研究背景：
無法控制和持續的攻擊行為會對家庭和社會造成無法彌補的傷害。先前研究表明，暴力攻擊行為可以引起施暴者腦內的正向強化，進而導致大腦中獎勵迴路的形成。根據我們實驗室先前的研究，揭示了從腹側海馬迴(vHip)投射到伏隔核殼區(NAc shell)的神經路徑參與了攻擊性獎勵生成及調節。伏隔核被認為是大腦中的獎勵中心，其外殼區域參與情緒的調控。中型多棘神經元(MSN)是伏隔核中的主要投射神經元，分為表達多巴胺受體的D1神經元和D2神經元。因此我們假設從腹側海馬迴投射到伏隔核的神經迴路會影響多巴胺訊號傳導，進而有效調節獎勵性攻擊。
研究目的：
本研究探討多巴胺受體是否對獎勵性攻擊相關的神經迴路有特殊貢獻。
研究結果：
在這項研究中，我們首先建立了透過場地制約偏好(CPP)使離乳後社會隔離的小鼠誘導出攻擊行為的動物模型，以研究重複的攻擊經驗是否會促成獎勵性行為。具有攻擊經驗的社會孤立小鼠在五天訓練階段的每一天，進入有入侵者配對的條件房室。在最後測試階段，小鼠在入侵者配對房室比在沒有入侵者配對房室度過更長的時間。結果表明，小鼠對與攻擊性相關的房室表現出更強的偏好，證實連續幾天的攻擊性經驗會促使獎勵相關特性在大腦形成。在沒有入侵者的情況下，我們進一步證實小鼠會將攻擊經驗與環境連結，只對有攻擊經驗的房室產生偏好。為了此種現象是否受到多巴胺受體的調控，我們在訓練階段的每一天離開入侵者配對房室時，透過顯微注射分別將多巴胺D1受體拮抗劑或多巴胺D2受體拮抗劑馬上注入伏隔核殼區。首先我們將SCH39166(多巴胺D1受體拮抗劑)注入，結果顯示經過SCH39166處理的小鼠在與攻擊經驗相關的房室中度過的時間顯著增加，表明D1受體可能不參與與獎勵性攻擊相關的神經迴路。然而，在伏隔核殼區注入雷氯必利(多巴胺D2受體拮抗劑)後，對入侵者配對房室的偏好沒有顯著差異，這表明伏隔核殼區中的多巴胺D2型MSN可能涉及獎勵性攻擊的迴路。同時我們也觀察到小鼠在注射雷氯必利後的攻擊行為沒有顯著差異，這意味注射雷氯必利並不影響小鼠的攻擊行為。接著我們使用雷氯必利與化學遺傳學結合，研究雷氯必利是否可以消除小鼠因活化腹側海馬迴投射到伏隔核殼區迴路而誘導出的獎勵性攻擊。在CPP實驗進行的三周前，我們將AAV(rg)-hSyn-hM3D(Gq)-mCherry轉導到社會隔離小鼠大腦內的伏隔核殼區，以模擬腹側海馬迴投射到伏隔核殼區迴路的活化表現。在每日訓練階段，要進入入侵者配對房室的15分鐘前，將氯氮平-N-氧化物(CNO)顯微注射至伏隔核殼區。而在離開入侵者配對房室後馬上以腹腔注射的方式注入雷氯必利。結果表明，腹腔注射雷氯必利不能抑制社會隔離小鼠以化學遺傳學活化所誘導出的獎勵性攻擊。我們的實驗結果表明，伏隔核殼區中的多巴胺D2型MSN參與獎勵性攻擊的神經迴路，而非多巴胺D1型MSN。
研究結論：
我們的研究強調了伏隔核殼區中的多巴胺D2型MSN在調節攻擊相關獎勵行為中的重要作用，為攻擊性獎勵背後的神經機制提供了新的見解。

Background:
Uncontrolled and persistent aggressive behavior can cause irreparable harm to family and society. Previous research has shown that violence can elicit positive reinforcement in perpetrators, leading to the formation of reward circuitry in the brain. According to our previous studies, we have revealed the involvement of the pathway from the ventral hippocampus (vHip) projecting to the nucleus accumbens shell (NAc shell) in aggression-related rewards. The nucleus accumbens is recognized as the reward center in the brain, and its shell region participates in emotional behavior. Medium spiny neurons (MSNs) are primarily the projection neurons in the NAc and are divided into those expressing dopamine receptors D1 and D2. Thus, we hypothesize that dopamine signaling from the vHip to the NAc shell may effectively influence the generation of reward aggression.
Purpose:
This study examines whether dopamine receptors specifically contribute to the neural circuitry of reward-related aggression.
Results:
In this study, we first established a conditioned place preference (CPP) animal model in isolation-induced aggression mice to investigate whether repeated aggressive experience induced rewarding. The socially isolated (SI) mice with aggressive experiences stayed in the chamber with an intruder (as the pairing chamber) for five days. SI mice spent a longer duration in the pairing chamber than in the unpairing chamber during the test phase. The results showed that mice exhibited a stronger preference for the chamber associated with aggression, confirming that consecutive days of aggressive experiences promote rewarding properties. In the absence of intruders, we further confirmed that mice associated aggression experience with the environment, developing a preference only for chambers where they had aggressive experiences. To investigate whether this phenomenon is regulated by dopamine signaling, we injected dopamine D1 receptor (D1R) or dopamine D2 receptor (D2R) antagonists into the NAc shell, respectively, via microinjection after leaving the intruder-paired chamber during the daily training phase. First, we infused SCH39166, a D1R antagonist, into NAc shell, the data showed that the time spent by mice treated with the SCH39166 in the chamber associated with aggressive experiences was significantly increased, suggesting that the D1 receptor may not be involved in the neural circuits related to aggression-associated reward. However, after the intra-NAc shell infusion of Raclopride, a D2R antagonist, during training phase, there was no significant difference in the preference for the intruder-paired in the Raclopride microinjection group, suggesting that D2-type MSNs in NAc may involve the formation of aggressive rewards. At the same time, we also observed that there was no significant difference in the aggressive behavior of mice after injecting Raclopride, which means that injecting Raclopride does not affect the aggressive behavior of mice. Next, we use Raclopride combined with chemogenetic to investigate whether Raclopride can eliminate aggressive reward induced by activation the vHip-NAc circuit in mice. We transduced AAV(rg)-hSyn-hM3D(Gq)-mCherry into NAc shell of the SI mice before the CPP training three weeks to mimic the activation of vHip-NAc shell neural circuit. During the training phase, clozapine-N-oxide (CNO) were microinjected into NAc shell before the SI mice placed in intruder-paired chamber 15 minutes every training day. The results showed that intraperitoneal injection of Raclopride could not inhibit aggression reward induced by chemogenetic activation in the SI mice. Our results suggested that D2-type MSNs in the NAc shell are involved in aggressive reward circuit, rather than D1-type MSNs.
Significance:
Our study highlights the significant role of D2-type MSNs in the NAc shell in modulating aggression-related reward behaviors, provide new insights into the neural mechanisms underlying aggressive reward.

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