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

摘要 虽然社会行为背后的神经机制已经得到了广泛的研究，神经胶质细胞的作用， 如星形胶质细胞，还不太了解。星形胶质细胞在出生后突触发育中起重要作用 和功能，并有助于信息处理和认知。尽管如此，星形胶质细胞在 突触细化神经元投射到内侧前额叶皮层（mPFC），这是一个关键领域， 社会行为，比其他大脑区域，如丘脑，研究得更少。拟议 研究，我们将解决星形胶质细胞在社会新奇识别中的作用，重点是对 星形胶质细胞富集的细胞因子，白细胞介素-33（IL-33），用于大脑皮层回路。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IL 1 RL 1在 小胶质细胞和一些神经元在发育和成人大脑。我们以前报道过缺乏IL-33的小鼠 （Il 33-/-小鼠）在三腔室中表现出社交新奇识别障碍，而没有社交能力缺陷。 社会互动测试我们的初步数据显示，星形胶质细胞中的IL-33缺失损害了社交能力， 新奇识别和减少神经元c-Fos表达的mPFC，表明神经元 从腹侧海马（vHPC）到mPFC的投射可能减弱。此外，小胶质细胞 在出生后早期在IL 33-/-小鼠中检测到改变。因此，在拟议的研究中，我们将 验证我们的假设，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需的 vHPC-mPFC投射的形成，有助于社会新奇识别。在目标1中，我们 评价vHPC-mPFC投射的结构和功能变化，并说明其在以下方面的因果作用： 星形胶质细胞特异性IL-33缺陷小鼠的社会新奇识别缺陷。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 投射和社会新奇识别来评估星形胶质细胞-小胶质细胞IL-33的发育需求 信号总之，这项探索性研究将评估vHPC-mPFC投射变化在社会中的作用。 在缺乏星形胶质细胞IL-33的情况下，新奇的识别缺陷，并决定了 星形胶质细胞-小胶质细胞IL-33信号传导，用于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.