大脑性别分化产生影响后，大脑在青春期再次受到睾丸睾酮的影响，此时大脑被男性化和排便，而青春期卵巢分泌的雌激素则起到女性化和去男性化大脑的作用（Campi 等人，2013 年）。

These results suggest that sex hormones organize structural connections and activate the brain areas they connect. Specifically, ovarian hormones (estradiol and progesterone) may enhance both cortico-cortical and subcortico-cortical functional connectivity, whereas androgens (testosterone) may decrease subcortico-cortical functional connectivity but increase functional connectivity be-tween subcortical brain areas (Peper et al., 2011). Studies exploring specifically EEG delta–beta coupling, considered a measure of coin-ciding activity in both cortical and subcortical regions (amygdala) of the brain, showed that negative emotions, such as fear and anxiety, are associated with higher delta–beta coupling of cortical (frontal cortex) and subcortical (amygdala) regions, both involved when pro-cessing the emotion (van Honk et al., 2010). Testosterone reduces this coupling similarly in both females who have been administered testosterone (Schutter & van Honk, 2004), and in males who have naturally occurring high levels of testosterone (Miskovic & Schmidt, 2009), suggesting a role for testosterone in reducing social anxiety in humans (Miskovic & Schmidt, 2012). Testosterone has been asso-ciated with approach motivations, and men with clinically low levels of testosterone are more apathetic and less motivated (Tostain & Blanc, 2008). In early adolescent boys, a higher risk of social with-drawal was associated with a lower salivary testosterone level after adjustment for age, body mass index, degree of anxiety/depression, and pubertal stage (Hayashi et al., 2020).
这些结果表明，性激素组织结构连接并激活它们连接的大脑区域。具体来说，卵巢激素（雌二醇和孕激素）可以增强皮质-皮质和皮质-皮质下功能连接，而雄激素（睾酮）可能会减少皮层下-皮质功能连接，但会增加皮质下脑区之间的功能连接（Peper et al.， 2011）。专门探索脑电图 delta-β 耦合的研究，被认为是大脑皮层和皮层下区域（杏仁核）的同步活动的量度，表明负面情绪，如恐惧和焦虑，与皮层（额叶皮层）和皮层下（杏仁核）区域的较高 delta-β 耦合有关，这两者都涉及情绪处理（van Honk 等人，睾酮在接受睾酮治疗的女性中（Schutter & van Honk，2004年）和自然具有高水平睾酮的男性（Miskovic & Schmidt，2009年）中都能类似地减少这种耦合，这表明睾酮在减少人类社交焦虑中的作用（Miskovic & Schmidt，2012年）。睾酮与接近动机有关，临床上睾酮水平低的男性更冷漠且动力不足（Tostain & Blanc），2008）。在青春期早期男孩中，在调整年龄、体重指数、焦虑/抑郁程度和青春期后，较高的社交收缩风险与较低的唾液睾酮水平相关（Hayashi et al.， 2020）。

Estradiol-mediated increases in cortico-subcortical functional connectivity may indicate a stronger link among systems involved in the reaction to socially relevant stimuli and brain regions involved in more detailed analysis of these signals. These models provide new insights into the important functional roles played by sex steroid hormones in the neural regulation of multiple social behaviors, possi-bly affecting gender differences in vulnerability to social withdrawal.
雌二醇介导的皮质-皮层下功能连接增加可能表明参与对社会相关刺激反应的系统与参与更详细分析这些信号的大脑区域之间的联系更强。这些模型为性类固醇激素在多种社会行为的神经调节中发挥的重要功能作用提供了新的见解，可能会影响社交退缩易感性的性别差异。

2. 4 | The role of oxytocin and vasopressin systems in the gender differences in social behavior
2. 4 |催产素和加压素系统在社会行为性别差异中的作用

Neuropeptides oxytocin (OT) and vasopressin (VP) may regulate so-cial behavior in gender-specific ways, related to gender differences in the brain. Unfortunately, their role in the neurobiological bases of normal and atypical social cognition are still poorly understood, particularly in humans, while some differences in the neurotransmit-ter systems have been found in animal models (Campi et al., 2014).
神经肽催产素（OT）和加压素（VP）可能以性别特异性方式调节社会行为，这与大脑中的性别差异有关。不幸的是，它们在正常和非典型社会认知的神经生物学基础中的作用仍然知之甚少，尤其是在人类中，而在动物模型中发现了神经传递系统的一些差异（Campi et al.， 2014）。

