小型田鼠:研究单配制进化与调控的模型

哺乳动物的单配制通常被认为是社会性单配制,它不是单纯地由性行为来决定,而是由诸多因素,包括长期的pair bond、夫妻双方共同抚育后代、免近亲交配以及雌雄两性相似等来决定的。在这篇综述中,我们论述了如何以啮齿类田鼠属(Microtus)为模型,通过比较研究来帮助我们理解社会性单配制的进化以及其神经调控机制。对田鼠属的研究不仅证实了单配制起源于艰苦的生存条件的假说,而且还证实了雌性性选择可能有利于维持单配制。不仅如此,哺乳动物单配制的进化还需要雄性的prosocial行为的不断强化。例如,亲近行为可以促进pairbond的形成并强化雄性对后代的哺育行为,而这种强化则来源于神经多肽催产素(OT)和加压素(AVP)与类固醇类激素的相互作用。催产素和加压素调控pairbond和双亲哺育行为的表达,而单配制和多配制田鼠的催产素和加压素受体在脑内的分布有显的不同。比较研究揭示了小型田鼠单配制的调控机制,而种内差异和行为上的可塑性则有助于我们进一步理解这种机制。比如,在某些条件下,多配制的草原田鼠(Microtus pennsylvanicu)的雄性个体具有哺育后代的行为。尽管草原田鼠的加压素Vla受体在脑内的分布与其他多配制的田鼠相似,但是如果脑室注射加压素,仍可以诱发其哺育后代的行为。同样是单配制的橙腹田鼠(Microtus ochrogaster),生活在：Illnois的显示出高水平的prosocial行为,而生活在Kansas的则表现出较低水平的社会性行为。即使两个种群的催产素或加压素Vla受体在脑内的分布相同,它们的雌激素受体表达水平显不同,这在雄性个体表现尤其明显。与Kansas的雄性个体相比,在终纹床核(bed rucleus of the stria tenninalis)和杏仁核中区(medial amygdala)这两个调控亲近行为和攻击行为的脑区,Illinois的雄性个体的α雌激素受体的水平要低得多。这些研究表明对雌激素的低敏感程度有利于高水平地表达prosocial行为并降低特定类型的攻击行为。     

以田鼠作为动物模型来研究社会行为的进化:基因、脑与行为

田鼠属的一些近缘种间具有独特的社会行为多态性。例如Microtusochrogaster和M .pinetorum为一夫一妻制 ,而M .montanus和M .pennsylvanicus则为独居和一夫多妻制。无论是在野外还是人工饲养的条件下 ,单配制的田鼠其雌、雄成年个体一经交配即在两者之间形成长期的配偶关系并且双亲共同哺育后代。已证明神经多肽加压素 (Vasopressin)参与了田鼠单配制行为的神经调控。本篇综述了过去以及近期关于加压素调控田鼠配偶关系形成的研究结果和进展。首先 ,阐述了加压素V1a受体 (V1aR)在脑分布的种间差异 ,并以此来鉴别特定脑区在配偶关系形成中的功能 ;其次 ,探讨了运用V1aR拮抗物的药理学方法来决定究竟哪些脑区参与配偶关系的形成 ,还描述了田鼠种间V1aR基因结构和功能的不同 ,以及这些不同对V1aR在大脑的分布和行为调控潜在的作用机制 ;最后 ,讨论了最新的研究结果 ,即对一夫多妻制田鼠进行脑V1aR基因的改造 ,从而使之表现出一夫一妻制田鼠的行为。总之 ,了解复杂的社会性行为的遗传和神经机制可以加深我们对种间和种内行为分歧进化的理解     

棕色田鼠的配偶选择和相关特征

为了确定野外生态研究中对棕色田鼠婚配制度为单配制的预测,在实验室观察记录了棕色田鼠的配偶选择箱内对配偶鼠（与选择鼠交配刚生过仔,雌鼠产后动情）与陌生鼠、熟悉鼠（雌雄田鼠山居一段时间后,开始进行交配）与陌生鼠的选择,发现棕色田鼠访问、追逐、嗅闻、爬胯配偶鼠和熟悉鼠以及与配偶鼠和熟悉鼠交配和相伴的时间明显地多于对 陌生鼠,而且攻击陌生鼠的时间明显多于配偶鼠和熟悉鼠（Wilcoxon检验,P＜0.05）。结果表明：雌雄棕色田鼠特异性地选择配偶鼠和熟悉鼠,对陌生鼠表现出较多的排斥,从而在配偶选择上呈现单配制特征。通过统计计算棕色田鼠社会组织特征和室内的个体形态、幼仔发育、交配行为、双亲育幼行为、社交倾向等参数,然后把这些参数和婚配制度较明确的草原田鼠、松田鼠、山地田鼠、草甸田鼠的相关数据进行比较,发现它与多配制种类差异较大,而与单配制的田鼠各类相似,通过以上实验分析结果推断棕色田鼠的婚配制度可能呈单配制,和野外生态研究的推测相一致。     

