Chemogenetic activation of the mPFC alleviates impaired fear memory extinction in an animal model of PTSD
Chemogenetic activation of the mPFC alleviates impaired fear memory extinction in an animal model of PTSD
复制标题
mPFC 的化学遗传学激活可减轻 PTSD 动物模型中受损的恐惧记忆消退
DOI：
10.1016/j.pnpbp.2020.110090
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发表时间：
2021
影响因子：
5.6
通讯作者：
Morinobu Shigeru
中科院分区：
文献类型：
--
作者：
Omura Jun;Fuchikami Manabu;Araki Motoaki;Miyagi Tatsuhiro;Okamoto Yasumasa;Morinobu Shigeru
背景和目的尽管恐惧记忆消退（EFM）受损是创伤后应激障碍（PTSD）的标志症状，但造成这种损害的机制尚不清楚。据报道，内侧前额叶皮层 (mPFC) 中边缘下皮层 (IL) 的激活可以预测成功的恐惧消退，而功能性破坏该区域则会损害消退。我们检查了 IL 的化学遗传学激活是否可以减轻 PTSD 的单一长期应激 (SPS) 大鼠模型中受损的 EFM。方法采用情境恐惧调节范式对 IL 和边缘前 (PL) 兴奋性神经元进行化学遗传学激活，以评估 EFM。使用 32 多通道硅电极记录 IL 中的神经元活动。为了检查 mPFC 的组织学变化，通过 TUNEL 染色测量细胞凋亡。结果 IL 中兴奋性神经元（而非 PL）的化学遗传学激活增强了假大鼠中的 EFM，并导致 SPS 大鼠中 EFM 损伤减轻。在消退测试过程中观察到 SPS 大鼠 EFM 受损的缓解情况。给予氯氮平-n-氧化物后，SPS 大鼠 IL 中的神经元活性低于假手术大鼠。在 SPS 大鼠的 IL 中发现细胞凋亡增加。结论这些发现表明，至少部分由于 SPS 大鼠细胞凋亡的增加而导致 IL 兴奋反应的减少，导致 EFM 受损，并且消退训练期间的神经元激活可能有助于治疗 PTSD 患者的 EFM 受损。
Background and aimAlthough impaired extinction of fear memory (EFM) is a hallmark symptom of posttraumatic stress disorder (PTSD), the mechanisms underlying the impairment are unknown. Activation of the infralimbic cortex (IL) in the medial prefrontal cortex (mPFC) has been reported to predict successful fear extinction, whereas functionally disrupting this region impairs extinction. We examined whether chemogenetic activation of the IL could alleviate impaired EFM in a single prolonged stress (SPS) rat model of PTSD.MethodsChemogenetic activation of IL and prelimbic (PL) excitatory neurons was undertaken to evaluate EFM using a contextual fear conditioning paradigm. Neuronal activity in the IL was recorded using a 32-multichannel silicon electrode. To examine histological changes in the mPFC, apoptosis was measured by TUNEL staining.ResultsChemogenetic activation of excitatory neurons in the IL, but not the PL, enhanced EFM in sham rats and resulted in alleviation of EFM impairment in SPS rats. The alleviation of impaired EFM in SPS rats was observed during the extinction test session. Neuronal activity in the IL of SPS rats was lower than that of sham rats after clozapine-n-oxide administration. Increased apoptosis was found in the IL of SPS rats.ConclusionsThese findings suggest that a decreased excitatory response in the IL due, at least in part, to an increase in apoptosis in SPS rats leads to impaired EFM, and that neuronal activation during extinction training could be useful for the treatment of impaired EFM in PTSD patients.
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影响因子：
3.3
作者：
Royer, S;Paré, D
通讯作者：
Paré, D
影响因子：
2.5
作者：
MCCORMICK, DA;CONNORS, BW;PRINCE, DA
通讯作者：
PRINCE, DA
影响因子：
6.9
作者：
Bremner, JD;Vermetten, E;Charney, DS
通讯作者：
Charney, DS
影响因子：
4.6
作者：
Manvich DF;Webster KA;Foster SL;Farrell MS;Ritchie JC;Porter JH;Weinshenker D
通讯作者：
Weinshenker D
影响因子：
6.8
作者：
Bloodgood DW;Sugam JA;Holmes A;Kash TL
通讯作者：
Kash TL