Department of Geriatric Endocrinology, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China.
Biomed Pharmacother. 2022 Sep;153:113495. doi: 10.1016/j.biopha.2022.113495. Epub 2022 Jul 30.
Cognitive dysfunction is common in hypothyroid patients, even after undergoing sufficient levothyroxine (LT4) replacement therapy for euthyroid. Our previous studies indicated that cholinergic neurons might contribute to the decline of cognition in adult-onset hypothyroidism. Nevertheless, the role of the cellular and neural control of basal forebrain (BF) cholinergic neurons in hypothyroidism-induced cognitive impairments is unknown. Using transgenic mice that specifically expressed chemogenetic activators in their BF cholinergic neurons, we systematically investigated the role of BF cholinergic neurons in hypothyroidism-induced cognitive dysfunction by the combined approaches of patch clamp electrophysiology, behavioral testing, and immunohistochemistry. The results showed that LT4 treatment in the adult-onset hypothyroid mice reversed only 78 % of the BF cholinergic neurons to their normal values of electrophysiological properties. LT4 monotherapy did not rehabilitate cognitive function in the hypothyroid mice. Chemogenetic selective activation of the BF cholinergic neurons combined with LT4 treatment significantly improved learning and memory functions in the hypothyroid mice. In addition, chemogenetic activation of the cholinergic neurons induced the robust expression of c-Fos protein in the BF, prefrontal cortex (PFC), and hippocampus. This indicated that the BF cholinergic neurons improved learning and memory functions in the hypothyroid mice via the BF-PFC and BF-hippocampus pathways. In the hypothyroid C57BL/6 J mice, combined treatment via LT4 and donepezil, a cholinesterase inhibitor, significantly increased cognitive functions. The results suggested that the BF cholinergic neurons are critical for regulating learning and memory and reveal a novel pathophysiological mechanism for hypothyroidism-induced cognitive impairments.
认知功能障碍在甲状腺功能减退症患者中很常见，即使在接受足够的左甲状腺素（LT4）替代治疗以达到甲状腺功能正常后也是如此。我们之前的研究表明，胆碱能神经元可能导致成年发病的甲状腺功能减退症患者认知能力下降。然而，基底前脑（BF）胆碱能神经元的细胞和神经控制在甲状腺功能减退症引起的认知障碍中的作用尚不清楚。使用在 BF 胆碱能神经元中特异性表达化学遗传激活剂的转基因小鼠，我们通过膜片钳电生理学、行为测试和免疫组织化学相结合的方法，系统地研究了 BF 胆碱能神经元在甲状腺功能减退症引起的认知功能障碍中的作用。结果表明，LT4 治疗仅使成年发病的甲状腺功能减退症小鼠的 BF 胆碱能神经元恢复到正常电生理特性的 78%。LT4 单药治疗不能使甲状腺功能减退症小鼠的认知功能恢复正常。BF 胆碱能神经元的化学遗传选择性激活与 LT4 治疗相结合，显著改善了甲状腺功能减退症小鼠的学习和记忆功能。此外，胆碱能神经元的化学遗传激活在 BF、前额叶皮层（PFC）和海马中诱导了 c-Fos 蛋白的强烈表达。这表明 BF 胆碱能神经元通过 BF-PFC 和 BF-海马途径改善了甲状腺功能减退症小鼠的学习和记忆功能。在甲状腺功能减退症 C57BL/6J 小鼠中，LT4 和多奈哌齐（一种乙酰胆碱酯酶抑制剂）的联合治疗显著提高了认知功能。结果表明 BF 胆碱能神经元对调节学习和记忆至关重要，并揭示了甲状腺功能减退症引起的认知障碍的新病理生理学机制。
