Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Neuroscience. 2019 Mar 1;401:106-116. doi: 10.1016/j.neuroscience.2019.01.013. Epub 2019 Jan 19.
The striatum of the basal ganglia is pivotal for voluntary movements and is implicated in debilitating movement disorders such as Parkinsonism and dystonia. Striatum projects to downstream nuclei through direct (dSPN) and indirect (iSPN) pathway projection neurons thought to exert opposite effects on movement. In rodent models of striatal function, unilateral dopamine deprivation induces ipsiversive rotational behavior. The dSPNs of the dorsal striatum are believed to engage distinct motor programs but underlying mechanisms remain unclear. Here, we show by employing chemogenetics [Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)] that unilateral inhibition of dorsomedial dSPNs is sufficient to selectively impair contraversive movement and elicit ipsiversive rotational behavior in mice. Adeno-associated virus (AAV) encoding Cre-dependent G-coupled DREADD was injected unilaterally into the dorsomedial striatum of Drd1-Cre mice, resulting in expression of the modified human M4 muscarinic receptor (hM4Di) in ∼20% of dorsostriatal dSPNs. Upon hM4Di activation, a striking positive linear correlation was found between turn ratio and viral expression, which corroborates a relationship between unilateral inhibition of dorsomedial dSPNs and rotational behavior. Bursts of ipsiversive rotations were interspersed with normal ambulation. However, partial unilateral inhibition of ∼20% of dorsostriatal dSPNs did not affect horizontal and vertical locomotion or forelimb use preference. Overall, our results substantiate a unique role of dSPNs in promoting response bias in rotational behavior and show this to be a highly sensitive measure of dSPN performance.
基底神经节的纹状体对于自主运动至关重要，并且与帕金森病和肌张力障碍等使人衰弱的运动障碍有关。纹状体通过直接（dSPN）和间接（iSPN）途径投射神经元向下游核投射，据认为这些神经元对运动产生相反的影响。在纹状体功能的啮齿动物模型中，单侧多巴胺剥夺会引起向对侧旋转的行为。背侧纹状体的 dSPN 被认为参与了不同的运动程序，但潜在的机制仍不清楚。在这里，我们通过使用化学遗传学（ Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)）表明，单侧抑制背侧纹状体的 dSPN 足以选择性地损害对侧运动，并在小鼠中引起向对侧旋转的行为。编码 Cre 依赖性 G 偶联 DREADD 的腺相关病毒（AAV）单侧注射到 Drd1-Cre 小鼠的背侧纹状体中，导致约 20%的背侧纹状体 dSPN 中表达修饰后的人类 M4 毒蕈碱受体（hM4Di）。当 hM4Di 被激活时，发现转向比与病毒表达之间存在显著的正线性相关性，这证实了单侧抑制背侧纹状体的 dSPN 与旋转行为之间的关系。一连串的向对侧旋转与正常的步行交替出现。然而，对约 20%的背侧纹状体 dSPN 的部分单侧抑制并不影响水平和垂直运动或前肢使用偏好。总的来说，我们的结果证实了 dSPN 在促进旋转行为中的反应偏向方面的独特作用，并表明这是衡量 dSPN 性能的一个高度敏感的指标。