幼体生长发育特征可导致橙腹田鼠的单配体制吗?

橙腹田鼠(Microtus ochrogaster)和草原田鼠(M. pennsylvanicus)是两种亲缘关系很近,但有着完全不同交配体制的田鼠。本文试图通过他们头骨的形态学比较来验证幼体生长发育(paedomorphosis)可以印证单配制交配体制进化的假说。通过几种头骨的测量,我们发现草原田鼠头骨的长与宽比例大于橙腹田鼠,说明前者具有相对狭长的头骨。进一步的测量发现,这种不同是由于草原田鼠具有相对较长的鼻骨造成的。最后,我们对同种内成年和幼年的头骨进行了比较,发现单配制的橙腹田鼠相对于多配制的草原田鼠,其成年的头骨与幼年的头骨更相似。这些测量结果说明与多配制的田鼠相比,单配制的田鼠在形态及行为上保留更多的幼年状态,而这种行为很可能与其交配体制有关。     

雌激素受体α和β免疫反应在雄性和雌性棕色田鼠脑区分布的比较

单配制和多配制动物社会行为有差异,这些差异可能与雌激素受体类型有关（ERs）。虽然多配制大鼠和小鼠中枢神经雌激素受体α（ERα）和β（ERβ）免疫反应在大脑的分布已有报道,单配制雄性草原田鼠中枢神经ERα的分布也有报道,但单配制田鼠ERα和（或）ERβ在雌性和雄性分布差异未见报道。本研究对雄性和雌性棕色田鼠前脑区域ERα和ERβ免疫反应（IR）细胞数量进行比较。研究结果表明：（1）免疫反应主要分布在细胞核中。 （2）ERα-IR和ERβ-IR细胞广泛分布于整个雌性和雄性前脑区域,在许多脑区表达有重叠。然而,不同受体在雌雄不同脑核中的分布数量是不同的。（3）ERα 和ERβ的分布存在性别差异。例如,雌性ERα在视前核中部（MPN）,终纹床和（BNST）和杏仁内侧核（MeA）比雄性多,相反雄性ERβ在MPN和BNST比雌性多。这些研究结果可能为我们理解如何通过ERα和ERβ调节动物的社会行为,及雌性和雄性社会行为的差异提供一个重要的神经解剖学基础。     

雌激素受体α和β免疫反应在雄性和雌性棕色田鼠脑区分布的比较（英文）

单配制和多配制动物社会行为有差异,这些差异可能与雌激素受体类型有关(ERs)。虽然多配制大鼠和小鼠中枢神经雌激素受体α(ERα)和β(ERβ)免疫反应在大脑的分布已有报道,单配制雄性草原田鼠中枢神经ERα的分布也有报道,但单配制田鼠ERα和(或)ERβ在雌性和雄性分布差异未见报道。本研究对雄性和雌性棕色田鼠前脑区域ERα和ERβ免疫反应(IR)细胞数量进行比较。研究结果表明:(1)免疫反应主要分布在细胞核中。(2)ERα-IR和ERβ-IR细胞广泛分布于整个雌性和雄性前脑区域,在许多脑区表达有重叠。然而,不同受体在雌雄不同脑核中的分布数量不同。(3)ERα和ERβ的分布存在性别差异。例如,雌性ERα在视前核中部(MPN),终纹床核(BNST)和杏仁内侧核(Me A)比雄性多,相反雄性ERβ在MPN和BNST比雌性多。这些研究结果可能为我们理解如何通过ERα和ERβ调节动物的社会行为,及雌性和雄性社会行为的差异提供一个重要的神经解剖学基础。     