Differences in the expression of the OT and VP and of their re-ceptors between genders have been reported in specific areas of the brain in sexually dimorphic structures, namely in the BNST, a key structure of the social brain, sometimes referred to as the extended amygdala (Dumais & Veenema, 2016).
在大脑的特定区域，即在社会大脑的关键结构BNST中，有时被称为扩展杏仁核（Dumais & Veenema，2016）中，已经报道了OT和VP及其受体在不同性别之间的表达差异。

Most studies (reviewed in Lu et al., 2019) have suggested that OT facilitates in rodents partner preference in both sexes (with fe-males presenting this effect more significantly), increased trust in others (more evident in males), enhanced memory (in both males and females), and reduced anxious emotion (in males). Regarding VP, relevant studies have indicated that this neuropeptide may improve partner preference, memory, empathy, positive-emotion recogni-tion, and induced anxiety, without significant differences between genders (Lu et al., 2019). Several brain regions implicated in social behaviors in animals and humans have gender-different and steroid- sensitive innervation related to VP, such as the lateral septum, ven-tral pallidum, lateral habenula (LHb), and several hypothalamic and midbrain areas, including the dorsal raphe nuclei (DR) (Dumais & Veenema, 2016). Most gender-different brain VP innervation likely originates from gender-different VP-expressing neurons within the BNST (de Vries & Panzica, 2006). Rigney et al. (2020) further sup-ported in mice significant gender differences in the VP regulation of social communication in LHb as well as DR, both important for social behavior in a sexually dimorphic manner.
大多数研究（Lu et al.， 2019 综述）表明，OT 促进了啮齿动物在两性中的伴侣偏好（女性男性表现出这种效果更显着），增加了对他人的信任（在男性中更明显），增强了记忆力（在男性和女性中），并减少了焦虑情绪（在男性中）。关于 VP，相关研究表明，这种神经肽可能会改善伴侣偏好、记忆力、同理心、积极情绪识别和诱导焦虑，而性别之间没有显着差异（Lu et al.， 2019）。与动物和人类的社会行为有关的几个大脑区域具有与VP相关的性别不同和类固醇敏感的神经支配，如外侧隔膜、苍白球静脉、外侧缰膜（LHb），以及几个下丘脑和中脑区域，包括背缝核（DR）（Dumais & Veenema，2016）。大多数性别不同的大脑VP神经支配可能源于BNST内性别不同的VP表达神经元（de Vries & Panzica，2006）。Rigney 等人（2020）进一步支持小鼠在 LHb 和 DR 中对社交交流的 VP 调节存在显着的性别差异，这两者都对性二态方式的社会行为很重要。

Our current knowledge on how VP and OT may influence so-cial behavior with gender-specific actions in humans is based on the use of intranasal administration. Studies on the gender effects of intranasal OT suggest a different role in the modulation of social information processing in men and women, particularly in the emo-tional valence when perceiving and recognizing social stimuli, and in brain activation in response to emotional social stimuli (Domes et al., 2007, 2010; Fischer-Shofty et al., 2013; Herzmann et al., 2013; Lynn et al., 2014; Theodoridou et al., 2013).
我们目前关于 VP 和 OT 如何通过性别特异性行为影响人类社会行为的知识是基于鼻内给药的使用。关于鼻内 OT 性别影响的研究表明，在男性和女性的社会信息处理调节中的作用不同，特别是在感知和识别社会刺激时的情感效价方面，以及在响应情绪社会刺激的大脑激活中的作用不同（Domes 等人，2007 年，2010 年;Fischer-Shofty等人，2013 年;Herzmann et al.， 2013;Lynn et al.， 2014;Theodoridou et al.， 2013）。

The few studies on the VP system that included men and women reveal gender-specific effects of VP on some behavioral responses, modulating cooperative social interactions differently in males and females via differential activation of reward, arousal, and memory- related brain areas (Feng et al., 2015; Rilling et al., 2012, 2014; Thompson et al., 2006). Other aspects of social functioning are more gender-independent from VP, such as empathic concern (Tabak et al., 2015). However, studies on the VP system have included only healthy individuals, thus it is matter of further research to determine the presence of gender associations of VP social dysfunction in spe-cific psychiatric disorders.
包括男性和女性在内的少数关于 VP 系统的研究揭示了 VP 对某些行为反应的性别特异性影响，通过奖励、唤醒和记忆相关大脑区域的差异激活，以不同的方式调节男性和女性的合作社交互动（Feng 等人，2015 年;Rilling 等人，2012 年、2014 年;Thompson et al.， 2006）。社会功能的其他方面与 VP 更加独立于性别，例如移情关注（Tabak et al.， 2015）。然而，对 VP 系统的研究仅包括健康个体，因此需要进一步研究来确定特定精神疾病中 VP 社交功能障碍是否存在性别关联。

