Role of Piriform Cortex Perineuronal Nets in Mouse Social Communication.

Rett综合征（RTT）被诊断为神经发育障碍，其特征在于部分或完全丧失 习得的口语，习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（MECP 2）是一种染色质重塑因子和基因调节因子， 典型的RTT RTT被假设为是由以下因素引起的突触连接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，很少有实验范例 已经探索了RTT中的突触可塑性如何随着时间的推移和细胞、电路的生理变化而受到影响 和行为级粒度。 使用Mecp 2-null和杂合子小鼠模型，我们先前已经表明，MECP 2调节时间， 经验依赖性可塑性在成人听觉皮层在学习母性行为范例。我们 发现Mecp 2杂合子女性（SurHet）是低效的采集者，可能是由于非典型的听觉障碍， 感知，由成熟神经元周围网（PNN）数量的异常、短暂增加引起。PNNs 是细胞外基质结构，作为可塑性的物理屏障，主要形成于 皮质小清蛋白GABA能神经元。 主要问题仍然存在：幼犬的检索行为是一个复杂的事件序列，涉及听觉，触觉， 嗅觉和目标导向的运动事件。不同的感觉输入（幼犬发声，感觉和 幼犬的气味）有助于运动输出（成人发声，目标导向的搜索和携带幼犬， 嘴对着鸟巢）。我们在这个R15提案中的目标是（1）表征发声/音节和相互作用 幼鼠和成年雌鼠在收集幼鼠任务中的声音和视频的综合分析 用新的机器学习算法记录;（2）确定PNN表达改变的时间线， 梨状皮质，一个被认为对嗅觉编码很重要的大脑区域，也是多感觉的中继站。 整合使用免疫染色/成像，然后，梨状皮质的手术操作。我们假设 成熟PNN在梨状皮质中的表达受MECP 2调节，并有助于适当的 整合和运作的不同组成部分的幼崽检索行为。这项研究的结果旨在 识别新的电路和机制参与多感觉整合的声音通信过程中， 复杂的社会行为，这是一个最引人注目的，但在RTT的探索表型。 与健康的相关性：Rett综合征被诊断为一种神经发育障碍，伴有感觉、运动和 社会障碍;然而，目前尚不清楚这些障碍在何处以及如何发展和变化 随着时间的推移，在成年。这项提议旨在了解大脑的可塑性，即大脑整合能力， 并适应其环境和周围环境的变化，受到RTT和相关基因突变的影响， 神经系统疾病

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.