Bárez-López Soledad, Montero-Pedrazuela Ana, Bosch-García Daniel, Venero César, Guadaño-Ferraz Ana
Department of Endocrine and Nervous System Pathophysiology, Instituto de Investigaciones Biomédicas "Alberto Sols'', Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Arturo Duperier, 4, 28029, Madrid, Spain; Department of Endocrine, U-708, Center for Biomedical Research on Rare Diseases (Ciberer), Instituto de Salud Carlos III, Madrid, Spain.
Department of Endocrine and Nervous System Pathophysiology, Instituto de Investigaciones Biomédicas "Alberto Sols'', Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Arturo Duperier, 4, 28029, Madrid, Spain.
Psychoneuroendocrinology. 2017 Oct;84:51-60. doi: 10.1016/j.psyneuen.2017.06.013. Epub 2017 Jun 16.
A euthyroid state in the brain is crucial for its adequate development and function. Impairments in thyroid hormones (THs; T3 or 3,5,3'-triiodothyronine and T4 or thyroxine) levels and availability in brain can lead to neurological alterations and to psychiatric disorders, particularly mood disorders. The thyroid gland synthetizes mainly T4, which is secreted to circulating blood, however, most actions of THs are mediated by T3, the transcriptionally active form. In the brain, intracellular concentrations of T3 are modulated by the activity of type 2 (D2) and type 3 (D3) deiodinases. In the present work, we evaluated learning and memory capabilities and anxiety-like behavior at adult stages in mice lacking D2 (D2KO) and we analyzed the impact of D2-deficiency on TH content and on the expression of T3-dependent genes in the amygdala and the hippocampus. We found that D2KO mice do not present impairments in spatial learning and memory, but they display emotional alterations with increased anxiety-like behavior as well as enhanced auditory-cued fear memory and spontaneous recovery of fear memory following extinction. D2KO mice also presented reduced T3 content in the hippocampus and decreased expression of the T3-dependent gene Dio3 in the amygdala suggesting a hypothyroid status in this structure. We propose that the emotional dysfunctions found in D2KO mice can arise from the reduced T3 content in their brain, which consequently leads to alterations in gene expression with functional consequences. We found a downregulation in the gene encoding for the calcium-binding protein calretinin (Calb2) in the amygdala of D2KO mice that could affect the GABAergic transmission. The current findings in D2KO mice can provide insight into emotional disorders present in humans with DIO2 polymorphisms.
大脑中的甲状腺功能正常状态对其正常发育和功能至关重要。甲状腺激素（THs；T3或3,5,3'-三碘甲状腺原氨酸以及T4或甲状腺素）水平及其在大脑中的可利用性受损会导致神经功能改变和精神疾病，尤其是情绪障碍。甲状腺主要合成T4，并分泌到循环血液中，然而，THs的大多数作用是由转录活性形式T3介导的。在大脑中，T3的细胞内浓度受2型（D2）和3型（D3）脱碘酶活性的调节。在本研究中，我们评估了缺乏D2的小鼠（D2KO）成年期的学习和记忆能力以及焦虑样行为，并分析了D2缺乏对杏仁核和海马体中TH含量以及T3依赖性基因表达的影响。我们发现，D2KO小鼠在空间学习和记忆方面没有缺陷，但它们表现出情绪改变——焦虑样行为增加，以及听觉提示恐惧记忆增强和恐惧记忆消退后的自发恢复。D2KO小鼠海马体中的T3含量也降低，杏仁核中T3依赖性基因Dio3的表达减少，表明该结构存在甲状腺功能减退状态。我们认为，D2KO小鼠中发现的情绪功能障碍可能源于其大脑中T3含量的降低，这进而导致基因表达改变并产生功能后果。我们发现D2KO小鼠杏仁核中编码钙结合蛋白钙视网膜蛋白（Calb2）的基因下调，这可能会影响GABA能传递。目前在D2KO小鼠中的研究结果可以为患有DIO2基因多态性的人类所出现的情绪障碍提供见解。
