From the Peking University, Shenzhen Graduate School, School of Chemical Biology and Biotechnology, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Shenzhen 518055, Peoples R China (Zhang, Wang, Zhou); the Precision Medicine Centre, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China (Ju); and the Pediatric Neurology, Shenzhen Children’s Hospital, Shenzhen, 518038, China (Zhang, Liao).
J Psychiatry Neurosci. 2021 Jun 2;46(3):E390-E401. doi: 10.1503/jpn.200151.
Effectively reducing the expression of certain aversive memories (fear or trauma memories) with extinction training is generally viewed to be therapeutically important. A deeper understanding of the biological basis for a more effective extinction process is also of high scientific importance.
Our study involved intraventricular injection or local injection into the dorsal dentate gyrus of anti-neuregulin 1 antibodies (anti-NRG1) before fear extinction training, followed by testing the expression of fear memory 24 hours afterward or 9 days later. We used local injection of chemogenetic or optogenetic viruses into the dorsal dentate gyrus to manipulate the activity of the dorsal dentate gyrus and test the expression of fear memory. We also examined the effect of deep brain stimulation in the dorsal dentate gyrus on the expression of fear memory.
Mice that received intraventricular injection with anti-NRG1 antibodies exhibited lower expression of fear memory and increased density of activated excitatory neurons in the dorsal dentate gyrus. Injection of anti-NRG1 antibodies directly into the dorsal dentate gyrus also led to lower expression of fear memory and more activated neurons in the dorsal dentate gyrus. Inhibiting the activity of dorsal dentate gyrus excitatory neurons using an inhibitory designer receptor exclusively activated by designer drugs (DREADD) eliminated the effects of the anti-NRG1 antibodies. Enhancing the activity of the dorsal dentate gyrus with an excitatory DREADD or optogenetic stimulation resulted in lower expression of fear memory in mice that did not receive infusion of anti-NRG1 antibodies. Deep brain stimulation in the dorsal dentate gyrus effectively suppressed expression of fear memory, both during and after fear extinction training.
The mechanism for the contribution of the dorsal dentate gyrus to the expression of fear memory needs further exploration.
Activation of the dorsal dentate gyrus may play an important role in modulating the expression of fear memory; its potential use in fear memory extinction is worthy of further exploration.
通过消退训练有效降低特定厌恶记忆（恐惧或创伤记忆）的表达，通常被认为具有治疗意义。更深入地了解更有效的消退过程的生物学基础也具有重要的科学意义。
我们的研究包括在恐惧消退训练前向侧脑室或背齿状回内注射抗神经调节素 1 抗体（抗 NRG1），然后在 24 小时或 9 天后测试恐惧记忆的表达。我们使用化学遗传或光遗传病毒局部注射到背齿状回，以操纵背齿状回的活动并测试恐惧记忆的表达。我们还检查了背齿状回深部脑刺激对恐惧记忆表达的影响。
接受脑室注射抗 NRG1 抗体的小鼠表现出较低的恐惧记忆表达和背齿状回中激活兴奋性神经元的密度增加。直接向背齿状回内注射抗 NRG1 抗体也导致恐惧记忆表达降低和背齿状回中更多的激活神经元。使用仅被设计药物激活的抑制性设计受体（DREADD）抑制背齿状回兴奋性神经元的活性消除了抗 NRG1 抗体的作用。用兴奋性 DREADD 或光遗传学刺激增强背齿状回的活性可导致未输注抗 NRG1 抗体的小鼠恐惧记忆表达降低。背齿状回深部脑刺激在恐惧消退训练期间和之后有效抑制恐惧记忆的表达。
背齿状回对恐惧记忆表达的贡献机制需要进一步探索。
背齿状回的激活可能在调节恐惧记忆表达中发挥重要作用；其在恐惧记忆消退中的潜在应用值得进一步探索。
