Coding and processing of error signals in inferior olivary-cerebellar networks

描述(申请人提供)：我们从错误中吸取教训。这个项目的目标是了解驱动学习的错误是如何在大脑中编码和处理的。所有的实验都是使用眨眼条件反射完成的，这是一种简单的联想学习形式，提供了许多优势：1)错误处于实验控制之下，可以很容易地操纵。在眨眼调节中，受试者学习眨眼并保护眼睛不受每次听到音调后使用的角膜喷气的影响。误差被定义为实际吹气与受试者预期之间的差异，可以通过在任何给定试验中意外地改变吹气的强度来操纵误差。2)可以在小鼠身上进行眨眼条件反射。这为利用遗传工具研究清醒行为动物错误处理的神经基础打开了大门。3)先前已经发现了调节眨眼条件反射的神经回路。对这些回路的连通性的了解导致了一种假设，即下橄榄中的神经元通过比较真实的喷气信息和预期的喷气信息来产生错误信号。真正的喷气可能是通过三叉神经核的兴奋通路传递到下橄榄的，而预期的喷气可能是通过抑制小脑的通路传递的。本研究利用上述三个优点来研究错误在眨眼条件反射中的作用，并阐明错误信号在下橄榄核神经元中的编码和处理。《特定目的1》挑战了一种普遍的观点，即为了更新预期(例如，关于未来喷气的强度)，大脑只考虑当前试验中的错误。通过出人意料地改变逐个试验的力度，这一目标将定义历史和先前错误的统计在更新对未来事件的预期方面的作用。具体目标2是关于破译下橄榄神经元用来代表不同大小错误的神经代码。通过对小鼠进行眨眼条件反射，同时记录下橄榄叶神经元的单个单位和成像群体，这一目标将揭示Synchrony是否提供了关于单项试验中错误大小的信息。具体目的3利用遗传工具来询问下橄榄的同步性是否必要和/或足以代表错误信号和驱动眨眼条件反射。是否同步是必要的，将通过评估缝隙连接蛋白36小鼠的眨眼条件作用来解决，这些小鼠下橄榄的活动是正常的，除了由于失去电紧张性偶联而降低了同步性水平。同步性是否足够将通过光遗传刺激在小鼠下橄榄中表达通道视紫红质来解决，并评估不同的神经激活时空模式可以发出错误信号来驱动眨眼条件反射的有效性。

DESCRIPTION (provided by applicant): We learn from our mistakes. The goal of this project is to understand how the errors that drive learning are encoded and processed in the brain. All experiments are done using eyeblink conditioning, a simple form of associative learning that offers a number of advantages: 1) Errors are under experimental control and can be easily manipulated. In eyeblink conditioning, subjects learn to blink and protect the eye from a corneal air-puff that is applied every time after they hear a tone. Error, defined as the discrepancy between the real air-puff and what the subject expected, can be manipulated simply by unexpectedly changing the strength of the air-puff on any given trial. 2) Eyeblink conditioning can be done in mice. This opens up the door for approaches that take advantage of genetic tools to investigate the neural basis of error processing in awake-behaving animals. 3) The neural circuits mediating eyeblink conditioning have been identified previously. Knowledge about the connectivity of these circuits has led to the hypothesis that neurons in the inferior olive generate error signals by comparing information about the real air-puff, presumably conveyed to the inferior olive via an excitatory pathway from the trigeminal nucleus, and the expected air-puff, presumably conveyed via an inhibitory cerebellar pathway. This project uses the 3 advantages listed above to investigate the role of errors in eyeblink conditioning, and to elucidate the coding and processing of error signals by neurons in the inferior olive. Specific aim 1 challenges the widely-held view that to update expectations (about the strength of future air- puffs, for example), the brain takes into account only the error in the current trial. By unexpectedly changing the strength of the air-puff trial-by-trial, this aim will define the role of history and statistics of prior errors in updating expectations about future events. Specific aim 2 is about deciphering the neural code used by neurons in the inferior olive to represent errors of different sizes. By doing eyeblink conditioning in mice, while recording single-units and imaging populations of neurons in the inferior olive, this aim will reveal whether synchrony provides information about the size of the error in single trials. Specific aim 3 takes advantage of genetic tools to ask if synchrony in the inferior olive is necessary and/or sufficient to represent the error signal and drive eyeblink conditioning. Whether synchrony is necessary will be addressed by assessing eyeblink conditioning in connexin36 mice, whose activity in the inferior olive is normal except for reduced levels of synchrony due to loss of electrotonic coupling. Whether synchrony is sufficient will be addressed using optogenetic stimulation in mice expressing channelrhodopsin in the inferior olive, and assessing the efficacy with which different spatio-temporal patterns of neural activation can signal error to drive eyeblink conditioning.