The plasticity-stability balance of auditory cortex synapses: role of sensory experience and synaptic mechanisms

许多动物(包括人类)的大脑在出生时是高度不成熟和可塑性的。这一特征使发育中的神经系统能够由出生后生活中经历的特定感觉环境塑造并以最佳方式适应。在发育和衰老过程中，可塑性通常会下降，从而产生更稳定的神经连接。然而，从大脑的“可塑性”到“稳定性”的转变至少部分是由适当的感官(例如，视觉、触觉、听觉)刺激引导的。例如，负责处理复杂声学信息的听觉皮质表现出一种发育停滞的形式，其特征是在成年后，如果声音输入在出生后早期缺乏或扭曲，则在成年期保持高度的青少年样可塑性。我的研究计划旨在描述感觉刺激在引导突触成熟方面的确切作用，并提供对突触和神经化学机制的详细分析，这些机制介导了经验对大脑发育的影响。提出了三条研究路线：目标1：确定不同声音特征(特别是响度/幅度、音调/频率和时间模式)在驱动听皮层突触成熟中的确切作用。目的#2：确定神经化学抑制不足在出生后早期缺乏适当的声音暴露而导致的发育停滞中的作用。目的#3：描述成熟听觉皮质可塑性“门控”的神经化学机制。这些目标是通过在出生后发育过程中对声音环境的精确操纵，结合电生理和药理学技术来确定听觉皮质的发育(可塑性)状态来实现的。每个目标都将为高素质的研究生和本科生人员创造培训职位，从而掌握先进的、最先进的技术和专业技能。总而言之，这项工作将导致我们在理解出生后听觉皮质成熟和控制复杂哺乳动物大脑感觉驱动发育的一般原则方面取得重大进展。

The brains of many animals (including humans) are highly immature and plastic at birth. This characteristic allows the developing nervous system to be shaped by, and optimally adapt to the specific sensory environment experienced during postnatal life. Over the course of development and aging, plasticity generally declines, resulting in more stable neural connections. However, this transition from brain "plasticity" to "stability" is guided, at least in part, by appropriate sensory (e.g., visual, tactile, auditory) stimulation. For example, the auditory cortex, responsible for processing complex acoustic information, shows a form of development arrest, characterized by the maintenance of high levels of juvenile-like plasticity into adulthood, if sound input is absent or distorted during early postnatal life. My research program is aimed at characterizing the precise role of sensory stimuli in guiding synaptic maturation, as well as providing a detailed analysis of the synaptic and neurochemical mechanisms that mediate the effect of experience on brain development. Three lines of investigation are proposed: Objective #1: Determine the precise role of different sound features (in particular loudness/amplitude, pitch/frequency, and temporal patterns) in driving maturation of auditory cortex synapses. Objective #2: Identify the role of insufficient neurochemical inhibition in the developmental arrest following lack of proper sound exposure during early postnatal life. Objective #3: Characterize neurochemical mechanisms involved in plasticity "gating" in the mature auditory cortex. These objectives are achieved by precise manipulations of the acoustic environment during postnatal development, combined with electrophysiological and pharmacological techniques to determine the developmental (plasticity) state of the auditory cortex. Each objective will create training positions for highly qualified personnel at both the graduate and undergraduate level, leading to the mastery of advanced, state-of-the-art technical and professional skills. Together, this work will lead to significant advances in our understanding of postnatal auditory cortex maturation and of general principles governing sensory-driven development of complex, mammalian brains.