甲状腺功能减退症脑默认网络损伤及康复机制

Hypothyroidism is related to multiple cognitive dysfunctions. However, whether thyroxine, which is the standard treatment for hypothyroid patients, is sufficient enough for fully restoring such dysfunctions remains controversial. Using functional magnetic resonance imaging (fMRI)，our group revealed significant dysfunctions within the bilateral medial prefrontal cortices, posterior cingulate cortices, and left inferior partial lobule in hypothyroid patients during a working memory task. These regions are considered as parts of the default mode network (DMN). Overt functional connectivity was shown between these regions by resting-state fMRI. Hence an urgent question arises: would hypothyroidism result in disturbed resting-state functional connectivity within DMN regions, as many other brain diseases do? In this proposal, we intend to investigate the potential alteration of functional connectivity within DMN regions in hypothyroid patients using resting state fMRI. Besides, the structure and molecular basis of such abnormality within DMN with be investigated via electrophysiological, histological, neurochemical and molecular biological approaches on adult-onset hypothyroid rat model， which induced by antithyroid agents. Accordingly, to investigate the rehabilitation mechanism of hypothyroidism-induced brain impairments in DMN, all patients and most hypothyroid rats were observed after having been treated with L-T4 or L-T4-plus-cholinesterase inhibitors, again, to examine the restoration of the altered functional connectivity, synaptic plasticity and synaptic proteins within DMN regions.

成年期甲状腺功能减退症(甲减)可引起认知相关的脑损害，左旋甲状腺素(L-T4)替代治疗至血清甲状腺激素水平正常时，损伤不能完全恢复。我们通过功能磁共振，首次在成年期甲减患者中发现执行工作记忆任务时内侧前额叶、后扣带回、下顶叶等脑区的功能损害。这些脑区隶属于默认网络，在静息态下存在功能连接。那么，甲减脑损伤是否可能与其它一些脑疾病一样，会引起这种功能连接的异常?这是亟待解决的问题。故本课题拟采用静息态功能磁共振观察甲减患者默认网络脑区及功能连接变化，并应用抗甲状腺药物建立成年期甲减大鼠模型，采用电生理学、组织学、神经化学及分子生物学手段，研究甲减时默认网络功能连接异常的结构基础及分子机制。同时对甲减患者和甲减鼠均分别给予L-T4或L-T4联合胆碱酯酶抑制剂治疗，观察两种治疗方法下甲减脑默认网络功能连接及突触可塑性、突触相关蛋白等的恢复状况，探讨甲减脑默认网络损伤的康复机制。

部分甲状腺功能减退症(甲减)患者用左旋甲状腺素(LT4)替代治疗后认知功能不能完全恢复。我们发现甲减患者执行工作记忆任务时脑默认网络的内侧前额叶、后扣带回等脑区功能受损。动物实验研究提示甲减时脑内与认知密切相关的胆碱能系统异常。因此，本课题的主要问题是脑默认网络及脑内胆碱能系统与甲减时认知功能降低的关系及作用机制。.采用韦氏记忆量表及面孔—联想学习任务，发现甲减患者记忆功能损伤，给予LT4治疗后部分恢复，而给予LT4联合多奈哌齐治疗后能完全恢复正常。正常对照人群及甲减患者治疗前后的静息态脑功能磁共振（fMRI）结果无显著性差异。LT4+多奈哌齐联合用药治疗后的患者学习记忆能力显著增强，任务态fMRI显示海马激活程度显著提高，穹窿体处白质纤维连接恢复。通过甲减动物模型发现LT4联合多奈哌齐治疗组的大鼠的认知行为、脑突触结构、海马及前额叶突触相关蛋白syt-1,munc-18,SNARE（SNAP-25，vamp-2,syntaxin-1）的表达水均显著恢复，与正常对照组均无显著差异，而单用LT4治疗则部分不能完全恢复。借助胆碱能神经元特异性（ChAT-Cre）小鼠，发现成年期甲减小鼠基底前脑胆碱能神经元静息膜电位增大、放电频率加快。被动逃避实验研究发现成年期甲减小鼠使用LT4替代治疗后，其认知功能不能完全恢复，特异性激活甲减及LT4替代治疗小鼠的基底前脑胆碱能神经元后，两组小鼠的认知功能均显著提高。以上结果从临床到实验室全面阐述甲减时认知功能损伤与甲减时脑默认网络海马、穹窿体白质纤维等功能连接，脑内胆碱能系统功能受损密切相关，LT4联合多奈哌齐治疗甲减对改善其认知功能及恢复默认网络功能连接效果显著。