Synaptic and intrinsic plasticity during sound offset encoding

这一建议将揭示大脑机制，在早期发育和听觉体验变化的反应中，调节大脑连接和重新连接自身的能力。正确的神经连接和适当的活动模式使我们能够发现环境的变化并迅速作出反应，例如声音等物体的出现或消失。声音的起始和偏移编码是高度发达的；发作时间和准确性是很好的特征，但偏移编码的离子机制在上副橄榄核（SPN）最近才被描述（由我和我的合作者）。这些神经元将声音中的强大抑制转化为声音终止时精确的动作电位放电。我有初步的证据表明，这个回路（和组成蛋白）是受活性依赖控制的。然而，目前尚不清楚导致偏移编码的抑制是如何在正常个体发育过程中或在声损伤后受到声环境中经验依赖变化的影响的。在这个提议中，我的实验室将探索脑干抑制约束的变化如何影响相位偏移反应，并（如初步数据所示）使异常的、连续的节律性放电成为可能。这种从相位到连续发射的经验依赖开关表明SPN的功能丧失，因此声音偏移检测受到损害。我们将采用两种方法来研究这种抑制约束：1)光遗传沉默MNTB神经元和2)声音过度暴露诱导声损伤，从而探索MNTB/SPN微电路的可塑性变化。切片和体内电生理学的互补使用将提供对控制SPN放电模式的分子机制的见解；而全动物记录将在系统水平上提供处理真实感官刺激的生理机制。揭示抑制输入强度与从相位偏移编码到连续节律放电的转换之间的关系将有助于对经验依赖学习和可塑性的一般理解。在iPod时代，由于个人暴露于极端声音水平和相应的损伤风险的巨大潜力，该项目将提供对听觉通路的短期和长期变化的机械见解，以响应声音过度暴露，并将有助于开发可以保护或恢复感官能力的治疗方法。

This proposal will reveal brain mechanisms which mediate the capacity of the brain to wire and rewire itself during early development and in response to changes in auditory experience. Correct wiring and appropriate activity patterns result in the ability to detect and respond quickly to changes in the environment, e.g. the appearance or disappearance of an object such as sound. The encoding of sound in terms of onset and offset is highly developed; onset timing and accuracy is well characterized, but the ionic mechanism of offset-encoding in the Superior Paraolivary Nucleus (SPN) has only recently been described (by myself and my collaborators). These neurons convert powerful inhibition during sound into precise action potential firing upon sound termination. I have preliminary evidence that this circuit (and component proteins) is under activity-dependent control. However, it is not yet understood how the inhibition leading to offset-encoding is affected by experience-dependent changes in the acoustic environment during normal ontogeny or following an acoustic insult. In this proposal my lab will explore how changes in the brainstem inhibitory constraint affect the phasic offset response and (as indicated by preliminary data) enables aberrant, continuous rhythmic firing. Such an experience-dependent switch from phasic to continuous firing suggests a loss of function in the SPN, so that sound offset detection is compromised. Two approaches will be used to investigate the inhibitory constraint: 1) optogenetic silencing of MNTB neurons and 2) sound over-exposure to induce an acoustic trauma, so that plasticity changes in the MNTB/SPN microcircuit can be explored. Complementary use of slice and in vivo electrophysiology will provide insights into the molecular mechanisms controlling firing patterns in the SPN; while whole animal recording will provide the physiological mechanisms for processing of realistic sensory stimuli on a systems level. Uncovering the relationship between inhibitory input strength and a switch from phasic offset-encoding to continuous rhythmic firing will provide general understanding of experience-dependent learning and plasticity. And in the age of the iPod, with the huge potential for personal exposure to extreme sound levels and the according risk of damage, this project will provide mechanistic insights into both, short- and long term changes to the auditory pathway in response to acoustic over-exposure and will contribute to the development of treatments that can protect or restore the sensory capacity.