Lackey Elizabeth P, Moreira Luis, Norton Aliya, Hemelt Marie E, Osorno Tomas, Nguyen Tri M, Macosko Evan Z, Lee Wei-Chung Allen, Hull Court A, Regehr Wade G
Department of Neurobiology, Harvard Medical School, Boston MA, United States.
Department of Neurobiology, Duke University Medical School, Durham, United States.
bioRxiv. 2023 Sep 15:2023.09.15.557934. doi: 10.1101/2023.09.15.557934.
The cerebellar cortex contributes to diverse behaviors by transforming mossy fiber inputs into predictions in the form of Purkinje cell (PC) outputs, and then refining those predictions. Molecular layer interneurons (MLIs) account for approximately 80% of the inhibitory interneurons in the cerebellar cortex, and are vital to cerebellar processing. MLIs are thought to primarily inhibit PCs and suppress the plasticity of excitatory synapses onto PCs. MLIs also inhibit, and are electrically coupled to, other MLIs, but the functional significance of these connections is not known. Behavioral studies suggest that cerebellar-dependent learning is gated by disinhibition of PCs, but the source of such disinhibition has not been identified. Here we find that two recently recognized MLI subtypes, MLI1 and MLI2, have highly specialized connectivity that allows them to serve very different functional roles. MLI1s primarily inhibit PCs, are electrically coupled to each other, fire synchronously with other MLI1s on the millisecond time scale , and synchronously pause PC firing. MLI2s are not electrically coupled, they primarily inhibit MLI1s and disinhibit PCs, and are well suited to gating cerebellar-dependent learning. These findings require a major reevaluation of processing within the cerebellum in which disinhibition, a powerful circuit motif present in the cerebral cortex and elsewhere, greatly increases the computational power and flexibility of the cerebellum. They also suggest that millisecond time scale synchronous firing of electrically-coupled MLI1s helps regulate the output of the cerebellar cortex by synchronously pausing PC firing, which has been shown to evoke precisely-timed firing in PC targets.
小脑皮质通过将苔藓纤维输入转化为浦肯野细胞（PC）输出形式的预测，然后完善这些预测，从而对多种行为产生影响。分子层中间神经元（MLI）约占小脑皮质抑制性中间神经元的80%，对小脑处理过程至关重要。人们认为MLI主要抑制PC，并抑制PC上兴奋性突触的可塑性。MLI还抑制其他MLI并与之形成电耦合，但这些连接的功能意义尚不清楚。行为学研究表明，小脑依赖的学习是通过对PC的去抑制来控制的，但这种去抑制的来源尚未确定。在这里，我们发现最近识别出的两种MLI亚型，即MLI1和MLI2，具有高度专业化的连接方式，使它们能够发挥非常不同的功能作用。MLI1主要抑制PC，相互之间形成电耦合，在毫秒时间尺度上与其他MLI1同步放电，并同步暂停PC放电。MLI2不形成电耦合，它们主要抑制MLI1并解除对PC的抑制，非常适合控制小脑依赖的学习。这些发现需要对小脑中的处理过程进行重大重新评估，其中去抑制是大脑皮质和其他地方存在的一种强大的电路模式，极大地提高了小脑的计算能力和灵活性。它们还表明，电耦合的MLI1在毫秒时间尺度上的同步放电通过同步暂停PC放电来帮助调节小脑皮质的输出，而这已被证明能在PC靶标中引发精确计时的放电。
