Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior
Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior
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DOI：
10.1523/jneurosci.1728-18.2018
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发表时间：
2019-04-10
影响因子：
5.3
通讯作者：
Ahmari, Susanne E.
中科院分区：
文献类型：
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作者：
Corbit, Victoria L.;Manning, Elizabeth E.;Ahmari, Susanne E.
纹状体的多动与强迫症(OCD)和相关疾病的强迫行为有关，但尚不清楚这种多动是由于固有的纹状体功能障碍还是皮质纹状体输入的异常。了解纹状体多动的细胞和电路特性有助于优化强迫症行为障碍的靶向刺激治疗。为了研究与强迫症相关的皮质纹状体功能障碍的细胞和突触异常，我们使用了Sapap3基因敲除(Sapap3-KO)小鼠的强迫行为模型，该模型在中央纹状体也表现出多动。采用双转基因小鼠的体外电生理学方法，研究了Sapap3-KO和野生型(WT)仔鼠中央纹状体中的棘突投射神经元(SPN)和快脉冲中间神经元(FSIS)的内在兴奋性和功能性突触传入。虽然我们发现Sapap3-KOS和WTS的SPN或FSIS的内在兴奋性没有差异，但KOS对FSIS的兴奋驱动显著增加。与预测相反，外侧眶前皮质-纹状体突触不是这种驱动增加的原因；光遗传刺激显示，外侧眶前皮质对SPN的输入在KOS中减少(类似于3倍)，在FSIS中没有变化。而中央纹状体的次级运动区(M2)突触后反应在强度和可靠性方面与WTS相比显著增加(接近6倍)。这些结果表明，M2纹状体驱动增加可能参与体内纹状体多动和强迫行为，并支持运动皮质前补充/补充区域在强迫行为障碍的病理和治疗中的潜在作用。
Hyperactivity in striatum is associated with compulsive behaviors in obsessive-compulsive disorder (OCD) and related illnesses, but it is unclear whether this hyperactivity is due to intrinsic striatal dysfunction or abnormalities in corticostriatal inputs. Understanding the cellular and circuit properties underlying striatal hyperactivity could help inform the optimization of targeted stimulation treatments for compulsive behavior disorders. To investigate the cellular and synaptic abnormalities that may underlie corticostriatal dysfunction relevant to OCD, we used the Sapap3 knock-out (Sapap3-KO) mouse model of compulsive behaviors, which also exhibits hyperactivity in central striatum. Ex vivo electrophysiology in double-transgenic mice was used to assess intrinsic excitability and functional synaptic input in spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in central striatum of Sapap3-KOs and wild-type (WT) littermates. While we found no differences in intrinsic excitability of SPNs or FSIs between Sapap3-KOs and WTs, excitatory drive to FSIs was significantly increased in KOs. Contrary to predictions, lateral orbitofrontal cortex-striatal synapses were not responsible for this increased drive; optogenetic stimulation revealed that lateral orbitofrontal cortex input to SPNs was reduced in KOs (similar to 3-fold) and unchanged in FSIs. However, secondary motor area (M2) postsynaptic responses in central striatum were significantly increased (similar to 6-fold) in strength and reliability inKOsrelative to WTs. These results suggest that increased M2-striatal drivemaycontribute to both in vivo striatal hyperactivity and compulsive behaviors, and support a potential role for presupplementary/supplementary motor cortical regions in the pathology and treatment of compulsive behavior disorders.