Role of auditory experience in the regulation of plasticity in the developing and adult brain

我的研究计划的长期目标是确定感觉体验如何调节发育中的和成人大脑的大脑可塑性。我未来五年的研究计划分为三个主要轴，如下所述，每个轴都侧重于研究影响大脑可塑性的特定因素，以及它们对行为的影响。这些实验提出了将最先进的体内电生理学、行为、药理学和大鼠初级听觉皮质(A1)的组织学结合起来，这是一个研究大脑可塑性的强大系统，我们对此有多年的经验。轴I确定听觉输入统计如何调节发育中和成人A1的可塑性。我们先前已经证明，环境中听觉输入模式的存在对于A1电路在功能和结构水平上的成熟是必要的。我们还表明，在成年生活中长期缺乏这种模式可以诱导成人A1的可塑性，并最终导致听觉皮质映射的不稳定。这些发现表明，听觉经验是可塑性的强大调节器，并表明必须有一种专门的大脑机制来持续监测A1中的模式活动水平。本研究的主要目标是准确确定声音输入特性，在质量和数量上，这些特性是在发育过程中诱导A1成熟或在成熟A1中诱导可塑性所必需的。然后，我们将确定小白蛋白阳性细胞，即与A1成熟有关的一组特定的中间神经元是否可能参与模式检测，如果是，是否人为操纵它们的活动可以触发或阻止A1的可塑性。轴二：确定经验对A1中“自上而下”调制的选择性的作用。A1对各种声音的敏感度根据我们在特定任务中需要听到的内容而强烈调制。该系统对于提高在噪声环境下或在存在相互竞争的听觉输入的情况下的听觉处理的稳健性至关重要。越来越多的人类相关证据表明，额叶皮质区域参与了这种自上而下的调制。Axis II的主要重点是使用我们的啮齿动物模型和皮质失活技术来确定情况是否属实，并了解听觉体验和更具体地说的听觉训练如何调节A1-额叶相互作用的强度和质量，以提高听觉编码的保真度。轴III：建立跨模式可塑性的调节机制。现在已经证实，盲人的视觉皮质在特定情况下可以重新专门化到听觉处理领域。由于未知的原因，这种被称为跨模式可塑性的过程显示出很大的个体间差异性。人类的相关数据表明，残留的视觉和竞争听觉输入的数量可能是造成这种差异的一个重要因素。在这项研究中，我们的目标是在不同程度失明和生活在不同听觉丰富水平的大鼠身上，确定感觉体验如何驱动和调节去传入皮层的交叉模式接管。我们提出的综合研究计划将在未来五年为至少15名学生提供丰富的综合培训环境。我们预期的实验结果将为感觉体验调节大脑可塑性的方式带来新的深入理解，并可能有助于为我们的人群开发基于神经可塑性的新治疗策略。

The long-term objective of my research program is to determine how sensory experience modulates brain plasticity in the developing and adult brain. My research plan for the next five years is divided into three main axes, described below, each focusing on investigating specific factors that influence brain plasticity, as well as their consequences on behavior. The experiments proposed combine state-of-the-art in-vivo electrophysiology, behavior, pharmacology and histology in the rat primary auditory cortex (A1), a powerful system to study brain plasticity with which we have years of experience. Axis I. Determining how auditory input statistics regulate plasticity in the developing and adult A1. We have previously demonstrated that the presence of auditory input patterns in the environment was necessary for the maturation of A1 circuits both at a functional and structural level. We have also showed that a prolonged absence of such patterns during adult life can induce plasticity in the adult A1 and ultimately lead to destabilization of auditory cortical maps. These findings demonstrate that auditory experience is a strong modulator of plasticity and indicate there must be a specialized brain mechanism that continuously monitors the level of patterned activity in A1. The main objective of this research Axis is to determine precisely the sound input characteristics, in quality and quantity that are necessary to induce A1 maturation during development or induce plasticity in the mature A1. We will then determine whether parvalbumin positive cells, a specific group interneurons linked to A1 maturation might be involved in pattern detection and, if yes, whether manipulating their activity artificially could trigger or block A1 plasticity. Axis II. Determining the role of experience on the selectivity of “top-down” modulation in A1. The sensitivity of A1 to various sounds is strongly modulated according to what we need to hear in the context of a specific task. This system is essential to improve the robustness of auditory processing in noisy situations or in the presence of competing auditory inputs. Growing correlational evidence in humans suggest that frontal cortical fields are involved in this top-down modulation. The main focus of Axis II is to use our rodent model and cortical inactivation techniques to determine if that is truly the case, and understand how auditory experiences and more specifically auditory training can modulate the strength and quality of A1-frontal interaction to improve the fidelity of auditory coding. Axis III: Establishing the mechanisms of regulation of cross-modal plasticity. It is now well established that the visual cortex of blind individuals can under certain circumstance re-specialize into an auditory processing field. For unknown reasons, this process known as cross-modal plasticity displays substantial inter-individual variability. Correlational data in humans suggest that the quantity of residual visual and competing auditory inputs might be an important factor contributing to this variability. In this research Axis our goal is to determine in rats with different degree of blindness and living in various levels of auditory enrichment how sensory experience drives and modulates the crossmodal takeover of de-afferented cortex. The integrative research plan we propose will provide a rich integrative training environment for a minimum of 15 students over the next five years. The experimental results we anticipate will bring a novel in-depth understanding of the way sensory experience regulates brain plasticity and are likely to contribute, as we have shown before to the development of new neuroplasticity-based therapeutic strategies for our population.