PDF(Pubmed)
Abstract：
Subconcussive head impacts are associated with the development of acute and chronic cognitive deficits. We recently reported that high-frequency head impact (HFHI) causes chronic cognitive deficits in mice through synaptic changes. To better understand the mechanisms underlying HFHI-induced memory decline, we used TRAP2/Ai32 transgenic mice to enable visualization and manipulation of memory engrams. We labeled the fear memory engram in male and female mice exposed to an aversive experience and subjected them to sham or HFHI. Upon subsequent exposure to natural memory recall cues, sham, but not HFHI, mice successfully retrieved fearful memories. In sham mice the hippocampal engram neurons exhibited synaptic plasticity, evident in amplified AMPA:NMDA ratio, enhanced AMPA-weighted tau, and increased dendritic spine volume compared with nonengram neurons. In contrast, although HFHI mice retained a comparable number of hippocampal engram neurons, these neurons did not undergo synaptic plasticity. This lack of plasticity coincided with impaired activation of the engram network, leading to retrograde amnesia in HFHI mice. We validated that the memory deficits induced by HFHI stem from synaptic plasticity impairments by artificially activating the engram using optogenetics and found that stimulated memory recall was identical in both sham and HFHI mice. Our work shows that chronic cognitive impairment after HFHI is a result of deficiencies in synaptic plasticity instead of a loss in neuronal infrastructure, and we can reinstate a forgotten memory in the amnestic brain by stimulating the memory engram. Targeting synaptic plasticity may have therapeutic potential for treating memory impairments caused by repeated head impacts.
摘要：
脑震荡下的头部撞击与急性和慢性认知缺陷的发展有关。我们最近报道，高频头部撞击（HFHI）通过突触变化导致小鼠慢性认知缺陷。为了更好地理解HFHI引起的记忆下降的潜在机制，我们使用了TRAP2/Ai32转基因小鼠来实现记忆图的可视化和操作。我们在暴露于厌恶经历的雄性和雌性小鼠中标记了恐惧记忆印迹，并对它们进行了假手术或HFHI。在随后暴露于自然记忆回忆线索后，sham,但不是HFHI小鼠，成功找回了可怕的记忆。在假手术小鼠中，海马Engram神经元表现出突触可塑性，在扩增的AMPA：NMDA比率中很明显，增强AMPA加权tau，与非Engram神经元相比，树突脊柱体积增加。相比之下,尽管HFHI小鼠保留了相当数量的海马神经元，这些神经元没有突触可塑性。这种可塑性的缺乏与Engram网络的激活受损同时发生，导致HFHI小鼠逆行性健忘症。我们通过使用光遗传学人工激活印迹，验证了HFHI诱导的记忆缺陷源于突触可塑性损伤，发现假手术和HFHI小鼠的刺激记忆回忆是相同的。我们的工作表明，HFHI后的慢性认知障碍是突触可塑性不足的结果，而不是神经元基础设施的丧失。我们可以通过刺激记忆印迹来恢复遗忘的记忆。靶向突触可塑性可能具有治疗由重复头部撞击引起的记忆障碍的治疗潜力。