Considering these gender differences, in most of the cases the two neuropeptides seem to modulate several social behaviors in a similar direction in males and females (i.e., facilitate social recog-nition, pair bonding, and aspects of social cognition), even if they may act in specific brain regions activating distinct neural circuits (Dumais & Veenema, 2016).
考虑到这些性别差异，在大多数情况下，这两种神经肽似乎以相似的方向调节男性和女性的几种社会行为（即促进社会认知、配对结合和社会认知的各个方面），即使它们可能在特定的大脑区域起作用，激活不同的神经回路（Dumais & Veenema，2016）。

It is noteworthy that both VP and OT have been implicated in different psychiatric disorders presenting with social dysfunctions and withdrawal (see for a review Rutigliano et al., 2016), such as schizophrenia (Jobst et al., 2014), ASD (LoParo & Waldman, 2015; Xu et al., 2013; Yang et al., 2010), depression (Jobst et al., 2015; Yueng et al., 2014), anxiety disorders (Yoon & Kim, 2020), and PTSD (Sipper et al., 2020). Knowledge on how OT and VP may mediate gender-specific social behavior may provide useful insight into gender-specific treatment strategies in these psychiatric dis-orders. However, according to a preliminary meta-analysis, find-ings are still inconsistent and do not allow to consider VP and OT as reliable biomarkers in these psychiatric disorders (Rutigliano et al., 2016)
值得注意的是，VP和OT都与表现为社交功能障碍和退缩的不同精神疾病有关（参见Rutigliano等人的评论，2016），如精神分裂症（Jobst等人，ASD，ASD（LoParo&Waldman，2015;Xu et al.， 2013;Yang et al.， 2010）、抑郁症（Jobst et al.， 2015;Yueng等人，2014年），焦虑症（Yoon & Kim，2020年）和PTSD（Sipper等人，2020年）。关于 OT 和 VP 如何介导性别特异性社会行为的知识可能为这些精神疾病中的性别特异性治疗策略提供有用的见解。然而，根据初步的荟萃分析，研究结果仍然不一致，不允许将 VP 和 OT 视为这些精神疾病的可靠生物标志物（Rutigliano et al.， 2016）

2.5 | Gender differences and vulnerability to social stress
2.5 |性别差异和对社会压力的脆弱性

The endocrine changes after stress rely on the involvement of the hypothalamic pituitary adrenal (HPA) axis, which is controlled by corticotropin-releasing hormone (CRH) neurons in the paraven-tricular nucleus of the hypothalamus (PVN). Sex hormones have important effects on the function of the HPA, and these effects may contribute to gender differences in vulnerability in stress situa-tions (Goel & Bale, 2009). In adult rats, estrogens generally amplify the effects of stress on glucocorticoid secretion (Weiser & Handa, 2009), while during postnatal development exposure to estro-gens decreases HPA activation in response to psychosocial stress (Evuarherhe et al., 2009; Patchev et al., 1995). Furthermore, chronic stressors are associated with more frequent and severe depression- like behaviors (anhedonia) in females compared to males (Dalla et al., 2005, 2008; Konkle et al., 2003).
应激后的内分泌变化依赖于下丘脑垂体肾上腺（HPA）轴的参与，该轴由下丘脑旁三核（PVN）中的促肾上腺皮质激素释放激素（CRH）神经元控制。性激素对HPA的功能有重要影响，这些影响可能导致压力情况下脆弱性的性别差异（Goel & Bale，2009）。在成年大鼠中，雌激素通常会放大压力对糖皮质激素分泌的影响（Weiser & Handa，2009），而在出生后发育过程中，暴露于雌激素会降低HPA的激活，以应对心理社会压力（Evuarherhe等人，2009;Patchev et al.， 1995）。此外，与男性相比，慢性压力源与女性更频繁和更严重的抑郁样行为（快感缺乏）有关（Dalla 等人，2005 年、2008 年;Konkle et al.， 2003）。

