研究動機:
　　根據精神疾病診斷準則手冊第五版，藥物成癮(物質使用障礙症)是一種慢性疾病且容易因為一些和當時服用藥物相關的環境線索(吸毒的同伴、毒品吸食器、吸食場所)誘發他們再次去使用藥物。臨床上針對治療藥物成癮的患者主要是針對在預防戒斷後成癮復發。中腦邊緣系統會參與在調控獎賞行為，例如: 物質(藥物)成癮。
　　伏隔核是大腦當中負責調控獎賞行為的腦區，在結構上可以細分為中間的核心(core)以及側邊的殼(shell)，其中，伏隔核核心是主要會參與在因為環境線索誘導所引起的尋找藥物行為中。
　　杏仁核會對正向或負向(獎賞或厭惡)刺激做出反應，並且和伏隔核之間有連結。然而，至今仍然不太清楚由杏仁核投射至伏隔核核心之神經迴路在調控藥物成癮上面的機轉。
研究目的:
　　觀察由杏仁核投射至伏隔核核心之神經迴路是否會調控甲基安非他命的成癮以及其記憶再固化過程，藉此發展出一個能有效破壞甲基安非他命的相關記憶的治療方針。
研究方法:
　　我們利用場地制約偏好 (CPP) 動物模型來研究藥物和環境相關記憶間的關聯。為了研究杏仁核投射至伏隔核核心之神經迴路是如何調控甲基安非他命成癮的，我們先利用Red RetroBeads來確認這條神經迴路，接著再利用化學遺傳學 (chemogenetic) 的技術來操弄神經活性。
研究結果:
　　實驗結果表明，經過甲基安非他命訓練後，小鼠會偏好待在和藥物配對的箱子當中較久，這表示小鼠獲得了甲基安非他命的相關環境記憶，然而當藥物記憶被提取後，給予茴香黴素，會破壞藥物記憶的再固化並導致甲基安非他命的環境相關記憶喪失。
　　接下來，想探討從杏仁核傳遞到伏隔核核心的這條神經迴路是否會參與在調控甲基安非他命成癮行為當中，我們在小鼠的伏隔核核心中打入AAV(rg)-hSyn-hM4D(Gi)-mCherry，讓病毒逆行生長至杏仁核，可以發現在記憶被提取後，將氯氮平N-氧化 (CNO) 打入表現hM4D(Gi)的老鼠杏仁核中，來抑制神經活性，使杏仁核以及伏隔核核心的c-Fos表現量下降，樹突棘數量減少，並且破壞甲基安非他命相關環境記憶。除此之外，透過免疫螢光染色圖可以發現在杏仁核中有高比例表達mCherry的細胞和用來標定興奮性神經細胞的CaMKIIα重疊，此結果暗示在杏仁核當中的谷氨酸神經元能投射到伏隔核核心，且調控了甲基安非他命相關記憶的再固化。
　　為了探討杏仁核當中的CaMKIIα神經元參與的階段，我們將帶有CaMKIIα promoter並表現hM4D(Gi)-mCherry的病毒 (AAV5-CaMKIIα-hM4D(Gi)-mCherry) 打入杏仁核，讓病毒順行生長到伏隔核核心，一致的是，在記憶被提取後，將氯氮平N-氧化 (CNO) 打入表現CaMKIIα-hM4D(Gi) 的老鼠伏隔核核心中，抑制了傳入伏隔核核心的杏仁核神經末梢，導致杏仁核以及伏隔核核心的c-Fos表現量下降，樹突棘數量減少，並且使甲基安非他命相關環境記憶喪失。因此可以知道杏仁核中的谷氨酸能神經元確實參與在調控甲基安非他命的環境相關記憶中。
　　先前許多文獻提及記憶提取後會進行再固化，此過程約略持續六個小時，若是在非記憶進行再固化的時間或是沒有經過記憶提取下給予茴香黴素，則無法破壞記憶，因此為了探討從杏仁核傳遞到伏隔核核心的這條神經迴路是否是透過調控記憶再固化來影響藥物相關記憶。我們在非記憶再固化的時間給予CNO。實驗結果表明在記憶提取後18個小時，在表現CaMKIIα-hM4D(Gi) 的老鼠伏隔核核心中打入氯氮平N-氧化 (CNO)，無法破壞甲基安非他命的環境相關記憶。此外，我們在小鼠的杏仁核中打入AAV5-CaMKIIα-hM3D(Gq)-mCherry，讓病毒順行生長至伏隔核核心，給予氯氮平N-氧化 (CNO) 活化這條迴路可以模擬記憶再固化過程，這些結果表示由杏仁核傳遞到伏隔核核心的這條神經迴路的活性確實會調控甲基安非他命相關記憶的再固化。最後，即使活化這條迴路也無法逆轉茴香黴素造成的記憶破壞。
研究重要性:
　　整體而言，我們的研究結果表明從杏仁核傳遞到伏隔核核心的這條神經迴路，參與在調控甲基安非他命相關環境記憶中；破壞藥物記憶的再固化可以藉由抑制杏仁核中谷氨酸能神經元傳遞到伏隔核核心的活性或破壞其蛋白質合成。針對甲基安非他命的成癮患者中，調控杏仁核傳遞到伏隔核核心的這條神經迴路可能發展出有效的治療方針。

Background:
　　In the Diagnostic and Statistical Manual of Mental Disorder (DSM-V), substance use disorder, also known as drug addiction, defines as a chronic condition. Addicted individual might relapse when exposing the drug-associated environmental cues (people, object, and place). The major clinical challenge for drug addiction therapies is how to prevent from relapses after withdrawal. Additionally, the mesolimbic pathway considerably regulates reward-associated behaviors such as substance (drug) addiction. One of the functions of the nucleus accumbens (NAc) is modulated the reward behavior and is classified into two anatomical regions: core and shell. Especially, the NAc core is participated in drug-seeking behavior triggered by environmental cues. The basolateral amygdala (BLA) responds to both positive and negative stimuli (reward or aversive) and connects with the NAc. However, little is known about the circuitry between the BLA to NAc core involves in the addiction mechanism.
