研究背景
甲基安非他命是台灣最嚴重的毒品濫用之一。當物質使用障礙（又稱作毒癮）患者接觸到與藥物相關的環境時，容易導致他們再度吸毒。臨床心理學家使用線索暴露療法治療成癮，是基於一種稱作「消除」的理論，讓患者反覆接觸藥物相關環境而不給予藥物獎勵，逐漸削弱對藥物相關環境所引起的刺激反應。不幸的是，消除並不會完全抹除對毒品的記憶，尋求毒品的行為再次發生。故此，復發成為臨床上治療毒癮的最大挑戰。在獎勵的神經迴路中，伏隔核核心（NAc core）調節對甲基安非他命的渴望孵化，並促進尋求毒品。伏隔核核心接受來自基底外側杏仁核（BLA）和前邊緣皮質（PL）的興奮性投射；其中，基底外側杏仁核參與對獎勵或厭惡刺激做出的行為反應和形成相關記憶；前邊緣皮質則是負責認知過程、決策和目標導向行為。然而，目前仍然不清楚基底外側杏仁核到伏隔核核心的神經迴路、前邊緣皮質到伏隔核核心的神經迴路以及伏隔核核心本身是否參與甲基安非他命相關記憶的消除和復發。
研究目的
研究宗旨是釐清參與在甲基安非他命的記憶消除和復發過程的神經迴路，開發出一個能夠破壞甲基安非他命記憶並有效預防復發的治療策略。
研究方法
我們使用條件位置偏好（CPP）建立小鼠復發模型並用來探討甲基安非他命記憶的消除和復發。使用逆行回溯珠（retrobeads）標定細胞本體，以確定投射到伏隔核核心的神經迴路。最後，我們使用化學遺傳學（chemogenetic）技術去操弄神經迴路的活性。
研究結果
成癮的老鼠原本偏好待在甲基安非他命配對室，經過消除訓練後，變成待在非藥物配對室比較久，表示他們獲得消除記憶。之後注射低劑量甲基安非他命，經過消除的小鼠又再度回到甲基安非他命配對室比較久。這些結果表明消除不會刪除藥物記憶，且仍然導致復發。因此，我們轉導AAV-CaMKIIα-hM4D(Gi)-mCherry到基底外側杏仁核並傳至伏隔核核心並調查在記憶被提取後，抑制基底外側杏仁核興奮性投射到伏隔核核心是否能刪除其記憶。結果顯示抑制在伏隔核核心中的基底外側杏仁核的谷氨酸能神經元末梢產生類似消除的效果，並減弱復發。接著，我們轉導AAV(rg)-hSyn-hM3D(Gq)-mCherry到伏隔核核心，評估其神經元是否參與甲基安非他命的復發。結果顯示在消除訓練後，活化伏隔核核心神經元能夠恢復甲基安非他命的記憶。然而，刺激基底外側杏仁核到伏隔核核心則無法喚起藥物記憶。結果表明活化伏隔核核心，而非基底外側杏仁核到伏隔核核心，足以誘發恢復甲基安非他命記憶。根據以上實驗結果顯示在沒有消除的情況下，在記憶被提取後，抑制基底外側杏仁核到伏隔核核心可以破壞甲基安非他命記憶。相反地，在有消除的情形下活化這條神經迴路卻無法喚起原本的甲基安非他命記憶。我們提出一個假設，即消除記憶抑制了原始藥物記憶的表達。先前研究表明伏隔核參與消除記憶的作用，為此調查伏隔核核心是否調節消除記憶，消除測試後在伏隔核核心注入蛋白質合成抑制劑──茴香黴素（Ani），並在隔天進行重測。結果顯示茴香黴素組恢復了甲基安非他命的記憶，表明在消除記憶被提取後，注入茴香黴素到伏隔核核心破壞了甲基安非命的消除記憶。在相似的實驗中，我們在前邊緣皮質轉導AAV-CaMKIIα-hM4D(Gi)-mCherry到伏隔核核心，調查前邊緣皮質到伏隔核核心這條神經迴路是否產生一樣的結果。結果顯示抑制在伏隔核核心中的前邊緣皮質的谷氨酸能神經元末梢未能破壞消除記憶。這些發現表明伏隔核核心，而非前邊緣皮質谷氨酸能投射到伏隔核核心，對於甲基安非他命的消除記憶是必要的。
研究重要性
在消除後，活化伏隔核核心足以恢復甲基安非他命的記憶。重複抑制伏隔核核心中的基底外側杏仁核的谷氨酸能神經元末梢導致與消除類似的藥物記憶減少。在提取消除記憶後，抑制伏隔核核心的蛋白質合成破壞了甲基安非他命的消除記憶。總結，伏隔核核心參與了甲基安非他命的消除和復發記憶。這些研究揭示了消除甲基安非他命記憶的神經迴路，可能為戒除毒癮開闢了一個有其前景的治療策略。

Background
In Taiwan, one of the most serious abused substances is methamphetamine (MeAM). When individuals with substance use disorder (SUD), also known as addiction, are exposed to drug-related environments, they easily engage in drug abuse again. Clinical psychologists use cue exposure therapy (CET) for addiction treatment which is based on the “extinction” theory. Repeatedly exposing patients to drug-related environments without providing drug rewards will gradually weaken the conditioned response to drug-related cues. Unfortunately, extinction does not eliminate drug memory, leading to the reoccurrence of drug-seeking behavior. Therefore, relapse remains the primary challenge in the clinical treatment of addiction. In the reward circuitry, the nucleus accumbens core (NAc core) mediates incubation of MeAM craving and facilitates drug-seeking behavior. The NAc core receives excitatory projections from the basolateral amygdala (BLA) and the prelimbic cortex (PL). The BLA is involved in behavioral responses to rewarding or aversive stimuli and the formation of related memories, while the PL is responsible for cognitive processes, decision-making, and goal-directed behaviors. However, it remains unclear whether the BLA-NAc core circuit, PL-NAc core circuit, and the NAc core itself are implicated in the extinction and reinstatement of MeAM-related memory.
