College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei Province, Shijiazhuang, 050017, PR China.
Hunan Province People's Hospital, The First-Affiliated Hospital of Hunan Normal University, Changsha, 410081, PR China.
J Psychiatr Res. 2023 Jul;163:180-194. doi: 10.1016/j.jpsychires.2023.05.057. Epub 2023 May 17.
Posttraumatic 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.
We 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.
Fear 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.
These 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.
创伤后应激障碍（PTSD）是一种由应激事件引起的精神障碍，其特征是持久的恐惧记忆。伏隔核壳（NAcS）是调节与恐惧相关行为的关键脑区。小电导钙激活钾通道（SK 通道）在调节 NAcS 中棘神经元（MSNs）的兴奋性方面起着关键作用，但它们在恐惧冻结中的作用机制尚不清楚。
我们使用条件性恐惧冻结范式建立了创伤性记忆的动物模型，并研究了恐惧条件后小鼠 NAc MSNs 中 SK 通道的变化。然后，我们利用腺相关病毒（AAV）转染系统过表达 SK3 亚基，探讨 NAcS MSNs SK3 通道在条件性恐惧冻结中的功能。
恐惧条件激活了 NAcS MSNs，使其兴奋性增强，SK 通道介导的后超极化（mAHP）幅度减小。NAcS SK3 的表达也随时间呈时间依赖性降低。过表达 NAcS SK3 损害了条件性恐惧巩固，而不影响条件性恐惧表达，并阻断了恐惧条件引起的 NAcS MSNs 兴奋性和 mAHP 幅度的改变。此外，恐惧条件引起 NAcS MSNs 的 mEPSC、AMPA/NMDA 比值和膜表面 GluA1/A2 表达增加，而过表达 SK3 后恢复正常水平，表明恐惧条件引起的 SK3 表达减少通过促进 AMPAR 向膜的传递引起了突触后兴奋。
这些发现表明，NAcS MSNs SK3 通道在条件性恐惧巩固中起着关键作用，它可能影响 PTSD 的发病机制，使其成为治疗 PTSD 的潜在靶点。
