Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.
J Neurosci. 2021 Dec 8;41(49):10091-10107. doi: 10.1523/JNEUROSCI.0683-21.2021. Epub 2021 Oct 29.
Despite being canonically considered a motor control structure, the cerebellum is increasingly recognized for important roles in processes beyond this traditional framework, including seizure suppression. Excitatory fastigial neurons project to a large number of downstream targets, and it is unclear whether this broad targeting underlies seizure suppression, or whether a specific output may be sufficient. To address this question, we used the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, male and female animals, and a dual-virus approach to selectively label and manipulate fastigial outputs. We examined fastigial neurons projecting to the superior colliculus, medullary reticular formation, and central lateral nucleus of the thalamus, and found that these comprise largely nonoverlapping populations of neurons that send collaterals to unique sets of additional, somewhat overlapping, thalamic and brainstem regions. We found that neither optogenetic stimulation of superior colliculus nor reticular formation output channels attenuated hippocampal seizures. In contrast, on-demand stimulation of fastigial neurons targeting the central lateral nucleus robustly inhibited seizures. Our results indicate that fastigial control of hippocampal seizures does not require simultaneous modulation of many fastigial output channels. Rather, selective modulation of the fastigial output channel to the central lateral thalamus, specifically, is sufficient for seizure control. More broadly, our data highlight the concept of specific cerebellar output channels, whereby discrete cerebellar nucleus neurons project to specific aggregates of downstream targets, with important consequences for therapeutic interventions. The cerebellum has an emerging relationship with nonmotor systems and may represent a powerful target for therapeutic intervention in temporal lobe epilepsy. We find, as previously reported, that fastigial neurons project to numerous brain regions via largely segregated output channels, and that projection targets cannot be predicted simply by somatic locations within the nucleus. We further find that on-demand optogenetic excitation of fastigial neurons projecting to the central lateral nucleus of the thalamus-but not fastigial neurons projecting to the reticular formation, superior colliculus, or ventral lateral thalamus-is sufficient to attenuate hippocampal seizures.
尽管小脑在传统框架之外的过程中具有重要作用已得到广泛认可，但它仍然被认为是一种运动控制结构。兴奋性 fastigial 神经元投射到大量下游靶点，目前尚不清楚这种广泛的靶向是否是抑制癫痫发作的基础，或者特定的输出是否就足够了。为了解决这个问题，我们使用了海马内侧颞叶癫痫的海马内海人酸小鼠模型，雄性和雌性动物，以及一种双病毒方法来选择性标记和操纵 fastigial 的输出。我们检查了投射到上丘、延髓网状结构和丘脑中央外侧核的 fastigial 神经元，发现这些神经元主要是非重叠的神经元群体，它们的侧支投射到独特的、略有重叠的丘脑和脑干区域。我们发现，光遗传学刺激上丘或网状结构输出通道都不能减弱海马的癫痫发作。相反，按需刺激靶向中央外侧核的 fastigial 神经元可强烈抑制癫痫发作。我们的结果表明，fastigial 对海马癫痫发作的控制不需要同时调节许多 fastigial 输出通道。相反，对中央外侧丘脑的 fastigial 输出通道的选择性调节，特别是，足以控制癫痫发作。更广泛地说，我们的数据突出了特定小脑输出通道的概念，即离散的小脑核神经元投射到特定的下游靶点集合，这对治疗干预有重要影响。小脑与非运动系统有着新兴的关系，可能代表着颞叶癫痫治疗干预的一个有力靶点。我们发现，如前所述，fastigial 神经元通过基本上分离的输出通道投射到许多脑区，并且投射目标不能简单地通过核内的躯体位置来预测。我们进一步发现，按需光遗传学刺激投射到丘脑中央外侧核的 fastigial 神经元——而不是投射到网状结构、上丘或腹外侧丘脑的 fastigial 神经元——足以减弱海马的癫痫发作。
