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

海马皮质回路星形胶质细胞衍生的免疫信号对社交新奇识别的需求

• 批准号: 10527179
• 负责人: Shinichi Kano
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527179
• 关键词: Address; Adult; Area; Astrocytes; Attenuated; Behavior; Brain; Brain region; Calcium; Cognition; Corpus Callosum; Data; Dependovirus; Development; Excitatory Synapse; Exhibits; FOS gene; Foundations; Future; Head; Hippocampus (Brain); Image; Immune signaling; Immunohistochemistry; Impairment; Interleukin Receptor; Interleukins; Label; Medial; Mental disorders; Microglia; Mus; Neuroglia; Neurons; Nuclear; Oligodendroglia; Play; Prefrontal Cortex; Reporting; Role; Signal Transduction; Social Behavior; Social Interaction; Spinal Cord; Synapses; Tamoxifen; Testing; Thalamic structure; Therapeutic Intervention; Weaning; base; cytokine; design; experimental study; fluorescence microscope; frontal lobe; in vivo; information processing; nerve supply; neural circuit; neuromechanism; neurotransmission; optogenetics; postnatal; postnatal development; postnatal period; receptor; relating to nervous system; response; social; synaptic pruning; synaptogenesis

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.

摘要 尽管社会行为背后的神经机制已经被广泛研究，但神经胶质细胞的作用， 例如星形胶质细胞，人们对此知之甚少。星形胶质细胞在出生后突触发育中起着至关重要的作用 和功能，并有助于信息处理和认知。然而，星形胶质细胞在 突触精细的神经元投射到内侧前额叶皮质(MPFC)，这是 与丘脑等其他大脑区域相比，对社交行为的研究较少。在建议的 研究中，我们将讨论星形胶质细胞在社会新颖性识别中的作用，重点是 富含星形胶质细胞的细胞因子，白介素33(IL-33)，用于海马区-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信号传导 发育中的和成人大脑中的小胶质细胞和一些神经元。我们之前曾报道，缺乏IL-33的小鼠 (Il33-/-小鼠)在三腔室中表现出社会新奇认知障碍，但没有社交能力缺陷 社交测试。我们的初步数据显示，星形胶质细胞中IL-33的缺失损害了社会 新颖性识别和减少神经元在mPFC的c-Fos表达，表明神经元 从腹侧海马区(VHPC)到mPFC的投射可能减弱。此外，小胶质细胞 在IL33-/-小鼠出生后的早期阶段，检测到这种变化。因此，在拟议的研究中，我们将 测试我们的假设，即星形胶质细胞-小胶质细胞IL-33信号是出生后突触所必需的 形成vHPC-mPFC投影，有助于社会新颖性识别。在目标1中，我们将 评估vHPC-mPFC投射的结构和功能变化，并探讨其在 星形胶质细胞特异性IL-33缺陷小鼠的社会新奇认知缺陷。在目标2中，我们将确定 小胶质细胞IL-33受体缺失和星形胶质细胞IL-33诱导缺失对vHPC-mPFC的影响 投射和社会新颖性识别评估星形胶质细胞-小胶质细胞IL-33的发育需求 发信号。总之，这项探索性研究将评估vHPC-mPFC预测变化在社会 缺乏星形细胞IL-33的新颖性识别缺陷及其决定的发育需求 星形胶质细胞-小胶质细胞IL-33为这一关键神经投射的成熟信号。