The dysregulation of the stress response is implicated in nu-merous neuropsychiatric diseases (Tost et al., 2015), often pre-senting gender-specific differences, which may be a consequence of the sexual dimorphism of the neuroendocrine response to stress, with different responses to the same stressor, according to both age and gender (Bale & Epperson, 2015). Human studies demonstrate that in conditions of social stress, young girls present greater corticosteroid reactivity than boys (Gunnar et al., 2009; de Veld et al., 2012).
压力反应的失调与多种神经精神疾病有关（Tost等人，2015年，通常预示着性别特异性的差异，这可能是神经内分泌反应对压力的性二态性的结果，对同一压力源的反应不同，根据年龄和性别的不同（Bale & Epperson，2015）。人类研究表明，在社会压力条件下，年轻女孩比男孩表现出更高的皮质类固醇反应性（Gunnar 等人，2009 年;de Veld 等人，2012 年）。

According to Senst et al. (2016), social isolation by itself alters the intrinsic properties of the neurons in the hypothalamic PVN secreting CRH in sexually dimorphic fashion, with corticosteroid- dependent effects in female, but not male mice. It is possible that males and females react differently to some stressors (i.e., social stressors), but not to others. However, these findings provide a neu-robiological framework for testing gender-specific therapeutic strat-egies in response to social stress (Taylor et al., 2000).
根据 Senst 等人（2016 年）的说法，社会隔离本身会改变下丘脑 PVN 中神经元的内在特性，以性二态方式分泌 CRH，对雌性小鼠具有皮质类固醇依赖性作用，但对雄性小鼠没有。男性和女性对某些压力源（即社交压力源）的反应可能不同，但对其他压力源的反应则不同。然而，这些发现为测试响应社会压力的性别特异性治疗策略提供了一个 neu-robiological 框架（Taylor et al.， 2000）。

An experimental approach to understanding neurobiological and behavioral responses to psychosocial stress in animal models is the social defeat stress, that is the repeated exposure to physical confrontations with a larger aggressive male (Golden et al., 2011; Huhman, 2006; Miczek et al., 2008). The most consistent behav-ioral response to social defeat stress is, in most species including primates, a withdrawal from social situations (Trainor et al., 2013).
在动物模型中理解神经生物学和行为对社会心理压力反应的一种实验方法是社交失败压力，即反复暴露于与更大的攻击性雄性的身体对抗（Golden 等人，2011 年;Huhman， 2006;Miczek et al.， 2008）。在包括灵长类动物在内的大多数物种中，对社交失败压力最一致的行为反应是退出社交场合（Trainor et al.， 2013）。

Social defeat stress in rodents directly affects the mesolimbic dopaminergic system, particularly the ventral striatum and nucleus accumbens (NAc) (Tidey & Miczek, 1996), and in the long-term, burst firing of the VTA DA neurons (Anstrom et al., 2009; Cao et al., 2010; Razzoli et al., 2011). Withdrawal from social contexts has been linked to hyperactivity of VTA DA neurons, while inhibi-tion of burst firing by VTA DA neurons increases social interaction behavior in male rodents exposed to social defeat (Krishnan et al., 2017). Increases in activity of VTA neurons projecting to the NAc, but not the mPFC, are especially critical for inducing social avoid-ance in both male and female rodents, and this increased activity in the NAc seems necessary for stress-induced social withdrawal behavior (Campi et al., 2014).
啮齿动物的社交失败压力直接影响中脑边缘多巴胺能系统，特别是腹侧纹状体和伏隔核（NAc）（Tidey & Miczek，1996），并且从长远来看，VTA DA神经元的爆发放电（Anstrom等人，2009;Cao et al.， 2010;Razzoli et al.， 2011）。退出社交环境与 VTA DA 神经元的过度活跃有关，而抑制 VTA DA 神经元的爆发放电会增加暴露于社交失败的雄性啮齿动物的社交互动行为（Krishnan等人，2017 年）。投射到 NAc 而不是 mPFC 的 VTA 神经元的活动增加对于诱导雄性和雌性啮齿动物的社交回避尤其重要，而 NAc 中活动的增加对于压力诱导的社交退缩行为似乎是必要的（Campi et al.， 2014）。

