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

描述（由申请人提供）：我们从错误中学习。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。所有的实验都是通过眨眼条件反射来完成的，这是一种简单的联想学习形式，具有许多优点：1)错误在实验控制之下，可以很容易地操纵。在眨眼调节中，受试者学会眨眼，并保护眼睛免受每次听到音调后使用的角膜充气剂的伤害。误差被定义为真实的空气喷射与受试者预期的空气喷射之间的差异，可以通过在任何给定的试验中意外地改变空气喷射的强度来简单地控制。2)眨眼条件反射可以在小鼠身上进行。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打开了大门。3)先前已经确定了介导眨眼条件反射的神经回路。对这些回路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充气信息产生错误信号，这些信息可能是通过三叉神经核的兴奋性途径传递给下橄榄的，而预期的充气信息可能是通过抑制性小脑途径传递的。本项目利用上述3个优势，研究差错在眨眼条件反射中的作用，阐明下橄榄神经元对差错信号的编码和处理。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，关于未来空气膨胀的强度），大脑只考虑当前试验中的错误。通过逐个试验出人意料地改变空气膨胀的强度，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中的作用。具体目标2是破解下橄榄神经元用来表示不同大小错误的神经密码。通过对小鼠进行眨眼条件反射，同时记录下下橄榄神经元的单个单位和成像群体，这一目标将揭示同步性是否提供了单次试验中误差大小的信息。具体目标3利用遗传工具来询问下橄榄中的同步性是否必要和/或充分地代表错误信号并驱动眨眼条件反射。是否同步是必要的，将通过评估connexin36小鼠的眨眼条件反射来解决，connexin36小鼠的下橄榄区活动正常，但由于电紧张偶联的丧失而导致同步水平降低。我们将利用光遗传刺激下橄榄中表达通道视紫质的小鼠，并评估不同时空模式的神经激活对错误信号驱动眨眼条件反射的影响。

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.