权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of Piriform Cortex Perineuronal Nets in Mouse Social Communication.

梨状皮层神经周围网络在小鼠社交交流中的作用。

基本信息

批准号：
10045956
负责人：
KEERTHI KRISHNAN
金额：
$ 45.08万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10045956
关键词：
Adult Affect Age Auditory Auditory Perception Auditory area Behavior Behavioral Brain Brain region Caring Code Cognition Communication Complex Cues Development Diagnosis Environment Event Extracellular Matrix Female Gene Expression Genes Genotype Goals Hand Health Image Impaired cognition Impairment Language Learning Link Maintenance Manuals Maternal Behavior Methyl-CpG-Binding Protein 2 Modeling Modernization Motor Motor Skills Motor output Movement Mus Mutate Mutation Neurodevelopmental Disorder Neurons Neurosciences Operative Surgical Procedures Oral cavity Parvalbumins Pathology Persons Phenotype Physiological Regulator Genes Research Retrieval Rett Syndrome Role Route Sensory Smell Perception Social Behavior Social Environment Social Interaction Speech Structure Synapses Synaptic plasticity Tactile Time TimeLine Ultrasonics Video Recording Vision Woman Work chromatin remodeling deep learning algorithm differential expression endophenotype experience experimental study girls in vivo machine learning algorithm male middle age motor control mouse model multisensory nervous system disorder neural circuit novel piriform cortex programs pup sensory input social social cognition social communication stereotypy undergraduate student vocalization

项目摘要

Rett Syndrome (RTT) is diagnosed as a neurodevelopmental disorder, characterized by partial or complete loss of acquired spoken language, acquired motor skills and stereotypic hand movements. Mutations in X-linked gene methyl CpG-binding protein 2 (MECP2), a chromatin remodeler and gene regulator, is the causative gene for typical RTT. RTT is hypothesized to be the result of altered synaptic connectivity and plasticity caused by abnormal experience-dependent synapse development and maintenance. However, few experimental paradigms have explored how synaptic plasticity in RTT is affected over time and physiological changes with cellular, circuit and behavioral level granularity. Using Mecp2-null and heterozygous mouse models, we have previously shown that MECP2 regulates the timing of experience-dependent plasticity in the adult auditory cortex in a learned maternal behavior paradigm. We found that Mecp2-heterozygous females (SurHet) were inefficient gatherers, likely due to atypical auditory perception, caused by an abnormal, transient increase in numbers of mature perineuronal nets (PNNs). PNNs are extracellular matrix structures that act as physical barriers for plasticity, and form predominantly around cortical parvalbumin GABAergic neurons. Major questions remain: Pup retrieval behavior is a complex sequence of events involving auditory, tactile, olfactory senses and goal-directed motor events. How do different sensory inputs (pup vocalizations, feel and smell of pups) contribute to the motor outputs (adult vocalizations, goal-directed search and carrying pups by mouth to the nest)? Our aims in this R15 proposal are to (1) characterize vocalizations/syllables and interactions between pups and adult females during pup gathering task, using integrated analysis of audio and video recordings with new machine learning algorithms; (2) identify the time line of altered PNN expression in piriform cortex, a brain region thought to be important for olfactory coding and a relay station for multisensory integration using immunostaining/imaging and then, surgical manipulations of piriform cortex. We hypothesize that expression of mature PNNs in the piriform cortex is regulated by MECP2 and contribute to proper integration and functioning of distinct components of pup retrieval behavior. The results from this study aims to identify novel circuits and mechanisms involved in multisensory integration of vocal communication during complex social behavior, which are one of the most striking yet underexplored phenotypes in RTT. Relevance to health: Rett Syndrome is diagnosed as a neurodevelopmental disorder with sensory, motor and social impairments; however, it is currently unknown where and how these impairments develop and change over time in adulthood. This proposal aims to understand how plasticity, the ability of the brain to incorporate and adapt to changes in its environment and surroundings, is affected by mutated genes in RTT and associated neurological disorders.

雷特综合症（RTT）被诊断为一种神经发育障碍，其特征是部分或完全丧失获得的口语、获得的运动技能和刻板的手部动作。 X连锁基因突变甲基 CpG 结合蛋白 2 (MECP2) 是一种染色质重塑剂和基因调节因子，是典型的RTT。 RTT 被假设是由以下因素引起的突触连接性和可塑性改变的结果：异常的经验依赖性突触发育和维持。然而，实验范式很少探索了 RTT 中的突触可塑性如何随时间以及细胞、电路的生理变化而受到影响和行为级别的粒度。使用 Mecp2 缺失和杂合小鼠模型，我们之前已经证明 MECP2 调节时间在习得的母亲行为范式中，成人听觉皮层的经验依赖性可塑性的研究。我们发现 Mecp2 杂合雌性（SurHet）采集效率低下，可能是由于非典型听觉所致感知，由成熟神经周围网（PNN）数量异常、短暂的增加引起。 PNN 是细胞外基质结构，充当可塑性的物理屏障，主要形成在皮质小白蛋白 GABA 能神经元。主要问题仍然存在：幼崽的检索行为是一系列复杂的事件，涉及听觉、触觉、嗅觉和目标导向的运动事件。不同的感官输入（幼犬的发声、感觉和幼崽的气味）有助于运动输出（成年发声、目标导向的搜索和携带幼崽）嘴到巢）？我们在此 R15 提案中的目标是 (1) 表征发声/音节和交互在幼崽收集任务期间，使用音频和视频综合分析在幼崽和成年雌性之间进行比较使用新的机器学习算法进行录音； (2) 确定 PNN 表达改变的时间线梨状皮层，被认为对嗅觉编码很重要的大脑区域和多感觉的中继站使用免疫染色/成像进行整合，然后对梨状皮层进行手术操作。我们假设梨状皮层中成熟 PNN 的表达受 MECP2 调节，并有助于适当的小狗检索行为的不同组成部分的整合和功能。这项研究的结果旨在识别涉及声音交流多感觉整合的新电路和机制复杂的社会行为，这是 RTT 中最引人注目但尚未得到充分探索的表型之一。与健康的相关性：雷特综合症被诊断为一种神经发育障碍，涉及感觉、运动和社交障碍；然而，目前尚不清楚这些损伤在何处以及如何发展和变化随着时间的推移，进入成年期。该提案旨在了解可塑性，即大脑整合的能力并适应其环境和周围环境的变化，受到RTT和相关突变基因的影响神经系统疾病。