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官体验如何调节发育中和成人大脑的可塑性。我未来五年的研究计划分为三个主轴，如下所述，每个主轴都专注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。所提出的实验结合了联合收割机在大鼠初级听觉皮层（A1）中的最先进的体内电生理学、行为学、药理学和组织学，这是一个研究大脑可塑性的强大系统，我们有多年的经验。轴心岛确定听觉输入统计如何调节发育和成人A1的可塑性。我们以前已经证明，在环境中的听觉输入模式的存在是必要的成熟的A1电路在功能和结构水平。我们还表明，在成年生活中长期缺乏这种模式可以诱导可塑性在成人A1，并最终导致听觉皮层地图的不稳定。这些发现表明，听觉经验是一个很强的可塑性调节器，并表明必须有一个专门的大脑机制，不断监测A1的模式活动的水平。本研究轴的主要目的是精确地确定声音输入特性，在质量和数量上，这是必要的，以诱导A1成熟在发展过程中或诱导可塑性成熟A1。然后，我们将确定是否parvalbumin阳性细胞，一个特定的组interneurons连接到A1成熟可能参与模式检测，如果是的话，是否人为地操纵他们的活动可以触发或阻止A1可塑性。第二轴确定经验对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声音而受到强烈调制。该系统是必不可少的，以提高在嘈杂的情况下，或在存在竞争的听觉输入的听觉处理的鲁棒性。越来越多的人类相关证据表明，额叶皮质领域参与了这种自上而下的调制。轴II的主要重点是使用我们的啮齿动物模型和皮层失活技术，以确定是否真的是这样，并了解听觉经验，更具体地说，听觉训练可以调节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：建立跨模态可塑性的调节机制。现在已经确定盲人的视觉皮层在某些情况下可以重新专门化为听觉处理领域。由于未知的原因，这个过程被称为跨模态可塑性显示出很大的个体间差异。人类的相关数据表明，剩余的视觉和竞争的听觉输入的数量可能是一个重要的因素，这种变化。在这项研究中，轴我们的目标是确定在不同程度的失明和生活在不同水平的听觉丰富的大鼠感觉经验如何驱动和调节去传入皮层的跨模态接管。我们提出的综合研究计划将在未来五年内为至少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带来对感觉体验调节大脑可塑性的方式的新的深入理解，并且很可能有助于为我们的人群开发新的基于神经可塑性的治疗策略。

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.