Purpose:
This study aims to investigate the BLA-NAc core circuitry underlying methamphetamine (MeAM) addiction as well as addictive memory reconsolidation process then develop a potential strategy for disrupting the MeAM-related memory.
Methods:
　　Here, we utilized the conditioned place preference (CPP) procedure to establish a relationship between MeAM and environmental cue-dependent memory. To investigate the BLA-NAc core circuit underlying MeAM addiction, we applied the Red RetroBeads to confirm this neuronal pathway and then utilized chemogenetic technique to modulate neural activity.
Results:
After the MeAM-training test, the addicted mice stayed in the drug-paired environment for a relatively long time. That means they acquired the MeAM-related environmental memory. However, treatment with anisomycin (ANI) after the retrieval test, the memory reconsolidation process was disrupted and accompanied by MeAM-related memory loss. Next, we investigated the BLA-NAc core pathway underlying MeAM addiction. We transduced AAV(rg)-hSyn-hM4D(Gi)-mCherry into NAc core and retrogradely transported to the BLA. The intra-BLA infusion of clozapine-N-Oxide (CNO) in hM4D(Gi)-expressing mice after memory retrieval caused MeAM-related memory loss. Additionally, c-Fos expression and dendritic spines in the BLA and NAc core markedly attenuated in the CNO-treated mice, indicating that inactivation of neural activity leads to disrupt the MeAM-related memory. Furthermore, the high proportion of mCherry-positive cells expressed CaMKIIα marker of excitatory neuron in BLA, suggesting that glutamatergic BLA neurons projecting to the NAc mediates MeAM-related memory during the reconsolidation process. Then, to investigate the function of BLA CaMKIIα neurons underlying MeAM addiction. We transduced AAV5-CaMKIIα-hM4D(Gi)-mCherry into BLA and anterogradely transported to the NAc core. The CaMKIIα-hM4D(Gi)-expressing mice were infused CNO into NAc core after memory retrieval. The results demonstrate that the hM4D(Gi)-mediated inhibition of BLA nerve terminals in the NAc core disrupts MeAM-related memory. Consistently, CNO infusion attenuated c-Fos expression and dendritic spines in the BLA and NAc core, suggesting glutamatergic neurons involve in regulating MeAM-related memories. Previous studies indicate that the memory reconsolidation process persists for 6 hours. Treatment with ANI without memory retrieval or beyond the reconsolidation time window has no effect. To investigate whether the BLA-NAc core pathway mediates MeAM-related memories through the process of memory reconsolidation. CNO was infused outside the reconsolidation time window. The results demonstrate that CNO infusion into the NAc core of hM4D(Gi)-expressing mice at the post-18 h of retrieval test has no effect. Moreover, we transduced AAV5-CaMKIIα-hM3D(Gq)-mCherry into BLA and anterogradely transported to the NAc core. We found that activation of the BLA-NAc core pathways mimicked the memory reconsolidation process, suggesting that the activity of the BLA-NAc core circuit indeed mediates the reconsolidation process of MeAM-related memory. Finally, activation of the BLA-NAc core failed to reverse ANI-induced effect.
Significance:
To conclude, the BLA projection to the NAc core regulated the MeAM-related memory. Inactivation of the BLA glutamatergic afferents to the NAc core or disruption of protein synthesis by ANI after memory retrieval disrupted the MeAM-related memory's reconsolidation. Targeting the BLA-NAc core circuit might develop to a potential therapy for the treatment of MeAM addicted individuals.

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