Ren Bingyu, Yuan Quan, Cha Shuhan, Liu Sinyi, Zhang Jifeng, Guo Guoqing
Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, Guangzhou, 510630, China.
School of Basic Medicine, Jiamusi University, Jiamusi, 154007, China.
Mol Neurobiol. 2025 Jun 23. doi: 10.1007/s12035-025-05152-5.
Chronic stress can lead to maladaptive neuroplastic changes in the brain, with the prefrontal cortex (PFC) being a critical site of vulnerability due to its role in executive function and emotional regulation. Extensive evidence has confirmed that chronic stress induces neuroplasticity changes at multiple scales, including functional reorganization, intrinsic neuronal excitability, and structural and synaptic plasticity. These alterations are particularly prominent in glutamatergic pyramidal neurons of the PFC and involve synaptic weakening, dendritic retraction, spine loss, and impaired long-term potentiation. The paradoxical findings regarding pyramidal neuron excitability-ranging from hyper- to hypoactivity-highlight the complex and dynamic nature of stress-induced plasticity. One proposed mechanism linking these alterations is excitotoxicity, characterized by excessive glutamate signaling, impaired astrocytic clearance, and calcium overload, ultimately leading to synaptic dysfunction and structural degeneration. Additionally, inhibitory interneurons and glial cells might also play essential roles in shaping and modulating the stress response. This review integrates findings across neuroplasticity levels to provide a comprehensive understanding of how chronic stress reshapes the PFC. We further discuss the therapeutic potential of targeting homeostatic plasticity as a compensatory mechanism and propose future directions to clarify temporal dynamics, circuit specificity, and molecular regulators underlying maladaptive neuroplasticity in stress-related disorders.
慢性应激可导致大脑中出现适应不良的神经可塑性变化，前额叶皮质（PFC）因其在执行功能和情绪调节中的作用而成为一个关键的易损部位。大量证据证实，慢性应激会在多个尺度上诱导神经可塑性变化，包括功能重组、内在神经元兴奋性以及结构和突触可塑性。这些改变在PFC的谷氨酸能锥体神经元中尤为突出，涉及突触减弱、树突回缩、棘突丢失以及长时程增强受损。关于锥体神经元兴奋性的矛盾发现——从活动亢进到活动减退——凸显了应激诱导可塑性的复杂和动态性质。一种将这些改变联系起来的机制是兴奋性毒性，其特征是谷氨酸信号过度、星形胶质细胞清除功能受损和钙超载，最终导致突触功能障碍和结构退化。此外，抑制性中间神经元和胶质细胞在塑造和调节应激反应中可能也起着重要作用。本综述整合了神经可塑性各水平的研究结果，以全面了解慢性应激如何重塑PFC。我们进一步讨论了将稳态可塑性作为一种补偿机制进行靶向治疗的潜力，并提出了未来的研究方向，以阐明应激相关疾病中适应不良神经可塑性背后的时间动态、回路特异性和分子调节因子。
