Synaptic and intrinsic plasticity during sound offset encoding

这一提议将揭示大脑机制，这些机制调节大脑在早期发育期间和对听觉体验的变化做出反应的能力。正确的布线和适当的活动模式能够检测并快速响应环境变化，例如声音等对象的出现或消失。声音在起始和偏移方面的编码是高度发达的；起始时间和准确性得到了很好的表征，但在高级孤束核(SPN)中偏移编码的离子机制直到最近才被描述(由我和我的合作者)。这些神经元将声音过程中的强大抑制转化为声音终止时的精确动作电位激发。我有初步证据表明，这个回路(和组成蛋白质)处于活性依赖的控制之下。然而，目前还不清楚导致偏移编码的抑制是如何受到正常个体发育期间或声学侮辱后声学环境中经验依赖的变化的影响。在这项建议中，我的实验室将探索脑干抑制限制的变化如何影响相位偏移反应，并(如初步数据所示)实现异常的、连续的有节奏的放电。这种从相位到连续激发的经验依赖的切换表明SPN功能的丧失，因此声音偏移检测受到影响。两种方法将被用来研究抑制限制：1)光遗传沉默MNTB神经元和2)声过度暴露诱导声损伤，以探索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为深入了解控制SPN放电模式的分子机制提供洞察力；而整个动物记录将提供在系统水平上处理真实感觉刺激的生理机制。揭示抑制输入强度和从相位偏置编码到连续有节奏放电的转换之间的关系将提供对经验依赖型学习和可塑性的一般理解。在iPod时代，个人暴露在极端声级下的可能性很大，相应的损害风险也很大，该项目将提供对听觉通路因声学过度暴露而发生的短期和长期变化的机械性见解，并将有助于开发能够保护或恢复感觉能力的治疗方法。

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.