Regarding possible gender differences, some studies suggest that dopamine D1-like receptor signaling induces social with-drawal in female rats, but not in males (Trainor et al., 2011, 2013). A D1 agonist SKF38393 infused in the NAc shell of female rodents naïve to social defeat decreased social interaction behavior, while inhibition of D1 receptors increased social approach behavior (Campi et al., 2014). The same dose of SKF38393 had no effect in males, suggesting that D1 receptor activation is crucial to in-duce social withdrawal in females but not in males (Campi et al., 2014). These gender differences in molecular pathways regulated by D1 receptors may thus contribute to gender differences in so-cial withdrawal behavior (Campi et al., 2014). Some findings indi-cate that the role of D1 receptors may be mediated by endogenous opioid signaling, because neurons in the NAc that express D1 re-ceptors also express dynorphin, the primary endogenous ligand for the kappa opioid receptor (KOR). Infusion of a KOR antagonist (norbinaltorphimine, nor-BNI) into the NAc shell reduces aggres-sive behavior (Resendez et al., 2012). Further studies of molecular pathways downstream of D1 receptor expressing neurons, par-ticularly the dynorphin-KOR pathway, may provide new insights for understanding gender differences in the behavioral effects of psychosocial stress (Campi et al., 2014) (Table 2).
关于可能的性别差异，一些研究表明，多巴胺 D1 样受体信号传导在雌性大鼠中诱导社交性收缩，但在雄性大鼠中则不会（Trainor et al.， 2011， 2013）。将 D1 激动剂SKF38393注入未达到社交失败的雌性啮齿动物的 NAc 壳中，减少了社交互动行为，而抑制 D1 受体增加了社交接近行为（Campi 等人，2014 年）。相同剂量的 SKF38393 对男性没有影响，这表明 D1 受体激活对于诱导女性社交退缩至关重要，但在男性中则不然（Campi et al.， 2014）。因此，D1 受体调节的分子通路的这些性别差异可能导致社会戒断行为的性别差异（Campi et al.， 2014）。一些研究结果表明，D1 受体的作用可能是由内源性阿片类药物信号介导的，因为 NAc 中表达 D1 受体的神经元也表达强啡肽，强啡肽是 κ 阿片受体（KOR）的主要内源性配体。将 KOR 拮抗剂（norbinaltorphimine， nor-BNI）注入 NAc 壳可降低攻击行为（Resendez et al.， 2012）。对表达 D1 受体的神经元下游分子通路的进一步研究，特别是强啡肽-KOR 通路，可能为理解社会心理压力行为影响的性别差异提供新的见解（Campi et al.， 2014）（表 2）。

TA B L E 2 Neurobiological bases and gender differences in social behavior: Main issues
TA B L E 2 社会行为中的神经生物学基础和性别差异：主要问题

Social stimuli processing has been developed in parallel to the specialization of specific portions of the human brain, resulting in the “social brain” (Porcelli et al., 2019)
社会刺激处理与人脑特定部分的专业化并行发展，从而产生了“社交大脑”（Porcelli et al.， 2019）

Brain structures and functions associated with social deficits may be the same across different disorders, reflecting defects in trans- diagnostic neural networks (Bickart et al., 2014)
与社交缺陷相关的大脑结构和功能在不同的疾病中可能相同，反映了跨诊断神经网络的缺陷（Bickart 等人，2014 年）

Sexually dimorphic nuclei in the social brain, regulated by sex hormones in different phases of development, can be the structural bases for gender differences in brain functions (Ogawa et al., 2020)
社会大脑中的性二态核在不同发育阶段受性激素的调节，可以成为大脑功能性别差异的结构基础（Ogawa et al.， 2020）

Neuropeptides oxytocine and vasopressine regulate social behavior in gender-specific ways, related to differences in their expression in specific areas of the brain (Dumais & Veenema, 2016), and
神经肽催产素和加压素以性别特定的方式调节社会行为，这与它们在大脑特定区域的表达差异有关（Dumais & Veenema，2016），以及

are implicated in different psychiatric disorders with social dysfunctions (Rutigliano et al., 2016)
与具有社交功能障碍的不同精神疾病有关（Rutigliano et al.， 2016）

Endocrine changes after social stress in the hypothalamic pituitary adrenal (HPA) axis, controlled by corticotropin releasing hormone (CRH), are modulated by sex hormones, and may contribute to gender differences in vulnerability in stress situations (Goel & Bale, 2009)
下丘脑垂体肾上腺（HPA）轴的社会压力后内分泌变化，由促肾上腺皮质激素释放激素（CRH）控制，受性激素调节，并可能导致压力情况下脆弱性的性别差异（Goel & Bale，2009）