Purpose
The study aims to identify the neural circuitry involved in the processes of extinction and reinstatement of MeAM-related memory and develop a therapeutic strategy to disrupt MeAM-related memory and effectively prevent relapse.
Methods
We established a reinstatement mouse model using conditioned place preference (CPP) to investigate extinction and reinstatement of MeAM-related memory. Retrobeads were employed to label cell bodies to identify the neural circuits projecting to the NAc core. Finally, we utilized chemogenetic techniques to manipulate the activity of the neural circuits.
Results
The addicted mice initially exhibited a preference for staying in the MeAM-paired compartment. After extinction training, they spent more time in the non-drug paired compartment, suggesting they had acquired extinction memory. After injecting a low dose of MeAM, the extinction mice returned to spending more time in the MeAM-paired compartment. These results indicate that extinction does not erase drug memory and still leads to relapse. Thus, we transduced AAV-CaMKIIα-hM4D(Gi)-mCherry into the BLA which transported to the NAc core to examine whether silencing excitatory projection from BLA to NAc core following memory retrieval affected MeAM-related memory. These results showed that the silencing of glutamatergic nerve terminals in the BLA within the NAc core mimicked extinction and attenuated priming effect. Next, we evaluated the involvement of the NAc core neuron in the reinstatement of MeAM-related memory by transducing AAV(rg)-hSyn-hM3D(Gq)-mCherry into the NAc core. These results showed that activation of the NAc core neuron reinstated MeAM-related memory after extinction. However, stimulation of the BLA-NAc core circuit failed to recall drug memory. The results demonstrate that activation of the NAc core, but not the BLA innervating the NAc core, is sufficient to induce the reinstatement of MeAM-related memory. Based on the above experimental results, it suggests that inhibition of the projection from the BLA to NAc core after memory retrieval disrupts MeAM-related memory in the absence of extinction. Conversely, activation of this circuit after extinction does not result in the recall of the original MeAM-related memory. We hypothesize that extinction memory suppresses the expression of the original drug memory. Previous studies indicate that the NAc is involved in extinction memory. To investigate whether the NAc core mediated extinction memory, infusing anisomycin (Ani), a protein synthesis inhibitor, into the NAc core after extinction test, and the retest was conducted on the following day. These results showed that MeAM-related memory was reinstated in Ani-treated group, suggesting that the Ani infusion to NAc core after retrieval of extinction memory blocks MeAM-related extinction memory. In the similar experiments, we transduced AAV-CaMKIIα-hM4D(Gi)-mCherry into the PL which transported to the NAc core to investigate whether the PL-NAc core circuit exhibits identical outcomes. The results showed that inhibition of glutamatergic transmission from the PL to the NAc core failed to disrupt extinction memory. These findings indicate that the NAc core, rather than the excitatory projection from the PL to the NAc core, is necessary for the MeAM-related extinction memory.
Significance
Activation of the NAc core neuron was sufficient to reinstate MeAM-related memory after extinction. Repetitive inhibition of excitatory projection from BLA to NAc core resulted in extinction-like reduction of MeAM-related memory. Inhibiting protein synthesis of the NAc core after extinction memory retrieval blocked MeAM-related extinction memory. To sum up, the NAc core is implicated in extinction and reinstatement of the MeAM-related memory. The study provides insights into the circuitry responsible for extinction of MeAM-related memory which may open a promising therapeutic strategy for stopping drug addiction.

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