Roles of nucleus accumbens shell small-conductance calcium-activated potassium channels in the conditioned fear freezing.
Roles of nucleus accumbens shell small-conductance calcium-activated potassium channels in the conditioned fear freezing.
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DOI：
10.1016/j.jpsychires.2023.05.057
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发表时间：
2023-05
影响因子：
4.8
通讯作者：
Minglong Zhang;Yixiao Luo;Jian Wang;Yufei Sun;B. Xie;Ludi Zhang;Bin Cong;Chunling Ma;D. Wen
中科院分区：
文献类型：
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作者：
Minglong Zhang;Yixiao Luo;Jian Wang;Yufei Sun;B. Xie;Ludi Zhang;Bin Cong;Chunling Ma;D. Wen
背景创伤后应激障碍（PTSD）是一种由压力事件引起的精神障碍，其特征是长时间的恐惧记忆。伏隔核壳（NAcS）是调节恐惧相关行为的关键大脑区域。小电导钙活化钾通道（SK通道）在调节NAcS中棘神经元（MSNs）的兴奋性中起关键作用，但其在恐惧冻结中的作用机制尚不清楚。方法采用条件性恐惧冻结模式建立创伤记忆动物模型，研究恐惧条件反射对小鼠NAc msn SK通道的影响。然后，我们利用腺相关病毒（AAV）转染系统过表达SK3亚基，并探索NAcS MSNs SK3通道在条件恐惧冻结中的功能。结果恐惧条件反射激活NAcS msn，使其兴奋性增强，降低了SK通道介导的中超极化（mAHP）振幅。NAcS SK3的表达也呈时间依赖性降低。NAcS SK3的过表达在不影响条件恐惧表达的情况下破坏了条件恐惧的巩固，并阻断了恐惧条件反射诱导的NAcS msn兴奋性和mAHP振幅的改变。此外，恐惧条件反射导致NAcS mnsmepsc、AMPAR/NMDAR比值和膜表面GluA1/A2表达的振幅升高，SK3过表达后恢复到正常水平，说明恐惧条件反射导致SK3表达的降低通过促进AMPAR向膜传递而引起突触后兴奋。结论NAcS MSNs - SK3通道在条件恐惧巩固中起关键作用，可能影响PTSD的发病机制，是治疗PTSD的潜在靶点。
BackgroundPosttraumatic stress disorder (PTSD), a psychiatric disorder caused by stressful events, is characterized by long-lasting fear memory. The nucleus accumbens shell (NAcS) is a key brain region that regulates fear-associated behavior. Small-conductance calcium-activated potassium channels (SK channels) play a key role in regulating the excitability of NAcS medium spiny neurons (MSNs) but their mechanisms of action in fear freezing are unclear.MethodWe established an animal model of traumatic memory using conditioned fear freezing paradigm, and investigated the alterations in SK channels of NAc MSNs subsequent to fear conditioning in mice. We then utilized an adeno-associated virus (AAV) transfection system to overexpress the SK3 subunit and explore the function of the NAcS MSNs SK3 channel in conditioned fear freezing.ResultsFear conditioning activated NAcS MSNs with enhanced excitability and reduced the SK channel-mediated medium after-hyperpolarization (mAHP) amplitude. The expression of NAcS SK3 were also reduced time-dependently. The overexpression of NAcS SK3 impaired conditioned fear consolidation without affecting conditioned fear expression, and blocked fear conditioning-induced alterations in NAcS MSNs excitability and mAHP amplitude. Additionally, the amplitudes of mEPSC, AMPAR/NMDAR ratio, and membrane surface GluA1/A2 expression in NAcS MSNs was increased by fear conditioning and returned to normal levels upon SK3 overexpression, indicating that fear conditioning-induced decrease of SK3 expression caused postsynaptic excitation by facilitating AMPAR transmission to the membrane.ConclusionThese findings show that the NAcS MSNs SK3 channel plays a critical role in conditioned fear consolidation and that it may influence PTSD pathogenesis, making it a potential therapeutic target against PTSD.