Woo Elizabeth, Sansing Lauren H, Arnsten Amy F T, Datta Dibyadeep
Department of Neuroscience, Yale Medical School, New Haven, CT, USA.
Department of Neurology, Yale Medical School, New Haven, CT, USA.
Chronic Stress (Thousand Oaks). 2021 Aug 29;5:24705470211029254. doi: 10.1177/24705470211029254. eCollection 2021 Jan-Dec.
Chronic exposure to uncontrollable stress causes loss of spines and dendrites in the prefrontal cortex (PFC), a recently evolved brain region that provides top-down regulation of thought, action, and emotion. PFC neurons generate top-down goals through recurrent excitatory connections on spines. This persistent firing is the foundation for higher cognition, including working memory, and abstract thought. However, exposure to acute uncontrollable stress drives high levels of catecholamine release in the PFC, which activates feedforward calcium-cAMP signaling pathways to open nearby potassium channels, rapidly weakening synaptic connectivity to reduce persistent firing. Chronic stress exposures can further exacerbate these signaling events leading to loss of spines and resulting in marked cognitive impairment. In this review, we discuss how stress signaling mechanisms can lead to spine loss, including changes to BDNF-mTORC1 signaling, calcium homeostasis, actin dynamics, and mitochondrial actions that engage glial removal of spines through inflammatory signaling. Stress signaling events may be amplified in PFC spines due to cAMP magnification of internal calcium release. As PFC dendritic spine loss is a feature of many cognitive disorders, understanding how stress affects the structure and function of the PFC will help to inform strategies for treatment and prevention.
长期暴露于无法控制的压力会导致前额叶皮质（PFC）中树突棘和树突的丧失，前额叶皮质是一个最近进化出来的脑区，负责对思维、行动和情绪进行自上而下的调节。PFC神经元通过树突棘上的反复兴奋性连接产生自上而下的目标。这种持续放电是包括工作记忆和抽象思维在内的高级认知的基础。然而，暴露于急性无法控制的压力会促使PFC中高水平的儿茶酚胺释放，这会激活前馈钙 - cAMP信号通路，打开附近的钾通道，迅速削弱突触连接性，从而减少持续放电。长期应激暴露会进一步加剧这些信号事件，导致树突棘丧失，并导致明显的认知障碍。在这篇综述中，我们讨论了应激信号机制如何导致树突棘丧失，包括BDNF - mTORC1信号、钙稳态、肌动蛋白动力学以及通过炎症信号促使神经胶质细胞清除树突棘的线粒体作用的变化。由于内部钙释放的cAMP放大作用，应激信号事件可能在前额叶皮质树突棘中被放大。由于前额叶皮质树突棘丧失是许多认知障碍的一个特征，了解压力如何影响前额叶皮质的结构和功能将有助于为治疗和预防策略提供依据。
