Role of Piriform Cortex Perineuronal Nets in Mouse Social Communication.

Rett综合征(RTT)被诊断为一种神经发育障碍，其特征是部分或完全丧失 包括习得的口语、习得的运动技能和刻板印象的手势。X连锁基因的突变 甲基CpG结合蛋白2(MECP2)是一种染色质重构体和基因调节因子，是导致 典型的RTT。RTT被认为是突触连通性和可塑性改变的结果，由 异常的经验依赖型突触发育和维持。然而，很少有实验范式 探讨了RTT的突触可塑性如何随时间的推移而受到影响，以及细胞、回路的生理变化 和行为级别的粒度。 使用MeCP2缺失和杂合的小鼠模型，我们先前已经证明MECP2调节时间 在习得的母性行为范式中，成人听觉皮质的经验依赖性可塑性。我们 发现MeCP2杂合子雌性(SurHet)是低效率的采集者，可能是由于非典型的听觉 感觉，由成熟神经周围神经网络(PNN)数量的异常、一过性增加引起。PNNS 是细胞外基质结构，作为可塑性的物理屏障，主要在周围形成 皮质小白蛋白GABA能神经元。 主要问题仍然存在：幼崽提取行为是一个复杂的事件序列，涉及听觉、触觉和 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 小狗的气味)有助于运动输出(成体发声、目标导向的搜索和通过 嘴对巢)？我们在R15提案中的目标是(1)描述发音/音节和相互作用 在幼崽采集任务中，幼崽和成年雌性幼崽之间的关系，使用音频和视频的综合分析 使用新的机器学习算法记录；(2)识别PNN表达变化的时间线 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 使用免疫染色/成像进行整合，然后进行梨状皮质的外科手术。我们假设 成熟的PNNS在梨状皮质中的表达受MECP2的调节，并有助于适当的 幼崽提取行为的不同组成部分的整合和功能。这项研究的结果旨在 识别新的电路和机制涉及的多感觉整合的声音交流 复杂的社会行为，这是RTT中最引人注目但未被研究的表型之一。 与健康相关：Rett综合征被诊断为一种神经发育障碍，具有感觉、运动和 社会障碍；然而，目前尚不清楚这些障碍在哪里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是如何结合 并适应环境和周围环境的变化，受到RTT基因突变的影响，并与 神经紊乱。

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.