Department of Neurobiology and Anatomy, the University of Texas McGovern Medical School, Houston, Texas 77225.
Department of Neurobiology and Anatomy, the University of Texas McGovern Medical School, Houston, Texas 77225
J Neurosci. 2018 Feb 28;38(9):2372-2384. doi: 10.1523/JNEUROSCI.1756-17.2018. Epub 2018 Jan 31.
Adult hippocampal neurogenesis has been shown to be required for certain types of cognitive function. For example, studies have shown that these neurons are critical for pattern separation, the ability to store similar experiences as distinct memories. Although traumatic brain injury (TBI) has been shown to cause the loss of newborn hippocampal neurons, the signaling pathway(s) that triggers their death is unknown. Endoplasmic reticulum (ER) stress activates the PERK-eIF2α pathway that acts to restore ER function and improve cell survival. However, unresolved/intense ER stress activates C/EBP homologous protein (CHOP), leading to cell death. We show that TBI causes the death of hippocampal newborn neurons via CHOP. Using CHOP KO mice, we show that loss of CHOP markedly reduces newborn neuron loss after TBI. Injured CHOP mice performed significantly better in a context fear discrimination task compared with injured wild-type mice. In contrast, the PERK inhibitor GSK2606414 exacerbated doublecortin cell loss and worsened contextual discrimination. Administration of guanabenz (which reduces ER stress) to injured male rats reduced the loss of newborn neurons and improved one-trial contextual fear memory. Interestingly, we also found that the surviving newborn neurons in brain-injured animals had dendritic loss, which was not observed in injured CHOP KO mice or in animals treated with guanabenz. These results indicate that ER stress plays a key role in the death of newborn neurons after TBI. Further, these findings indicate that ER stress can alter dendritic arbors, suggesting a role for ER stress in neuroplasticity and dendritic pathologies. The hippocampus, a structure in the temporal lobe, is critical for learning and memory. The hippocampus is one of only two areas in which neurons are generated in the adult brain. These newborn neurons are required for certain types of memory, and are particularly vulnerable to traumatic brain injury (TBI). However, the mechanism(s) that causes the loss of these cells after TBI is poorly understood. We show that endoplasmic reticulum (ER) stress pathways are activated in newborn neurons after TBI, and that manipulation of the CHOP cascade improves newborn neuron survival and cognitive outcome. These results suggest that treatments that prevent/resolve ER stress may be beneficial in treating TBI-triggered memory dysfunction.
成人海马神经发生对于某些类型的认知功能是必需的。例如，研究表明这些神经元对于模式分离至关重要，模式分离是将相似的经历存储为不同记忆的能力。尽管创伤性脑损伤 (TBI) 已被证明会导致新生海马神经元的丧失，但触发其死亡的信号通路尚不清楚。内质网 (ER) 应激激活 PERK-eIF2α 途径，该途径作用是恢复 ER 功能并提高细胞存活率。然而，未解决的/强烈的 ER 应激会激活 C/EBP 同源蛋白 (CHOP)，导致细胞死亡。我们表明 TBI 通过 CHOP 导致海马新生神经元死亡。使用 CHOP KO 小鼠，我们表明 TBI 后 CHOP 的缺失显著减少了新生神经元的丢失。与受伤的野生型小鼠相比，受伤的 CHOP 小鼠在情景恐惧辨别任务中的表现明显更好。相比之下，PERK 抑制剂 GSK2606414 加剧了双皮质细胞丢失并恶化了情景辨别。给予受伤雄性大鼠胍法辛（可减轻 ER 应激）可减少新生神经元的丢失并改善单次情景恐惧记忆。有趣的是，我们还发现脑损伤动物中的存活新生神经元存在树突丢失，但在受伤的 CHOP KO 小鼠或胍法辛处理的动物中未观察到这种情况。这些结果表明 ER 应激在 TBI 后新生神经元死亡中起关键作用。此外，这些发现表明 ER 应激可以改变树突分支，表明 ER 应激在神经可塑性和树突病理中的作用。海马体是颞叶中的一个结构，对于学习和记忆至关重要。海马体是成人脑中产生神经元的仅有的两个区域之一。这些新生神经元是某些类型记忆所必需的，并且特别容易受到创伤性脑损伤 (TBI) 的影响。然而，导致 TBI 后这些细胞丢失的机制尚不清楚。我们表明 TBI 后新生神经元中的内质网 (ER) 应激途径被激活，并且 CHOP 级联的操作改善了新生神经元的存活和认知结果。这些结果表明，预防/解决 ER 应激的治疗方法可能有益于治疗 TBI 引发的记忆功能障碍。
