Cell-specific Synaptic Plasticity in the Auditory Brainstem

描述(申请人提供)：我们之前对听觉脑干核--耳蜗背核(DCN)的研究发现了突触可塑性的新形式，这种可塑性发生在感觉加工的最早水平。我们的长期目标是确定过去的经验如何塑造网络功能，以及如何呈现传入的感觉信息。我们应用的目的是确定听觉脑干兴奋性和抑制性输入突触强度的活性依赖变化背后的机制和突触规则。该应用的中心假设是，突触上相反形式的长期突触可塑性在DCN中对不同细胞类型的协同操作决定了输出细胞的激活和尖峰定时精度。在第一个目标中，我们将确定信号机制及其相互作用，以形成在DCN上观察到的独特类型的可塑性。在目标2中，我们将研究内源性大麻素信号的突触特异性表达及其决定不同类型突触可塑性的能力。在目标3中，我们将确定不同形式的突触可塑性对输出细胞的棘波计时精度的综合影响。了解活动依赖可塑性在形成DCN回路活动中的机制和作用，不仅有助于统一理解神经反应的产生，而且将对我们理解和治疗由神经可塑性类似机制引起的疾病，包括耳鸣、超敏、听觉过敏、年龄相关性听力损失和言语识别障碍具有重要影响。

DESCRIPTION (provided by applicant): Our previous studies in the dorsal cochlear nucleus (DCN), an auditory brainstem nucleus, have uncovered novel forms of synaptic plasticity that occur at the earliest levels of sensory processing. Our long-term goal is to determine how past experience shapes network function and representations of incoming sensory information. The objective of our application is to determine mechanisms and synaptic rules underlying activity-dependent changes in synaptic strength of excitatory and inhibitory inputs to the auditory brainstem. The central hypothesis of the application is that the concerted operation of opposing forms of long-term synaptic plasticity at synapses onto different cell types in the DCN determines activation and spike timing precision of the output cell. In the first Aim, we will determine the signaling mechanisms and their interactions in shaping the unique types of plasticity observed on the DCN. In Aim 2, we will investigate the synapse- specific expression of endocannabinoid signaling and its ability to determine different types of synaptic plasticity. In Aim 3, we will determine the combined effect of different forms of synaptic plasticity on spike timing precision of the output cell. Understanding the mechanisms and role of activity-dependent plasticity in shaping the activity of the DCN circuitry should not only contribute to a unified understanding of the generation of neural responses, but will also have a significant impact on our understanding and cures for disorders caused by neural plasticity-like mechanisms, including tinnitus, hypersensitivity, hyperacousis, age-related hearing loss, and impaired speech discrimination.