Mapelli Lisa, Gagliano Giuseppe, Soda Teresa, Laforenza Umberto, Moccia Francesco, D'Angelo Egidio U
Department of Brain and Behavioral Sciences.
Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi, 00184 Rome, Italy, and.
J Neurosci. 2017 Feb 1;37(5):1340-1351. doi: 10.1523/JNEUROSCI.2025-16.2016. Epub 2016 Dec 30.
Neurovascular coupling (NVC) is the process whereby neuronal activity controls blood vessel diameter. In the cerebellum, the molecular layer is regarded as the main NVC determinant. However, the granular layer is a region with variable metabolic demand caused by large activity fluctuations that shows a prominent expression of NMDA receptors (NMDARs) and nitric oxide synthase (NOS) and is therefore much more suitable for effective NVC. Here, we show, in the granular layer of acute rat cerebellar slices, that capillary diameter changes rapidly after mossy fiber stimulation. Vasodilation required neuronal NMDARs and NOS stimulation and subsequent guanylyl cyclase activation that probably occurred in pericytes. Vasoconstriction required metabotropic glutamate receptors and CYP ω-hydroxylase, the enzyme regulating 20-hydroxyeicosatetraenoic acid production. Therefore, granular layer capillaries are controlled by the balance between vasodilating and vasoconstricting systems that could finely tune local blood flow depending on neuronal activity changes at the cerebellar input stage.
The neuronal circuitry and the biochemical pathways that control local blood flow supply in the cerebellum are unclear. This is surprising given the emerging role played by this brain structure, not only in motor behavior, but also in cognitive functions. Although previous studies focused on the molecular layer, here, we shift attention onto the mossy fiber granule cell (GrC) relay. We demonstrate that GrC activity causes a robust vasodilation in nearby capillaries via the NMDA receptors-neuronal nitric oxide synthase signaling pathway. At the same time, metabotropic glutamate receptors mediate 20-hydroxyeicosatetraenoic acid-dependent vasoconstriction. These results reveal a complex signaling network that hints for the first time at the granular layer as a major determinant of cerebellar blood-oxygen-level-dependent signals.
神经血管耦合（NVC）是神经元活动控制血管直径的过程。在小脑中，分子层被视为主要的NVC决定因素。然而，颗粒层是一个因活动大幅波动而代谢需求可变的区域，该区域显示出NMDA受体（NMDARs）和一氧化氮合酶（NOS）的显著表达，因此更适合有效的NVC。在此，我们在急性大鼠小脑切片的颗粒层中发现，苔藓纤维刺激后毛细血管直径迅速变化。血管舒张需要神经元NMDARs和NOS刺激以及随后可能发生在周细胞中的鸟苷酸环化酶激活。血管收缩需要代谢型谷氨酸受体和CYP ω-羟化酶，该酶调节20-羟基二十碳四烯酸的产生。因此，颗粒层毛细血管受血管舒张和收缩系统之间平衡的控制，这可以根据小脑输入阶段的神经元活动变化精细调节局部血流。
控制小脑局部血流供应的神经元回路和生化途径尚不清楚。鉴于这个脑结构不仅在运动行为中，而且在认知功能中发挥的新作用，这一点令人惊讶。尽管先前的研究集中在分子层，但在此我们将注意力转移到苔藓纤维颗粒细胞（GrC）中继上。我们证明GrC活动通过NMDA受体-神经元型一氧化氮合酶信号通路在附近毛细血管中引起强烈的血管舒张。同时，代谢型谷氨酸受体介导20-羟基二十碳四烯酸依赖性血管收缩。这些结果揭示了一个复杂的信号网络，首次暗示颗粒层是小脑血氧水平依赖性信号的主要决定因素。
