Patrono Enrico, Hrůzova Karolina, Svoboda Jan, Stuchlík Aleš
Institute of Physiology of the Czech Academy of Sciences, Videnska, 1830, 142 20 Prague 4, Czech Republic.
Institute of Physiology of the Czech Academy of Sciences, Videnska, 1830, 142 20 Prague 4, Czech Republic; Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic.
Schizophr Res. 2023 Feb;252:198-205. doi: 10.1016/j.schres.2022.12.047. Epub 2023 Jan 17.
Schizophrenia research has increased in recent decades and focused more on its neural basis. Decision-making and cognitive flexibility are the main cognitive functions that are impaired and considered schizophrenia endophenotypes. Cognitive impairment was recently connected with altered functions of N-methyl-d-aspartate (NMDAR) glutamatergic receptors, which increased cortical activity. Selective NMDAR antagonists, such as MK-801, have been used to model cognitive inflexibility in schizophrenia. Decreased GABAergic inhibitory activity has been shown elsewhere with enhanced cortical activity. This imbalance in the excitatory/inhibitory may reduce the entrainment of prefrontal gamma and hippocampal theta rhythms and result in gamma/theta band de-synchronization. The current study established an acute MK-801 administration model of schizophrenia-like cognitive inflexibility in rats and used the attentional set-shifting task in which rats learned to switch/reverse the relevant rule. During the task, we used in vivo optogenetic stimulations of parvalbumin-positive interneurons at specific light pulses in the prefrontal cortex and ventral hippocampus. The first experiments showed that acute dizocilpine in rats produced schizophrenia-like cognitive inflexibility. The second set of experiments demonstrated that specific optogenetic stimulation at specific frequencies of parvalbumin-positive interneurons in the prefrontal cortex and ventral hippocampus rescued the cognitive flexibility rats that received acute MK-801. These findings advance our knowledge of the pivotal role of parvalbumin interneurons in schizophrenia-like cognitive impairment and may guide further research on this severe psychiatric disorder.
近几十年来，精神分裂症的研究有所增加，并且更多地聚焦于其神经基础。决策和认知灵活性是主要的认知功能，它们受到损害并被视为精神分裂症的内表型。最近，认知障碍与N-甲基-D-天冬氨酸（NMDAR）谷氨酸能受体功能改变有关，这种改变增加了皮层活动。选择性NMDAR拮抗剂，如MK-801，已被用于模拟精神分裂症中的认知灵活性受损。在其他地方已经表明，GABA能抑制活动的降低伴随着皮层活动的增强。这种兴奋/抑制的失衡可能会减少前额叶γ波和海马θ波节律的同步，并导致γ/θ波段去同步。本研究建立了大鼠精神分裂症样认知灵活性受损的急性MK-801给药模型，并使用了注意力转换任务，即大鼠学会切换/反转相关规则。在任务过程中，我们在特定光脉冲下对前额叶皮层和腹侧海马中的小白蛋白阳性中间神经元进行了体内光遗传学刺激。第一个实验表明，大鼠急性给予地佐环平会产生精神分裂症样的认知灵活性受损。第二组实验表明，对前额叶皮层和腹侧海马中特定频率的小白蛋白阳性中间神经元进行特定的光遗传学刺激，挽救了接受急性MK-801的大鼠认知灵活性。这些发现推进了我们对小白蛋白中间神经元在精神分裂症样认知障碍中关键作用的认识，并可能为进一步研究这种严重精神疾病提供指导。