棕色田鼠脑中雌激素α受体分布和社会互作的两性差异

通过记录分析雌雄棕色田鼠同性间的社会互作并用免疫组织化学方法对雌激素α受体（ERα）在雌雄棕色田鼠脑内的分布进行定位,以揭示ERα在不同性别棕色田鼠社会行为中的调控作用。结果发现：雌性棕色田鼠攻击行为显著多于雄性;雌性棕色田鼠亲密行为明显少于雄性,差异极显著;此外,雌性棕色田鼠的防御行为极显著多于雄性。免疫组织化学结果显示：ERα免疫阳性细胞主要分布在弓状核（ARC）、杏仁内侧核（MeA）、杏仁中央核（Ce）、下丘脑视前区（MPOA）、下丘脑腹内侧核（VMH）和终纹床核（BST）,其中ERα在BST、MPOA、MeA和Ce中的分布存在着极显著性二型性,且雌性田鼠表达的ERα较多;在ARC中的分布也存在显著性二型性,雄性田鼠表达的ERα多于雌性田鼠;ERα在VMH中的分布无明显的性二型性。结果揭示了雌雄棕色田鼠在同性间社会互作中攻击、防御以及亲密行为存在显著差异,而ERα在雌雄棕色田鼠脑内的分布模式也有显著性差异,社会互作和ERα免疫阳性细胞分布的两性差异都呈现单配制鼠类的特征,ERα在大脑分布模式的两性差别和不同种类间的差别可能是单配制啮齿类呈现相关生殖和社会行为的一个重要机制[动物学报54（6）：1020-1028,2008]。     

断乳前棕色田鼠幼仔对双亲和可卡因的条件位置偏爱（英文）

个体间的社会互作是一种天然奖赏,这种社会性奖赏诱导的条件位置偏爱(Conditioned place preference,CPP)是通过环境信息和社会互作奖赏效应间建立条件反射形成的,与药物奖赏诱导的CPP相似。棕色田鼠(Microtus mandarinus)是一种社会性单配制田鼠,具有紧密的亲-子联系和社会互作;雄鼠对断乳前幼仔也提供较高水平的亲本抚育。幼仔强化能够诱导母鼠及父鼠形成CPP,但双亲对幼仔是否也具有强化效应还不清楚。为探讨断乳前幼仔与双亲形成的奖赏联系,本实验检测了出生后13-17 d和19-23 d两个发育龄段的棕色田鼠幼仔对母鼠、父鼠以及可卡因(20 mg/kg)的CPP反应。数据显示在分别用母鼠、父鼠或可卡因强化后,两个年龄段的幼仔在CPP箱的强化室与非强化室所处时间没有显著性差异。这些结果表明断乳前棕色田鼠幼仔不能形成对母鼠、父鼠及可卡因的位置偏爱。     

自由生活橙腹田鼠的社会组织和婚配制度

在美国伊利诺伊州中东部地区对橙腹田鼠(Microtus ochrogaster) 进行的广泛研究基础上, 我们对该鼠的社会组织和婚配制度进行了总结。橙腹田鼠的基本社会组织由最初的雌雄配偶或者单一的雌鼠(常为一对配偶的幸存者) 与留居的后代和非亲缘成体的同居群组成。留居的后代占了原始繁殖单位之外的70%。另外, 直到至少两个留居后代达到成年后, 多数(80%) 的非亲缘个体才加入家族群。因此, 同居群的形成是以高水平的留居为基础的。雌雄配偶表现出与行为单配制有关的特征, 包括共享一个巢穴和家域, 雄性保卫配偶, 以及双亲行为(修饰, 拥抱和衔回幼鼠)。同居群的成员也保卫领域。     

田鼠种群波动的原因和时间

本文总结了橙腹田鼠（Microtus ochrogaster）和草原田鼠（M．permsylvanicus）25年的种群统计学研究结果和结论。探讨了田鼠种群波动周期性、诱发种群波动以及导致波动期间峰值变异的因素。并对种群存活值和繁殖活动的作用进行了分析和评价。根据两种田鼠种群波动周期性、波动峰值出现的时间以及特定年份峰值的高度等特征,证明两物种波动均具有不稳定性。两种田鼠存活值的变化是由特定年份是否发生波动以及波动峰值出现的时间决定。增加初始阶段的种群密度及时间长度是造成两种动物种群波动峰值不同的主要原因。橙腹田鼠种群停止增长的原因是存活值降低,而草原田鼠则是繁殖活动减少。据推测,与种群波动初始密度相关的种群死亡率的差异是由捕食者的净效应（Net effect）决定的,调控两种群密度的因素均为非密度的其它生态学因子。由于特定年份田鼠种群捕食压力的不确定性,导致了橙腹田鼠和草原田鼠种群波动的不稳定性。     

