Requirement of astrocyte-derived immune signaling for the hippocampal-cortical circuit for social novelty recognition

摘要 尽管社会行为背后的神经机制已被广泛研究，神经胶质细胞的作用， 例如星形胶质细胞，人们对其了解较少。星形胶质细胞在出生后突触发育中起着至关重要的作用 并发挥作用并有助于信息处理和认知。尽管如此，星形胶质细胞在 神经元投射到内侧前额叶皮层（mPFC）的突触细化，这是大脑中的一个关键区域 与其他大脑区域（例如丘脑）相比，对社会行为的研究较少。在提议的 研究中，我们将探讨星形胶质细胞在社会新颖性识别中的作用，重点关注以下要求： 富含星形胶质细胞的细胞因子，白细胞介素 33 (IL-33)，用于海马皮质回路。 IL-33 是一种核细胞因子 在星形胶质细胞和少突胶质细胞中大量表达，并通过其受体 IL1RL1 发出信号 发育中和成年大脑中的小胶质细胞和一些神经元。我们之前报道过缺乏IL-33的小鼠 （Il33-/- 小鼠）表现出社交新颖性识别障碍，但三腔室没有社交能力缺陷 社交互动测试。我们的初步数据显示星形胶质细胞中 IL-33 的缺失会损害社交能力 新奇识别并减少 mPFC 中神经元 c-Fos 的表达，表明神经元 从腹侧海马 (vHPC) 到 mPFC 的投射可能会减弱。此外，小胶质细胞 在出生后早期阶段，在 Il33-/- 小鼠中检测到了变化。因此，在拟议的研究中，我们将 检验我们的假设，即星形胶质细胞-小胶质细胞 IL-33 信号传导是出生后突触所必需的 vHPC-mPFC 投影的形成，有助于社会新颖性的识别。在目标 1 中，我们将 评估 vHPC-mPFC 投影的结构和功能变化并解决其因果作用 星形胶质细胞特异性 IL-33 缺陷小鼠的社交新奇识别缺陷。在目标 2 中，我们将确定 小胶质细胞 IL-33 受体缺失和诱导型星形胶质细胞 IL-33 缺失对 vHPC-mPFC 的影响 预测和社会新颖性识别来评估星形胶质细胞-小胶质细胞 IL-33 的发育需求 发信号。这项探索性研究将共同评估 vHPC-mPFC 预测变化在社会中的作用。 缺乏星形细胞 IL-33 时的新颖性识别缺陷，并确定星形细胞的发育要求 星形胶质细胞-小胶质细胞 IL-33 信号传导促进这一关键神经投射的成熟。

ABSTRACT Although the neural mechanisms underlying social behaviors have been extensively studied, the role of glia, such as astrocytes, has been less understood. Astrocytes play crucial roles in postnatal synaptic development and function and contribute to information processing and cognition. Nevertheless, the role of astrocytes in the synaptic refinement of neuronal projections into the medial prefrontal frontal cortex (mPFC), a key area in social behaviors, has been less studied than in other brain regions, such as the thalamus. In the proposed study, we will address the role of astrocytes in social novelty recognition, with a focus on the requirement of astrocyte-enriched cytokine, interleukin-33 (IL-33) for a hippocampal-cortical circuit. IL-33 is a nuclear cytokine abundantly expressed in astrocytes and oligodendrocytes and signals through its receptor, IL1RL1, on microglia and some neurons in the developing and adult brain. We previously reported that mice lacking IL-33 (Il33-/- mice) exhibited social novelty recognition impairment without sociability deficits in the three-chamber social interaction test. Our preliminary data have revealed that IL-33 deletion in astrocytes impairs social novelty recognition and reduces neuronal c-Fos expression in the mPFC, indicating that the neuronal projection from the ventral hippocampus (vHPC) to the mPFC may be attenuated. In addition, microglial alterations are detected in Il33-/- mice during the early postnatal period. Thus, in the proposed study, we will test our hypothesis that astrocyte-microglia IL-33 signaling is required for the postnatal synaptic formation of the vHPC-mPFC projection, contributing to social novelty recognition. In Aim 1, we will evaluate the structural and functional changes of the vHPC-mPFC projection and address its causal role in social novelty recognition deficits in astrocyte-specific IL-33 deficient mice. In Aim 2, we will determine the effects of microglial IL-33 receptor deletion and inducible astrocyte IL-33 deletion on the vHPC-mPFC projection and social novelty recognition to assess the developmental requirement of astrocyte-microglia IL-33 signaling. Together, this exploratory study will assess the role of the vHPC-mPFC projection changes in social novelty recognition deficits in the absence of astrocytic IL-33 and determine the developmental requirement of astrocyte-microglia IL-33 signaling for the maturation of this key neural projection.