藍斑核抑制性中間神經元在小鼠驚嚇反應與前刺激抑制行為的角色

Abstract

藍斑核（locus coeruleus, LC）神經元主要分泌正腎上腺素（noradrenaline, NA），並且廣泛投射於中樞神經系統，已知其細胞放電型態轉換，持續性（tonic）與相位性（phasic activation），對認知行為有適應性增益（adaptive gain）作用。持續性放電喚醒個體並使之敏銳於環境刺激；而當訊息統合後，前於任務執行的相位性放電能夠過濾無關刺激，進而優化表現。此系統的受損也已知關乎許多神經失調病徵，例如焦慮與憂鬱、阿茲海默症與帕金森氏症等病症。儘管如此，兩種放電型態轉換的細胞機制仍未被完全了解。作為了解感覺動作閾控（sensorimotor gating）常用的一項前注意訊息處理（preattentive information processing）指標，前刺激抑制作用（pre-pulse inhibition）越強，過濾不相干訊息效率越高。過去研究指出以藥理操作興奮藍斑核的持續性放電，會減弱前刺激抑制作用。實驗室研究亦發現當以化學遺傳學（chemogenetic）方法降低藍斑核旁丙胺基丁酸抑制性中間神經元（GABAergic inhibitory interneuron）之活性，會增加藍斑核神經元的相位性放電。此篇研究使用前述化學遺傳學抑制方法提升了前刺激抑制作用，並排除此行為改變源於其他因素的可能性，例如所施打藥物在其他腦區造成的預期外影響，或是此操作損及一般運動能力進而導致行為變化的可能性，亦證實了藍斑核確實參與此行為變化。因此，此研究顯示老鼠會因抑制丙胺基丁酸抑制性中間神經元，提升藍斑核相位性放電，傾向注意力更集中的行為。換句話說，此抑制性中間神經元參與在相位性到持續性放電的轉換中。

Global innervation of locus coeruleus-noradrenaline (LC-NA) system to central nervous system modulates functions correlated to LC firing patterns, tonic and phasic activities. The tonic activation regulates wakefulness and alertness whereas phasic activation responds to environmental stimuli and optimizes task-related performance. Nevertheless, the cell mechanism underlying the integration of two activations remains largely unknown. The suppression of inhibitory interneurons (IntNs) in peri-LC region causing a higher frequency of LC phasic activation has be provided in our lab with designer-receptor-exclusively-activated-by-designer-drug (DREADD). The hM4Di receptor, an inhibitory DREADD, would specifically express on the inhibitory IntNs with injection carried by Cre-dependent adeno-associated virus (AAV) into vesicular GABA transporter (VGAT)-Cre knock-in mice. Thus, this study attempts to offer a behavioral explanation to this chemogenetic operation. Pre-pulse inhibition (PPI) is a robust operational measurement of sensorimotor gating, a preattentive form of information-processing to filter irrelevant information. Previous study has shown that pharmacological activation of tonic LC activity decreased PPI. In this study, we reported an enhancement of PPI with DREADD. And excluded are the possible effects from virus infection, CNO offsite bindings, and the offsite chemogenetic effect owing to virus leakage. Meanwhile, the increased PPI is not secondary to general motor deficits. Furthermore, the involvement of LC is also confirmed with 6-OHDA. These results demonstrate that the mice showed more attentive possibly due to the enhanced phasic activation when local inhibitory IntNs in the LC were suppressed.