3 | CONCLUSIONS
3 |结论

This review aimed at providing a general overview of social with-drawal and more specifically of gender differences, gleaned from clinical, psychological, social, and biological evidence. The social brain is a complex system highly susceptible to many pathogenic stimuli, leading to specific psychiatric disorders presenting social withdrawal as a prominent feature. Even if social dysfunctions are frequently observed in a number of disorders, social withdrawal in turn can contribute to a further worsening of the disorder symp-tomatology, in a vicious circle, probably related to a negative impact on the social brain. A growing knowledge about the complex inter-play between oxytocin/vasopressin systems and sex hormones in the development of social brain may increase our knowledge about the substantial differences between males and females. However, the knowledge gap between the workings of the normal function-ing of the social brain, based primarily on animal models, and the underpinnings of social dysfunctions in neuropsychiatric disorders is still enormous. Although growing evidence supports gender re-lated differences in social brain structure and function, few data are still available on gender differences in withdrawal behaviors in hu-mans across different psychiatric disorders (i.e., ASD, schizophrenia, depression).
本综述旨在提供从临床、心理学、社会和生物学证据中收集的社会吸引力，更具体地说是性别差异的一般概述。社交脑是一个复杂的系统，对许多致病性刺激高度敏感，导致特定的精神疾病将社交退缩作为一个突出特征。即使在许多疾病中经常观察到社交功能障碍，社交退缩反过来也会导致疾病症状学的进一步恶化，形成恶性循环，可能与对社交大脑的负面影响有关。对催产素/加压素系统和性激素在社交大脑发育中复杂的相互作用的了解不断增加，可能会增加我们对男性和女性之间实质性差异的了解。然而，主要基于动物模型的社会大脑正常运作的工作原理与神经精神疾病中社会功能障碍的基础之间的知识差距仍然巨大。尽管越来越多的证据支持社会大脑结构和功能的性别相关差异，但关于不同精神疾病（即 ASD、精神分裂症、抑郁症）的胡患者戒断行为的性别差异的数据仍然很少。

Social dysfunctions and social withdrawal as its most evident ex-pression, may represent a trans-diagnostic domain being a potentially independent entity in terms of biologic roots. The brain structures and neurotransmitters associated with social deficits may be the same across the disorders, and the alterations of the social brain may likely lead to social withdrawal (Porcelli et al., 2019). Taking into account the Research Domain Criteria (RDoc) project launched by the National Institute of Mental Health (NIMH) in the early 2009 (Cuthbert, 2015; Cuthbert & Insel, 2013; Insel et al., 2010), no studies investigated so-cial functioning as a specific psychopathological dimension with a com-bined approach in different neuropsychiatric disorders, independent from the diagnosis. Implementing knowledge in the RDoC perspective may improve the management and the treatment of these disorders, underlining the overlaps among them. A combined approach applying phenotypical characterization across neuropsychiatric disorders, ad-equate diagnostic tools, complementary techniques (e.g., functional magnetic resonance imaging, electrophysiological measures, hormonal dosages) may help to fill the gap between preclinical models and clini-cal findings, that is for targeted, gender-specific, treatments for similar deficits in different disorders, such as schizophrenia and ASDs (Barlati et al., 2020). Given the strong influence of socio-cultural environments, the translation of neurobiological differences in real life should take into account trans-cultural studies, including both community and clinical samples. This approach is highly needed to promote a comprehensive framework for a better understanding of social withdrawal as a unique psychopathological dimension, with specificities across genders and cultures.
社交功能障碍和社交退缩作为其最明显的压迫，可能代表一个跨诊断领域在生物学根源方面是一个潜在的独立实体。与社交缺陷相关的大脑结构和神经递质在疾病中可能相同，社交大脑的改变可能导致社交退缩（Porcelli et al.， 2019）。考虑到美国国家心理健康研究所（NIMH）于 2009 年初启动的研究领域标准（RDoc）项目（Cuthbert，2015 年;Cuthbert & Insel， 2013;Insel et al.， 2010），没有研究将社会功能作为特定的精神病理学维度进行调查，并采用独立于诊断的不同神经精神疾病的组合方法。从 RDoC 的角度实施知识可能会改善这些疾病的管理和治疗，强调它们之间的重叠。在神经精神疾病中应用表型特征、等效诊断工具、补充技术（例如，功能性磁共振成像、电生理测量、激素剂量）的组合方法可能有助于填补临床前模型和临床研究结果之间的空白，即针对不同疾病（如精神分裂症和 ASD）中的类似缺陷进行有针对性的、性别特异性的治疗（Barlati et al.， 2020）。鉴于社会文化环境的强大影响，现实生活中神经生物学差异的翻译应考虑跨文化研究，包括社区和临床样本。这种方法对于促进一个全面的框架来更好地理解社交退缩是一个独特的精神病理学维度，具有跨性别和文化的特殊性，是非常必要的。