Expanding the mouse repertoire of the synaptic activity-driven transcriptional program with a primate-specific gene: consequences for neuronal functions and cognitive abilities.

神经元活动驱动的基因表达是大脑长期适应的基础，这对包括学习和记忆在内的认知功能至关重要。主要的活性诱导基因，如BDNF、Egr1或Npas4，主要在啮齿类动物中被研究。这些研究揭示了它们的中心可塑性相关功能，人们普遍认为，原则上，它们的作用在其他哺乳动物物种中是保守的，包括灵长类和人类。总的来说，这很可能是正确的。然而，活动驱动的基因表达程序并不完全通用，不同物种之间也不完全相同。例如，最近有研究表明，人类神经元中由突触活动激活的一小部分基因在啮齿类动物中没有同源基因。其中一个突出的基因是长的非编码RNA基因LINC00473，这是一种灵长类特有的基因，在人类神经元中的突触活动迅速而特别强劲地上调。然而，正如一个缺乏老鼠对应物的基因所预期的那样，它在神经元中的功能尚未确定。由于活动驱动的基因表达程序是认知功能所必需的，我们假设LINC00473可能影响了导致人类的谱系中大脑功能的进化。我们的初步数据显示，表达LINC00473的人源化小鼠神经元影响可塑性相关的过程，这一结果与我们的假设一致。在这个项目中，我们建议使用小鼠神经元在培养和体内的功能获得实验，以及人iPS细胞来源的神经元功能丧失的方法来研究灵长类动物特异性基因LINC00473对神经元形态、细胞内信号、基因调控和电生理特性的影响，以及潜在的机制。将进行行为研究，以检验通过扩展带有显著的灵长类动物特有的活动反应基因的小鼠转录组来人性化小鼠神经元是否会影响认知能力。鉴定LINC00473在神经元中的功能可能揭示参与推动人类认知能力进化增强的机制。

Neuronal activity-driven gene expression is the basis for long-lasting adaptations of the brain that are crucial for cognitive functions including learning and memory. The functions of prominent activity-induced genes, such as Bdnf, Egr1 or Npas4, have been mostly examined in rodents. These studies have revealed central, plasticity-related functions for them and it is generally believed that, in principle, their roles are conserved in other mammalian species, including primates and humans. By and large, this is most likely correct. However, the activity-driven gene expression program is not fully generic and not identical between species. For example, it has been shown recently that a small number of the genes that are turned on by synaptic activity in human neurons do not have orthologs in rodents. One of those genes that stands out is the long non-coding RNA gene, LINC00473, a primate-specific gene that is rapidly and particularly robustly upregulated by synaptic activity in human neurons. However, as anticipated for a gene that lacks a mouse counterpart, its functions in neurons are uncharacterized. Since the activity-driven gene expression program is required for cognitive functions, we hypothesize that LINC00473 may have influenced the evolution of brain functions in the lineage leading to humans. Our preliminary data show that humanizing mouse neurons with LINC00473 expression affects plasticity-associated processes, a result that is in line with our hypothesis. In this project, we propose to use gain-of-function experiments in mouse neurons in culture and in mice in vivo, as well as loss-of-function approaches with human iPS cell-derived neurons to study the impact of the primate-specific gene, LINC00473 on neuronal morphology, intracellular signaling, gene regulation and electrophysiological properties, as well as the underlying mechanisms. Behavior studies will be done to examine if humanizing mouse neurons via expansion of the mouse transcriptome with an eminent primate-specific, activity responsive gene affects cognitive performance. Identification of the functions of LINC00473 in neurons may reveal mechanisms that have taken part in driving evolutionary enhancement of human cognitive abilities.