PDF(Pubmed)
Abstract：
Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits, and in particular their ability to distinguish between externally and self-generated activity patterns, is still largely unclear. To have experimental control over self-generated sensory feedback, we used a virtual reality environment in which the coupling between movement and visual feedback can be altered. We then used widefield calcium imaging to determine the cell type-specific functional effects of antipsychotic drugs in mouse dorsal cortex under different conditions of visuomotor coupling. By comparing cell type-specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex is long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is a selective alteration of long-range layer 5-mediated communication.
摘要：
精神病的特征在于大脑区分外部驱动的活动模式与自我生成的活动模式的能力减弱。抗精神病药物是一类对多种神经调质受体具有相对广泛结合亲和力的小分子,在人类中,可以预防或改善精神病。这些药物如何影响皮质回路的功能，特别是他们区分外部活动模式和自我活动模式的能力，基本上还不清楚。为了对自我产生的感官反馈进行实验控制，我们使用了虚拟现实环境，其中运动和视觉反馈之间的耦合可以改变。然后，我们使用宽场钙成像来确定抗精神病药物在不同视觉运动耦合条件下在小鼠背侧皮质中的细胞类型特异性功能作用。通过比较实验耦合到自生成视觉反馈的运动开始与未耦合的运动开始之间的细胞类型特异性激活模式，我们表明，在这两种情况下，深层皮质层被差异激活。然后，我们表明抗精神病药物氯氮平在运动开始时也主要在皮质深层破坏了视觉运动整合。鉴于皮层视觉运动整合的关键组成部分之一是远程皮质-皮质连接，我们测试了在背侧皮质活动模式的相关结构中是否可以检测到氯氮平的作用。我们发现氯氮平和另外两种抗精神病药物,阿立哌唑和氟哌啶醇，导致皮层区域之间第5层活动的相关性大大降低，并损害了视觉皮层中产生的视觉运动预测错误的传播。我们的结果与抗精神病药物的主要功能作用是远程5层介导的通讯的选择性改变的解释一致。
