Molecular control of social memory in mice

在老鼠身上，像大多数哺乳动物一样，社会行为提高了存活率和生殖适合度。社会记忆是社会互动的核心要素，可以识别陌生人和熟悉的人。海马区的CA2区是编码社会记忆和控制社会攻击性的关键中枢。CA2在社会记忆中的作用仅在雄性小鼠身上进行了研究；因此，是否存在性别差异尚不清楚。其他形式的海马体介导的记忆(即空间记忆)依赖于刚刚开始识别的蛋白质的基因转录和信使核糖核酸翻译的诱导。然而，CA2介导的社会记忆编码的分子基础仍然知之甚少。几个编码mRNA翻译调节因子的基因，如TSC1(结节性硬化症复合体1)和CNOT3(CCR4-NOT转录复合体3)，影响海马体的发育和突触生理，以及社会相互作用的几个方面。尽管TSC1和CNOT3作用于不同的靶点，但它们抑制了负责启动mRNA翻译的分子复合体。然而，目前还不清楚它们是否调节了社会记忆编码。这项研究的长期目标是了解社会行为的分子基础以及信使核糖核酸翻译调节因子在社会记忆编码中的作用。在这个项目的头5年里，我们的短期目标将是确定CA2兴奋性神经元中参与社会记忆形成的转录和翻译景观。然后，我们将确定TSC1和CNOT3如何参与调控CA2记忆相关基因和突触生理、社会记忆形成和社会攻击。在计划的第一部分，我们将调查CA兴奋性神经元的失活是否也影响雌性小鼠的社会记忆编码。然后，我们将测量雄性和雌性小鼠CA2兴奋性神经元在社会记忆编码过程中转录(使用单细胞RNA测序)和翻译(使用细胞特异性核糖体mRNA免疫沉淀，然后测序)的变化，以及TSC1和CNOT3如何参与调节社会记忆形成过程中基因的翻译。最后，我们将研究CA2中的TSC1和CNOT3如何控制社会记忆、攻击性、CA2突触反应和神经元兴奋性。总体而言，这个项目将提供对控制社会记忆形成和其他形式的社会行为的分子因素的深入了解，这些因素由海马区CA2控制。此外，我们的计划将在社会行为的分子理解方面开辟新的研究途径。

In mice, like most mammals, social behaviours increase survival and reproductive fitness. Social memory is a core element of social interaction, allowing recognition of stranger and familiar individuals. The CA2 subregion of the hippocampus is a crucial hub for encoding social memory and the control of social aggression. The role of CA2 in social memory has only been investigated in male mice; thus, it is unclear whether sex differences exist. Other forms of hippocampal-mediated memory (i.e., spatial memory) depend on the induction of gene transcription and mRNA translation of proteins that are just beginning to be identified. However, the molecular underpinnings of CA2-mediated social memory encoding remain poorly understood. Several genes that encode regulators of mRNA translation, such as Tsc1 (tuberous sclerosis complex 1) and Cnot3 (CCR4-NOT transcription complex subunit 3), affect the development and synaptic physiology of the hippocampus, as well as several aspects of social interaction. Despite acting on different targets, TSC1 and CNOT3 inhibit the molecular complex responsible for the initiation of mRNA translation. However, it is unclear whether they regulate social memory encoding. The long-term objective of this research program is to understand the molecular basis of social behaviours and the involvement of mRNA translation regulators in social memory encoding. During the first 5 years of this program, our short-term objectives will be to determine the transcriptomic and translatomic landscapes in CA2 excitatory neurons involved in social memory formation. Then, we will determine how TSC1 and CNOT3 are involved in regulating CA2 memory-related genes and synaptic physiology, social memory formation and social aggression. In the first part of the program, we will investigate whether the inactivation of CA excitatory neurons also affects social memory encoding in female mice. Then, we will measure transcriptomic (using single-cell RNA sequencing), and translatomic (using cell-specific ribosomal immunoprecipitation of mRNA, followed by sequencing) changes during social memory encoding in the CA2 excitatory neurons in male and female mice and how TSC1 and CNOT3 are involved in regulating translation of genes during social memory formation. Finally, we will investigate how TSC1 and CNOT3 in CA2 control social memory, aggression and CA2 synaptic responses and neuronal excitability. Overall, this program will provide an in-depth understanding of the molecular factors that control social memory formation and other forms of social behaviour controlled by the hippocampal region CA2. Furthermore, our program will open new research avenues in the molecular understanding of social behaviour.