Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington.
Department of Pharmacology, University of Washington, Seattle, Washington.
Biol Psychiatry. 2018 Sep 15;84(6):401-412. doi: 10.1016/j.biopsych.2018.01.019. Epub 2018 Feb 2.
Studies in humans and nonhuman primates have identified a region of the dentate nucleus of the cerebellum, or the lateral cerebellar nucleus (LCN) in rodents, activated during performance of cognitive tasks involving complex spatial and sequential planning. Whether such a subdivision exists in rodents is not known. Dopamine and its receptors, which are implicated in cognitive function, are present in the cerebellar nuclei, but their function is unknown.
Using viral and genetic strategies in mice, we examined cellular phenotypes of dopamine D receptor-positive (D1R+) cells in the LCN with whole-cell patch clamp recordings, messenger RNA profiling, and immunohistochemistry to examine D1R expression in mouse LCN and human dentate nucleus of the cerebellum. We used chemogenetics to inhibit D1R+ neurons and examined behaviors including spatial navigation, social recognition memory, prepulse inhibition of the acoustic startle reflex, response inhibition, and working memory to test the necessity of these neurons in these behaviors.
We identified a population of D1R+ neurons that are localized to an anatomically distinct region of the LCN. We also observed D1R+ neurons in human dentate nucleus of the cerebellum, which suggests an evolutionarily conserved population of dopamine-receptive neurons in this region. The genetic, electrophysiological, and anatomical profile of mouse D1R neurons is consistent with a heterogeneous population of gamma-aminobutyric acidergic, and to a lesser extent glutamatergic, cell types. Selective inhibition of D1R+ LCN neurons impairs spatial navigation memory, response inhibition, working memory, and prepulse inhibition of the acoustic startle reflex.
Collectively, these data demonstrate a functional link between genetically distinct neurons in the LCN and cognitive behaviors.
在人类和非人类灵长类动物中的研究已经确定了小脑的齿状核或啮齿动物的外侧小脑核（LCN）的一个区域，该区域在涉及复杂空间和序列规划的认知任务中被激活。目前尚不清楚啮齿动物是否存在这样的细分。参与认知功能的多巴胺及其受体存在于小脑核中，但它们的功能尚不清楚。
我们使用病毒和遗传策略在小鼠中，通过全细胞膜片钳记录、信使 RNA 谱分析和免疫组织化学检查 LCN 中多巴胺 D 受体阳性（D1R+）细胞的细胞表型，检查 D1R 在小鼠 LCN 和人小脑齿状核中的表达。我们使用化学遗传学抑制 D1R+神经元，并检查包括空间导航、社会识别记忆、听觉起始反射的前脉冲抑制、反应抑制和工作记忆在内的行为，以测试这些神经元在这些行为中的必要性。
我们鉴定出一群位于 LCN 解剖学上不同区域的 D1R+神经元。我们还观察到人小脑齿状核中的 D1R+神经元，这表明该区域存在进化保守的多巴胺反应神经元群体。小鼠 D1R 神经元的遗传、电生理和解剖学特征与 GABA 能神经元的异质性群体一致，并且在较小程度上与谷氨酸能神经元一致。选择性抑制 D1R+LCN 神经元会损害空间导航记忆、反应抑制、工作记忆和听觉起始反射的前脉冲抑制。
总的来说，这些数据表明 LCN 中遗传上不同的神经元与认知行为之间存在功能联系。
