研究生: |
錢柏宇 Chien, Po-Yu |
---|---|
論文名稱: |
探討由背側縫核投射至海馬迴之神經迴路並海馬迴中血清素1B受體如何調控衝動型暴力行為 Hippocampal 5-HT1B Receptor mediates Impulsive Aggression through Neural Input from the Dorsal Raphe |
指導教授: |
簡伯武
Gean, Po-Wu |
學位類別: |
碩士 Master |
系所名稱: |
醫學院 - 藥理學研究所 Department of Pharmacology |
論文出版年: | 2020 |
畢業學年度: | 108 |
語文別: | 英文 |
論文頁數: | 72 |
中文關鍵詞: | 衝動型暴力行為 、血清素1B受體 、腹側海馬迴 、背側縫核 |
外文關鍵詞: | Impulsive aggression, 5-HT1B receptor, Ventral hippocampus, Dorsal raphe |
相關次數: | 點閱:66 下載:1 |
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研究動機:
當生活中遇到急性的壓力或刺激時,具有衝動型暴力行為傾向的病人往往無法控制怒氣,因而容易表現出與刺激程度不成比例的情緒爆發,這種肢體或言語上的暴力行為是陣發性暴怒症的核心症狀之一。
目前對於陣發性暴怒症的治療上,第一線藥品是選擇性血清素再回收抑制劑,這樣的治療策略暗示腦中血清素活性的變化,在調節衝動型暴力行為上,扮演著一個重要的角色。另外,報導曾指出人類血清素1B受體的基因多型性以及海馬迴的構造變化,與陣發性暴怒症具有相關性。
然而其細部機轉以及相關神經迴路在中間的功能仍存在著糢糊待釐清的地方。
研究目的:
本研究旨在探討位於腹側海馬迴中的血清素1B受體,以及其神經迴路,是如何調控衝動型暴力行為。
研究結果:
為了模擬人類因幼年時期被家人或社會孤立,而造成青少年或成年時衍生出的衝動型暴力行為,我們以離乳後進行社會隔離的小鼠模式來進行研究。
經歷社會隔離的小鼠,在給予腳掌電擊模擬急性壓力後,與群居小鼠相比,攻擊行為有顯著地提高。由海馬迴內給予血清素1B受體致效劑:anpirtoline或CP-93129後,則顯著降低了隔離小鼠的攻擊行為。相反的,如果事先給予血清素1B受體拮抗劑:SB-224289,則阻斷了CP-93129的作用。
為了觀察血清素1B受體訊息傳導路徑對於暴力行為的影響,我們使用PKA抑制劑:H89或Rp-8-Br-cAMPS。給藥後,小鼠的攻擊行為表現出降低的現象,有趣的是,如立即再給予CP-93129,則CP-93129降低攻擊行為的效果會較不顯著。
中樞神經系統裡製造血清素的主要腦區為縫核,許多證據指出由中縫核有神經迴路投射至海馬迴,為了探討此神經迴路在衝動型暴力行為所扮演的角色,首先,我們在隔離小鼠的中縫核打入AAV5-hSyn-hM3D(Gq)-mCherry,給予時間讓病毒順行生長後,我們由免疫螢光分析中發現在小鼠腹側海馬迴中有mCherry的表現,代表中縫核-腹側海馬迴神經投射的存在。接著我們嘗試活化這條迴路,訝異的是,以致效劑CNO打入海馬迴後,小鼠的攻擊行為並沒有顯著改變;除此之外,腹側海馬迴中的c-Fos表現,並不會因著打入CNO而有變化;接著,我們在隔離小鼠的腹側海馬迴打入AAVrg-hSyn-hM3D(Gq)-mCherry,給予病毒時間以逆向生長後,再從中縫核打入CNO,一致的是,以CNO活化中縫核-腹側海馬迴的投射後,小鼠的攻擊行為以及腹側海馬迴中c-Fos的表現量也沒有顯著改變,此結果暗示腹側海馬迴對衝動型暴力行為的調控,不是來自中縫核的神經投射。
接著我們好奇另一條證據較少的迴路:背側縫核投射至海馬迴的神經迴路,與衝動型暴力行為是否存在相關性。首先,我們將AAV5-hSyn-hM3D(Gq)-mCherry施打進隔離小鼠的背側縫核中,給予病毒時間以順行生長後,我們以免疫螢光分析中發現腹側海馬迴中同樣具有mCherry的表現,證實此迴路確實存在。驚訝的是,以CNO打進小鼠的腹側海馬迴後,小鼠的攻擊行為有顯著的降低;同時這樣的降低會因為先行施打SB-224289而被消除。免疫螢光分析中指出,若給予CNO活化背側縫核-腹側海馬迴路徑,會使小鼠腹側海馬迴的c-Fos表現量顯著降低,代表抑制了該腦區的神經活性。最後,我們將AAVrg-hSyn-hM3D(Gq)-mCherry施打進隔離小鼠的腹側海馬迴,給予病毒時間以逆行生長後,再以CNO注入背側縫核,行為實驗顯示施打藥品的組別,其攻擊行為有顯著降低,然而若先行給予SB-224289,此降低的效果會被抵銷。免疫螢光分析同樣發現給予CNO能顯著降低電擊後小鼠腹側海馬迴中的c-Fos表現亮。
研究結論:
我們的實驗結果暗示背側縫核-腹側海馬迴的神經迴路,參與在調控社會隔離小鼠因壓力而產生的攻擊行為中;並且在衝動型暴力行為的治療上,血清素1B受體會是一個有潛力的標的。
Background:
Impulsive aggression is characterized by outbursts of rage and violence. It is a core symptom of intermittent explosive disorder (IED). Currently, the first-line medication for impulsive aggression is selective serotonin reuptake inhibitor (SSRI) suggesting changing in serotonin (5-HT) activity is involved in the regulation of impulsive aggression. However, the neural circuitry and underlying mechanism remain elusive.
Purpose:
This study aims to investigate the role of 5-HT1B receptor (5-HT1BR) within ventral hippocampus (vHip) as well as neural circuitry underlying impulsive aggression.
