放射疗法是治疗脑瘤和头颈部肿瘤的主要方法。然而，治疗后可引起急、慢性认知损伤及精神心理障碍，严重影响愈后生存质量。由于发病机制不明，尚无针对性疗法可有效逆转放射性认知精神障碍，因而成为当前医学研究的重要课题和迫切目标。我们前期对放射性脑损伤患者及动物模型的研究发现，其大脑内神经肽VGF表达量显著减少。在动物行为水平，VGF不仅促进记忆形成，还可改善情绪。在细胞水平，VGF衍生肽TLQP-62同时具有促进神经元突触关键蛋白合成和抑制小胶质细胞活化的功能。这些发现提示，放疗后VGF表达量减少，可能是认知障碍发生的关键因素。在大量前期工作的基础上，本项目将关注于放射导致的VGF减少是否通过协同影响小胶质细胞和神经元突触，过度增强突触修剪，导致突触功能受损和数量减少，进而引发记忆和情绪障碍。我们的研究将增进对放射性认知损伤基础机制的认识，为防治放射后认知损伤以及其它脑损伤疾病提供新靶点和实验证据。

Radiation therapy is an effective treatment for brain, head and neck tumors, yet with radiation-induced brain injury (RIBI) as the most common side effect. RIBI results in cognitive deficits, manifested as memory impairment and depression in as many as 90% patients. It has become an urgent need for a better understanding of the basic mechanisms underlying RIBI, not only to improve the quality of the life of patients, but also to reduce associated social burden. Our previous study has shown that the expression of neuropeptide VGF was reduced in the brains of the patients who received radiation therapy as well as in radiation mouse model. At the animal behavioral level, hippocampal VGF expression is required for memory formation and mood stabilization. At the cellular level, VGF-derived C-terminal peptide, TLQP-62, can enhance synaptic protein synthesis and repress microglia activation. Our findings suggest that reduced hippocampal VGF expression may be an important factor leading to cognitive impairment post radiation. In this proposed study, we will examine whether VGF coordinately regulates synaptic protein expression and radiation-induced microglia activation, leading to synaptic pruning, and whether hippocampal application of VGF will restore microglial and synaptic homeostasis, and rescue cognitive function in RIBI mouse model. Our findings will advance the mechanistic understanding of RIBI, and pave the way for the development of better prevention and treatment strategies for RIBI.