Neuron (IF 17.17)

机体内在状态极大地影响行为表征，包括社交行为，而雌性动物处于不同状态，比如发情期、孕期或哺乳期时，伴随体内激素水平的变化，它们对相同刺激会表现出不同的社交行为。一个典型情况是，处于不同繁殖期的雌性在面对雄性时会做出截然相反的社交行为：发情期雌性会呈现出所谓的脊柱前凸的交配准备动作，而哺乳期雌性会发出攻击，即母性攻击。雌性的这两种社交行为切换的神经机制一直不清楚，而来自加州理工的研究成果提供了答案。他们利用活性依赖的单细胞RNA测序技术，在小鼠腹中侧下丘脑的腹外侧区（VMHvl）中发现表达雌激素受体的两个亚神经元类型分别介导了这两种行为。其中一种为神经肽Y受体（Npy2r）阴性神经元，也被称为a细胞，被激活后无论雌性处于何种繁殖状态都能诱发其交配行为，而且能即时终止哺乳期雌鼠的母性攻击。另一种叫做b细胞的Npy2r阳性神经元，被激活后即使在发情期雌性中也能诱导其攻击行为，而被抑制后能即时终止母性攻击。利用在体荧光光度计技术对同一雌性在发情期，哺乳期和断奶后3个不同状态下面对雄性社交时进行钙成像，作者进一步发现b细胞的反应在哺乳期升高，在断奶后会下降至发情期水平，而a细胞的反应大小不变。这表明，b细胞呈现出与繁殖状态相关的活动水平变化，从而介导了雌性在不同内在状态下的社交行为切换。

作者首先利用单细胞RNA测序技术确定了与雌性不同繁殖状态相对应的被激活的神经元亚型，在此基础上通过光遗传技术对这两类神经元分别进行激活或抑制，明确其在雌性面对雄性表现出交配或攻击行为中的充分性和必要性作用，最后显示了其中一种细胞的激活水平与雌性的不同繁殖期及行为对应，揭示了雌性社交行为切换的神经机制。

文章链接：

https://www.cell.com/neuron/fulltext/S0896-6273(21)00995-8

关键词：

母性攻击、交配、社交行为切换

activity-dependent scRNAseq; female mice; internal state; maternal aggression; sexual receptivity; social behavior; state-dependent neural plasticity; ventromedial hypothalamus.

Abstract

Female mice exhibit opposing social behaviors toward males depending on their reproductive state: virgins display sexual receptivity (lordosis behavior), while lactating mothers attack. How a change in reproductive state produces a qualitative switch in behavioral response to the same conspecific stimulus is unknown. Using single-cell RNA-seq, we identify two distinct subtypes of estrogen receptor-1-positive neurons in the ventrolateral subdivision of the female ventromedial hypothalamus (VMHvl) and demonstrate that they causally control sexual receptivity and aggressiveness in virgins and lactating mothers, respectively. Between- and within-subject bulk-calcium recordings from each subtype reveal that aggression-specific cells acquire an increased responsiveness to social cues during the transition from virginity to maternity, while the responsiveness of the mating-specific population appears unchanged. These results demonstrate that reproductive-state-dependent changes in the relative activity of transcriptomically distinct neural subtypes can underlie categorical switches in behavior associated with physiological state changes.

PNAS (IF 11.2)

哺乳期雌性的母性攻击对于保护幼仔免于危险置关重要，而产后抑郁等可能会导致雌性的过度攻击。催乳素，作为孕期和产后机体内水平升高的激素之一，可能在其中发挥重要作用。本文研究了催乳素通过作用于小鼠腹中侧下丘脑（VMN/VMH）来调节哺乳期雌性的母性攻击行为。通过全局敲除或是注射病毒在VMN特异敲除谷氨酸能神经元的催乳素受体基因（Prlr），作者发现敲除后的哺乳期雌鼠表现出更强烈的攻击行为：1）针对未成年入侵雄鼠，其攻击延迟缩短，攻击次数和时间增加；2）针对成年入侵雄鼠，与未敲除哺乳期雌鼠不会进行攻击相比，其攻击延迟短，次数多，时间长。虽然通过对即刻早期基因cFos的免疫组化染色实验发现，哺乳期雌鼠在引入未成年雄鼠后，VMN的Prlr+细胞被激活，但体外实验表明催乳素只能激活脑片组织的很小部分VMN神经元。进一步地，给非哺乳期雌性注射催乳素，或在哺乳期雌鼠中注射溴隐亭药物来抑制催乳素分泌，或者通过化学遗传学方法激活VMN的Prlr+细胞，都不能明显影响入侵者导向的攻击行为，这些结果说明催乳素可能是通过长期的转录通路来调控行为。

本文作者——来自新西兰奥塔哥大学的研究人员之前已证明催乳素通过作用于内侧视前区（MPOA）可促进雌鼠对幼仔的产后护理行为。本文结果表明催乳素通过作用于VMN的谷氨酸能神经元可约束哺乳期雌鼠的母性攻击行为，使母鼠能更专注于对幼仔的护理。

文章链接：

https://www.pnas.org/doi/10.1073/pnas.2116972119

关键词：

催乳素、母性攻击

female aggression; lactation; prolactin; prolactin receptor; ventromedial nucleus of the hypothalamus.