Results:
The post-weaning social isolation (SI) model in mice was established to mimic early-childhood maltreatment in human. Mice experienced SI showed increased attack number after receiving footshocks compared to group housing (GH) mice. The increased attack behavior was reversed after bilateral hippocampal microinjection of the 5-HT1BR agonists anpirtoline or CP-93129. Inversely, pretreatment with a 5-HT1BR antagonist SB-224289 blocked the response of SI mice to CP-93129. Moreover, application of PKA inhibitors H89 or Rp-8-Br-cAMPS reduced the attack behavior and importantly occluded the effect of 5-HT1BR agonist. SI mice showed reduction in response to anti-aggressive effect of CP-93129. The serotonergic neurons are mostly innervated by raphe nucleus (RN). To investigate the functional role of neural circuitry from RN to vHip in impulsive aggression, firstly, we transduced AAV5-hSyn-hM3D(Gq)-mCherry into the median raphe (MR) of the SI mice. mCherry expression was found in vHip by immunofluorescence assay (IF), suggesting a neural circuitry from the MR output to the vHip. Surprisingly, microinjection of Clozapine-N-Oxide (CNO) into the vHip failed to decrease attack behavior in SI mice. Additionally, c-Fos expression in the vHip showed no significant change in the CNO-injected mice. In parallel, we transduced AAVrg-hSyn-hM3D(Gq)-mCherry into the vHip and implanted cannulas into the MR. Consistently, infusion of CNO into the MR showed no influence in attack behavior nor c-Fos expression in the vHip, indicating that MR-vHip neural circuit plays a relative non-significant role in aggressive modulation. Accordingly, AAV5-hSyn-hM3D(Gq)-mCherry was transduced into the dorsal raphe (DR) of the SI mice. Interestingly, CNO infusion into the vHip reduced the stress-induced attack behavior in hM4D(Gq)-expressing mice and the effect was abolished by SB-224289 pretreatment. In addition, c-Fos expression in the vHip was significantly decreased in the CNO-injected mice, indicating that activation of DR neurons effectively inhibits neural activity of the vHip. Correspondingly, AAVrg-hSyn-hM3D(Gq)-mCherry was bilaterally transduced into the vHip and cannulas were implanted into the DR of the SI mice. Infusion of CNO into the DR resulted in the inhibition of stress-provoked attack behavior and c-Fos expression in the vHip. Remarkably, the anti-aggressive effect of CNO was also abolished by SB-224289 pretreatment.
Conclusion:
Our results suggest that the DR-vHip pathway is critical for the regulation of stress-provoked attack behavior in SI mice. Targeting 5-HT1BR could be a new strategy for the treatment of impulsive aggression.
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