PDF(Pubmed)
Abstract：
Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1-BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/-) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/- rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/- rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.
摘要：
行为灵活性受损是神经精神疾病的核心特征，并且与前纹状体电路的潜在功能障碍有关。Cyfip1的剂量减少是神经精神疾病的危险因素，正如其参与15q11.2（BP1-BP2）拷贝数变异所证明的那样：缺失携带者对CYFIP1的单倍体不足，并且精神分裂症的风险增加了两到四倍，自闭症和/或智力障碍。这里,我们使用最近开发的单倍体不足，对Cyfip1对行为灵活性和相关的额纹状体神经网络功能的贡献进行建模，杂合敲除大鼠系。在静息状态下使用多点局部场电位（LFP）记录，我们表明，Cyfip1杂合大鼠（Cyfip1+/-）港口破坏网络活动跨越内侧前额叶皮质，海马CA1区和腹侧纹状体。特别是,Cyfip1+/-大鼠显示伏隔核的影响减少，前额叶和海马输入的优势增加，与野生型对照相比。成年Cyfip1+/-大鼠能够学习单个提示-反应关联，然而，在不同杠杆和线索组合的灵活配对过程中，无法学习参与正面纹状体相互作用的条件辨别任务。一起,这些结果暗示Cyfip1在皮质-边缘-纹状体网络完整性的发育或维持中，进一步支持以下假设：该电路的改变有助于在包括精神分裂症和自闭症在内的神经精神疾病中观察到的行为不灵活。
