Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania 15260.
eNeuro. 2024 Apr 11;11(4). doi: 10.1523/ENEURO.0090-24.2024. Print 2024 Apr.
Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive obsessive thoughts and compulsive behaviors. Multiple studies have shown the association of polymorphisms in the gene with OCD. The most common of these OCD-associated polymorphisms increases the expression of the encoded protein, excitatory amino acid transporter 3 (EAAT3), a neuronal glutamate transporter. Previous work has shown that increased EAAT3 expression results in OCD-relevant behavioral phenotypes in rodent models. In this study, we created a novel mouse model with targeted, reversible overexpression of in forebrain neurons. The mice do not have a baseline difference in repetitive behavior but show increased hyperlocomotion following a low dose of amphetamine (3 mg/kg) and increased stereotypy following a high dose of amphetamine (8 mg/kg). We next characterized the effect of amphetamine on striatal cFos response and found that amphetamine increased cFos throughout the striatum in both control and -overexpressing (OE) mice, but -OE mice had increased cFos expression in the ventral striatum relative to controls. We used an unbiased machine classifier to robustly characterize the behavioral response to different doses of amphetamine and found a unique response to amphetamine in -OE mice, relative to controls. Lastly, we found that the differences in striatal cFos expression in -OE mice were driven by cFos expression specifically in D1 neurons, as -OE mice had increased cFos in D1 ventral medial striatal neurons, implicating this region in the exaggerated behavioral response to amphetamine in -OE mice.
强迫症（OCD）是一种使人衰弱的精神疾病，其特征是存在侵入性的强迫性思维和强迫性行为。多项研究表明， 基因中的多态性与 OCD 有关。这些与 OCD 相关的多态性中最常见的一种会增加编码蛋白兴奋性氨基酸转运体 3（EAAT3）的表达，EAAT3 是一种神经元谷氨酸转运体。以前的工作表明，EAAT3 表达的增加会导致啮齿动物模型中与 OCD 相关的行为表型。在这项研究中，我们创建了一种新型的小鼠模型，其在大脑前神经元中靶向、可逆地过表达 。这些小鼠在重复行为方面没有基线差异，但在低剂量安非他命（3mg/kg）后表现出过度活跃，在高剂量安非他命（8mg/kg）后表现出刻板行为增加。我们接下来研究了安非他命对纹状体 cFos 反应的影响，发现安非他命增加了对照和过表达（OE）小鼠纹状体中的 cFos，但 OE 小鼠的腹侧纹状体中的 cFos 表达增加。我们使用无偏机器分类器来准确描述对不同剂量安非他命的行为反应，并发现 OE 小鼠对安非他命有独特的反应，与对照组相比。最后，我们发现 OE 小鼠纹状体 cFos 表达的差异是由 D1 神经元中 cFos 表达的特异性驱动的，因为 OE 小鼠的 D1 腹侧内侧纹状体神经元中 cFos 表达增加，这表明该区域在 OE 小鼠对安非他命的过度行为反应中起作用。
