- 學位論文
探索思覺失調症候選基因AKT1影響GABA神經元亞型在酬賞型決策作業扮演之角色
Investigate the role of AKT1, a schizophrenia candidate gene, on GABAergic neuron subtypes in reward-based decision making task in male mice
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摘要
認知缺損為思覺失調症重要的臨床症狀，但現行治療效果不彰，可能來自於我們對病患的認知缺損了解不夠徹底。過去研究指出病患在涉及執行功能與酬賞學習的決策作業上有所缺損。此外，近來許多研究指出AKT1這個思覺失調症之候選基因和認知缺損高相關，可能由於其涉及神經傳導物和神經活動異常導致。但，AKT1基因缺損和GABA神經傳導物系統異常是否和思覺失調症認知缺損有關，仍是未解之謎。故，本研究目標即為了解AKT1是否影響相關腦區神經活動，或特定GABA神經元亞型表現量，並進一步導致酬賞型決策作業缺損。首先，使用AKT1缺損小鼠發現其異常行為表現，及在背內側紋狀體發現神經活動異常。又，觀察到其在背內側紋狀體中，GABA神經元亞型: parvalbumin的表現量下降。所以我們再進一步使用一般小鼠，使其Akt1在背內側紋狀體表現量下降，發現行為異常模式與AKT1缺損小鼠缺損老鼠很相似。最後，我們操弄Akt1在parvalbumin神經元之表現，發現Akt1此特定神經元表現下降，亦會產生相似之缺損。這顯示，AKT1之缺損主要影響到背內側紋狀體parvalbumin神經元之表現量，造成神經活動異常，進一步導致酬賞學習決策作業表現異常。
並列摘要
The treatment of cognitive impairment in patients with schizophrenia is of great importance due to unmet medical needs. Previous research has shown that schizophrenia affects reward-based decision making, which are related to executive functions and motivation/reinforcement learning. Increasing evidence implicates the involvement of AKT1, a schizophrenia candidate gene, in cognitive impairment of schizophrenia, which involves neuromodulation and neuronal connectivity. However, the impact of AKT1 deficiency on GABAergic neurons has been less explored so far. It is of great interest to investigate the importance of AKT1 on GABAergic neuron subtypes, especially in reward-based decision making. Thus, taking advantage of Akt1 heterozygous mutant mice (Akt1+/-) as a mouse model of schizophrenia, our study aimed to investigate the involvement of Akt1 in GABAergic neuron function and its impact on brain activity in relevant brain regions in a probabilistic decision-making task. First, Akt1+/- mice exhibited a distinct behavioral pattern during the task, and an altered neural activity in DMS. Then, Akt1+/- mice exhibited a region-specific reduction of PV, and a selective decrease of Akt1 was also found in PV neurons. Furthermore, DMS-specific knockdown Akt1 mice reproduced the alterations in Akt1+/- mice. Finally, we found that mice with conditional Akt1 knockout in parvalbumin (PV), not in GABAergic neuron (GAD), recapitulated behavioral alterations in Akt1+/- mice. Akt1+/- mice, DMS-specific knockdown Akt1 mice, and conditional knockout mice of Akt1 in PV neurons all showed an increase in the lose-stay rate for high reward choice and no-reward learning. Furthermore, all mice demonstrated a decrease in choice consistency. These findings suggest that Akt1 affects PV neurons, particularly in DMS, potentially influencing distinct cognitive processes.
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