The neurobiology of social attachment: A comparative approach to behavioral, neuroanatomical, and neurochemical studies

The formation and maintenance of social bonds in adulthood is an essential component of human health. However studies investigating the underlying neurobiology of such behaviors have been scarce. Microtine rodents offer a unique comparative animal model to explore the neural processes responsible for pair bonding and its associated behaviors. Studies using monogamous prairie voles and other related species have recently offered insight into the neuroanatomical, neurobiological, and neurochemical underpinnings of social attachment. In this review, we will discuss the utility of the microtine rodents in comparative studies by exploring their natural history and social behavior in the laboratory. We will then summarize the data implicating vasopressin, oxytocin, and dopamine in the regulation of pair bonding. Finally, we will discuss the ways in which these neurochemical systems may interact to mediate this complex behavior.     

Neural mechanisms of mother–infant bonding and pair bonding: Similarities,differences, and broader implications

This article is part of a Special Issue “Parental Care”.Mother–infant bonding is a characteristic of virtually all mammals. The maternal neural system may have provided the scaffold upon which other types of social bonds in mammals have been built. For example, most mammals exhibit a polygamous mating system, but monogamy and pair bonding between mating partners occur in ~ 5% of mammalian species. In mammals, it is plausible that the neural mechanisms that promote mother–infant bonding have been modified by natural selection to establish the capacity to develop a selective bond with a mate during the evolution of monogamous mating strategies. Here we compare the details of the neural mechanisms that promote mother–infant bonding in rats and other mammals with those that underpin pair bond formation in the monogamous prairie vole. Although details remain to be resolved, remarkable similarities and a few differences between the mechanisms underlying these two types of bond formation are revealed. For example, amygdala and nucleus accumbens–ventral pallidum (NA–VP) circuits are involved in both types of bond formation, and dopamine and oxytocin actions within NA appear to promote the synaptic plasticity that allows either infant or mating partner stimuli to persistently activate NA–VP attraction circuits, leading to an enduring social attraction and bonding. Further, although the medial preoptic area is essential for maternal behavior, its role in pair bonding remains to be determined. Our review concludes by examining the broader implications of this comparative analysis, and evidence is provided that the maternal care system may have also provided the basic neural foundation for other types of strong social relationships, beyond pair bonding, in mammals, including humans.     

Central oxytocin receptors mediate mating-induced partner preferences and enhance correlated activation across forebrain nuclei in male prairie voles

Oxytocin (OT) is a deeply conserved nonapeptide that acts both peripherally and centrally to modulate reproductive physiology and sociosexual behavior across divergent taxa, including humans. In vertebrates, the distribution of the oxytocin receptor (OTR) in the brain is variable within and across species, and OTR signaling is critical for a variety of species-typical social and reproductive behaviors, including affiliative and pair bonding behaviors in multiple socially monogamous lineages of fishes, birds, and mammals. Early work in prairie voles suggested that the endogenous OT system modulates mating-induced partner preference formation in females but not males; however, there is significant evidence that central OTRs may modulate pair bonding behavior in both sexes. In addition, it remains unclear how transient windows of central OTR signaling during sociosexual interaction modulate neural activity to produce enduring shifts in sociobehavioral phenotypes, including the formation of selective social bonds. Here we re-examine the role of the central OT system in partner preference formation in male prairie voles using a selective OTR antagonist delivered intracranially. We then use the same antagonist to examine how central OTRs modulate behavior and immediate early gene (Fos) expression, a metric of neuronal activation, in males during brief sociosexual interaction with a female. Our results suggest that, as in females, OTR signaling is critical for partner preference formation in males and enhances correlated activation across sensory and reward processing brain areas during sociosexual interaction. These results are consistent with the hypothesis that central OTR signaling facilitates social bond formation by coordinating activity across a pair bonding neural network.     

