Department of Neurobiology, Duke University Medical School , Durham, North Carolina.
J Neurophysiol. 2019 Jan 1;121(1):105-114. doi: 10.1152/jn.00492.2018. Epub 2018 Oct 3.
Understanding how afferent information is integrated by cortical structures requires identifying the factors shaping excitation and inhibition within their input layers. The input layer of the cerebellar cortex integrates diverse sensorimotor information to enable learned associations that refine the dynamics of movement. Specifically, mossy fiber afferents relay sensorimotor input into the cerebellum to excite granule cells, whose activity is regulated by inhibitory Golgi cells. To test how this integration can be modulated, we have used an acute brain slice preparation from young adult rats and found that encoding of mossy fiber input in the cerebellar granule cell layer can be regulated by serotonin (5-hydroxytryptamine, 5-HT) via a specific action on Golgi cells. We find that 5-HT depolarizes Golgi cells, likely by activating 5-HT2A receptors, but does not directly act on either granule cells or mossy fibers. As a result of Golgi cell depolarization, 5-HT significantly increases tonic inhibition onto both granule cells and Golgi cells. 5-HT-mediated Golgi cell depolarization is not sufficient, however, to alter the probability or timing of mossy fiber-evoked feed-forward inhibition onto granule cells. Together, increased granule cell tonic inhibition paired with normal feed-forward inhibition acts to reduce granule cell spike probability without altering spike timing. Hence, these data provide a circuit mechanism by which 5-HT can reduce granule cell activity without altering temporal representations of mossy fiber input. Such changes in network integration could enable flexible, state-specific suppression of cerebellar sensorimotor input that should not be learned or enable reversal learning for unwanted associations. NEW & NOTEWORTHY Serotonin (5-hydroxytryptamine, 5-HT) regulates synaptic integration at the input stage of cerebellar processing by increasing tonic inhibition of granule cells. This circuit mechanism reduces the probability of granule cell spiking without altering spike timing, thus suppressing cerebellar input without altering its temporal representation in the granule cell layer.
理解感觉信息如何被皮质结构整合，需要确定在其输入层中塑造兴奋和抑制的因素。小脑皮层的输入层整合了各种感觉运动信息，从而实现了使运动动态得以细化的学习关联。具体而言，苔藓纤维传入纤维将感觉运动输入传递到小脑，以兴奋颗粒细胞，其活动受抑制性高尔基细胞调节。为了测试这种整合如何被调节，我们使用了来自成年早期大鼠的急性脑切片制备，并发现小脑颗粒细胞层中苔藓纤维输入的编码可以通过高尔基细胞上的特定作用被 5-羟色胺（5-羟色胺，5-HT）调节。我们发现 5-HT 通过激活 5-HT2A 受体使高尔基细胞去极化，但不直接作用于颗粒细胞或苔藓纤维。由于高尔基细胞去极化，5-HT 显著增加了对颗粒细胞和高尔基细胞的紧张性抑制。然而，5-HT 介导的高尔基细胞去极化不足以改变苔藓纤维诱发的对颗粒细胞的前馈抑制的概率或时间。总的来说，增加的颗粒细胞紧张性抑制与正常的前馈抑制相结合，可降低颗粒细胞的尖峰概率，而不改变尖峰时间。因此，这些数据提供了一种电路机制，通过该机制，5-HT 可以降低颗粒细胞的活动而不改变苔藓纤维输入的时间表示。这种网络整合的变化可以使小脑感觉运动输入的灵活、特定状态的抑制得以实现，而不会产生不应学习的内容，或者为不需要的关联提供反向学习。新的和值得注意的是，5-羟色胺（5-HT）通过增加颗粒细胞的紧张性抑制来调节小脑处理输入阶段的突触整合。这种电路机制降低了颗粒细胞放电的概率而不改变尖峰时间，从而在不改变颗粒细胞层中其时间表示的情况下抑制小脑输入。