Abstract

Aggressive behavior is rarely observed in virgin female mice but is specifically triggered in lactation where it facilitates protection of offspring. Recent studies demonstrated that the hypothalamic ventromedial nucleus (VMN) plays an important role in facilitating aggressive behavior in both sexes. Here, we demonstrate a role for the pituitary hormone, prolactin, acting through the prolactin receptor in the VMN to control the intensity of aggressive behavior exclusively during lactation. Prolactin receptor deletion from glutamatergic neurons or specifically from the VMN resulted in hyperaggressive lactating females, with a marked shift from intruder-directed investigative behavior to very high levels of aggressive behavior. Prolactin-sensitive neurons in the VMN project to a wide range of other hypothalamic and extrahypothalamic regions, including the medial preoptic area, paraventricular nucleus, and bed nucleus of the stria terminalis, all regions known to be part of a complex neuronal network controlling maternal behavior. Within this network, prolactin acts in the VMN to specifically restrain male-directed aggressive behavior in lactating females. This action in the VMN may complement the role of prolactin in other brain regions, by shifting the balance of maternal behaviors from defense-related activities to more pup-directed behaviors necessary for nurturing offspring.

Cell (IF 41.58)

性激素在不同性别和不同激素周期的个体中发挥作用相差很大。本文聚焦了发情期性接受雌鼠（FR）、发情间期性不接受雌鼠（FNR）和性腺完整的雄鼠（M）中，终纹床核（BNSTpr）、内侧杏仁核（MeA）、视前下丘脑（POA）和腹中侧下丘脑的腹外侧区（VMHvl）4个脑区的1型雌激素受体阳性（Esr1+）细胞，以探索其依赖性别和发情周期的基因表达模式及对社交行为的调制。作者首先利用翻译核糖体亲和纯化测序（TRAPseq）技术识别了1415个差异表达基因（DEGs），在此基础上通过单细胞RNA测序，定义了137个细胞类型，并结合原位杂交（ISH），显示了DEGs在4个脑区的Esr1+群体中表达分布模式的异质性。为找到调控社交行为的单个细胞类型，作者具体分析了DEGs的性别和发情周期特异性，分别发现：1）相比FR和FNR，BNSTTac1/Esr1在M鼠中上调，并通过功能缺失实验，验证了该细胞类型对雄鼠的性别识别及随后的交配或攻击的必要性；2）VMHvlCCKar/Esr1呈现性别二态性，并在FR鼠中高度富集，其投射模式也与发情周期相关，功能缺失实验证明这个细胞类型对雌鼠的交配行为置关重要，而不影响发情间期的母性攻击行为。

这篇来自斯坦福大学的研究成果详尽分析了Esr1+细胞的性别和发情周期依赖的基因表达差异，并猜测可能通过调节突触传递、突触可塑性、神经元兴奋性和对胞外信号的响应等等，来调控社交行为。作者还发现很多性别二态性DEGs与一些疾病的性别偏好相关，比如阿尔兹海默症，多样硬化症和自闭症等。

文章链接：

https://www.sciencedirect.com/science/article/pii/S009286742101494X

关键词：

性别和发情周期依赖的基因表达

aggression; deep sequencing; estrous cycle; maternal behavior; mating; menstrual cycle; sex differences; social behaviors; synaptic plasticity; transcriptomically defined cell types.

Abstract

Sex hormones exert a profound influence on gendered behaviors. How individual sex hormone-responsive neuronal populations regulate diverse sex-typical behaviors is unclear. We performed orthogonal, genetically targeted sequencing of four estrogen receptor 1-expressing (Esr1+) populations and identified 1,415 genes expressed differentially between sexes or estrous states. Unique subsets of these genes were distributed across all 137 transcriptomically defined Esr1+ cell types, including estrous stage-specific ones, that comprise the four populations. We used differentially expressed genes labeling single Esr1+ cell types as entry points to functionally characterize two such cell types, BNSTprTac1/Esr1 and VMHvlCckar/Esr1. We observed that these two cell types, but not the other Esr1+ cell types in these populations, are essential for sex recognition in males and mating in females, respectively. Furthermore, VMHvlCckar/Esr1 cell type projections are distinct from those of other VMHvlEsr1 cell types. Together, projection and functional specialization of dimorphic cell types enables sex hormone-responsive populations to regulate diverse social behaviors.