Oxytocin-like receptors mediate pair bonding in a socially monogamous songbird

Although many species form socially monogamous pair bonds, relevant neural mechanisms have been described for only a single species, the prairie vole (Microtus ochrogaster). In this species, pair bonding is strongly dependent upon the nonapeptides oxytocin (OT) and vasopressin, in females and males, respectively. Because monogamy has evolved many times in multiple lineages, data from additional species are required to determine whether similar peptide mechanisms modulate bonding when monogamy evolves independently. Here we test the hypothesis that OT-like receptor activation is required for pair bond formation in the socially monogamous zebra finch (Taeniopygia guttata). Males and females were administered chronic intracerebroventricular infusions of saline or an OT receptor antagonist and were observed twice daily for 3 days in a colony environment. A variety of affiliative, aggressive and other behaviours were quantified. The antagonist produced significant and selective effects on pair bonding (latency to pair; number of sessions paired; stable pairing) and the associated behaviour of allopreening. Importantly, findings for males follow the trends of females; this yields main effects of treatment in two-way ANOVAs, although within-sex analyses are significant only for females. These data provide evidence for both convergent evolution and species diversity in the neuroendocrine mechanisms of pair bonding.     

Oxytocin, vasopressin and pair bonding: implications for autism

Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour. Here, we review the literature which suggests that the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours, with a focus on their role in the regulation of social bonding in monogamous rodents. Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding. The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain. Comparative studies in voles with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take part in rearing the young. Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species. High levels of oxytocin receptor (OTR) in the nucleus accumbens and high levels of vasopressin 1a receptor (V1aR) in the ventral pallidum contribute to monogamous social structure in the prairie vole. While little is known about the genetic factors contributing to species-differences in OTR distribution, the species-specific distribution pattern of the V1aR is determined in part by a species-specific repetitive element, or 'microsatellite', in the 5' regulatory region of the gene encoding V1aR (avpr1a). This microsatellite is highly expanded in the prairie vole (as well as the monogamous pine vole) compared to a very short version in the promiscuous montane and meadow voles. These species differences in microsatellite sequence are sufficient to change gene expression in cell culture. Within the prairie vole species, intraspecific variation in the microsatellite also modulates gene expression in vitro as well as receptor distribution patterns in vivo and influences the probability of social approach and bonding behaviour. Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders. In sum, comparative studies in pair-bonding rodents have revealed neural and genetic mechanisms contributing to social-bonding behaviour. These studies have generated testable hypotheses regarding the motivational systems and underlying molecular neurobiology involved in social engagement and social bond formation that may have important implications for the core social deficits characterizing autism spectrum disorders.     

Neuropeptidergic regulation of affiliative behavior and social bonding in animals

Social relationships are essential for maintaining human mental health, yet little is known about the brain mechanisms involved in the development and maintenance of social bonds. Animal models are powerful tools for investigating the neurobiological mechanisms regulating the cognitive processes leading to the development of social relationships and for potentially extending our understanding of the human condition. In this review, we discuss the roles of the neuropeptides oxytocin and vasopressin in the regulation of social bonding as well as related social behaviors which culminate in the formation of social relationships in animal models. The formation of social bonds is a hierarchical process involving social motivation and approach, the processing of social stimuli and formation of social memories, and the social attachment itself. Oxytocin and vasopressin have been implicated in each of these processes. Specifically, these peptides facilitate social affiliation and parental nurturing behavior, are essential for social recognition in rodents, and are involved in the formation of selective mother-infant bonds in sheep and pair bonds in monogamous voles. The convergence of evidence from these animal studies makes oxytocin and vasopressin attractive candidates for the neural modulation of human social relationships as well as potential therapeutic targets for the treatment of psychiatric disorders associated with disruptions in social behavior, including autism.     

A positive Link Between Male Testosterone and Spacing Behavior in Pair‐Bonded California Mice

The effects of testosterone (T) on male sexual behavior are well established, but its roles in several associated social behaviors such as pair‐bonding and paternal behavior are diverse. Recently, we reported that male T in response to pairing with a female predicts future paternal behavior in the monogamous and biparental California mouse (Peromyscus californicus). Here, we examined whether T in response to pairing is also associated with spacing behavior between mates under laboratory conditions and if these behavioral patterns are continued during pup care. Pairs of California mice were observed throughout their pair bond before and again after pups were born. We found that males with higher T post‐pairing remained closer to their mates in the weeks before pups were born, and pairs with higher proximity measures during the pair bond spent more time caring for pups together. Overall, these results suggest a similar mechanism for spacing behavior across distinct phases of the pair bond.