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

描述（由申请人提供）：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如何在大脑中编码和处理。所有的实验都是使用眨眼条件反射来完成的，眨眼条件反射是一种简单的联想学习形式，它提供了许多优点：1）错误在实验控制之下，可以很容易地操纵。在眨眼条件反射中，受试者学会眨眼，并保护眼睛免受每次听到音调后都会施加的角膜喷气的影响。误差，定义为真实的空气抽吸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空气抽吸的强度来简单地操纵。2)眨眼条件反射可以在小鼠中进行。这为利用遗传工具来研究清醒行为动物错误处理的神经基础的方法打开了大门。3)介导眨眼条件反射的神经回路先前已经被确定。关于这些回路的连通性的知识导致了一种假设，即下橄榄核中的神经元通过比较关于真实的喷气的信息来产生错误信号，推测该喷气是通过三叉神经核的兴奋性通路传递到下橄榄核的，而预期的喷气是通过抑制性小脑通路传递的。本研究利用上述三个优点，探讨错误在眨眼条件反射中的作用，并阐明下橄榄核神经元对错误信号的编码和处理。具体目标1挑战了一种广泛持有的观点，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。通过意外地改变一次又一次试验的喷气强度，这一目标将确定历史和先前误差的统计在更新对未来事件的预期中的作用。具体目标2是破译下橄榄核神经元用来代表不同大小错误的神经代码。通过在小鼠中进行眨眼条件反射，同时记录下橄榄核中的单个神经元和成像神经元群体，这一目标将揭示同步是否提供了关于单次试验中错误大小的信息。具体目标3利用遗传工具来询问下橄榄的同步是否是必要的和/或足以代表错误信号并驱动眨眼条件反射。通过评估connexin 36小鼠的眨眼条件反射来解决是否需要同步性，connexin 36小鼠的下橄榄体活动正常，除了由于电紧张性耦合丧失导致的同步性水平降低。同步性是否足够将使用在下橄榄中表达通道视紫红质的小鼠中的光遗传学刺激来解决，并评估神经激活的不同时空模式可以发出错误信号以驱动眨眼条件反射的功效。

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.