Developmental Neuroscience

早期生命中高水平的突触发生和突触可塑性使未成熟的大脑特别容易受到早期生活经验的影响。众所周知，早期生活经历(如应激和癫痫发作)会对神经网络发育和晚年认知功能(包括社会记忆和社会行为)产生长期影响。早期生活经历如何调节大脑发育和相关的社会行为仍是个未知数。以前被忽视的海马区CA2最近成为社会记忆和社会行为的重要参与者。值得注意的是，海马区神经元的结构和生理异质性已被认为是决定海马区功能的关键因素。因此，阐明未成熟CA2神经元的异质性活动对于进一步了解早期生活经历对脑发育的影响至关重要。利用一种新的活性依赖标记和化学发生操作系统，我们旨在研究早期生活经验激活的海马CA2神经元在其对神经回路发育和社会行为的长期影响中所扮演的角色。为了实现这一目标，我们将首先建立早期生活经验对海马CA2区神经元激活的影响(目标1)。然后，我们将使用全细胞膜片钳记录来确定早期生活经历在多大程度上诱导海马CA2神经元兴奋和抑制电路的变化(目标2)。最后，我们将研究早期生活经验激活的CA2神经元是否通过使用化学遗传学工具精确调节海马CA2神经元选择性亚群的活动来中介大脑发育和社会行为的变化(目标3)。这些实验将促进我们对CA2神经元在早期生命经验对大脑发育影响的中介作用的理解，为早期生命经验和社会行为提供细胞和分子机制的见解。

High levels of synaptogenesis and synaptic plasticity during early life render the immature brain particularly vulnerable to early-life experience influences. Early-life experiences (i.e., stress and seizures) have been known to induce long-lasting impacts on neural network development and later-life cognitive functions, including social memory and social behaviors. How early-life experiences regulate brain development and the associated social behaviors remains elusive. The previously overlooked hippocampal subregion CA2 has recently emerged as an essential player in social memory and social behavior. It is important to note that the structural and physiological heterogeneity across the neurons in hippocampus has been recognized as a critical factor determining hippocampal functions. Therefore, clarifying the heterogenous activity of immature CA2 neurons is crucial to further understanding the effects of early life experience on brain development. Using a novel activity-dependent labeling and chemogenetic manipulation system, we aim to examine the role of early-life experience-activated hippocampal CA2 neurons in its long-term effects on neural circuit development and social behaviors. To achieve this aim, we will first establish the impacts of early-life experience on neuronal activation in hippocampal CA2 (Aim 1). We will then determine to what extent early-life experience induces changes in excitatory and inhibitory circuits in hippocampal CA2 neurons using whole-cell patch clamp recordings (Aim 2). Finally, we will investigate whether early-life experience-activated CA2 neurons mediate changes in brain development and social behaviors by using chemogenetic tools to precisely modulate the activity of the selective subpopulation of hippocampal CA2 neurons (Aim 3). These experiments will advance our understanding of the role of CA2 neurons in mediating the effects of early-life experience on brain development, providing cellular and molecular mechanistic insights into early-life experience and social behaviors.