Center of Brain, Behavior and Metabolism CBBM/Medizinische Klinik I, University of Lübeck, Lübeck, Germany.
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
J Neuroendocrinol. 2018 Mar;30(3):e12573. doi: 10.1111/jne.12573.
Thyroid hormone (TH) is crucial for brain development and function. This becomes most evident in untreated congenital hypothyroidism, leading to irreversible mental retardation. Likewise, maternal hypothyroxinaemia, a lack of TH during pregnancy, is associated with neurological dysfunction in the offspring, such as autism and reduced intellectual capacity. In the brain, TH acts mainly through TH receptor α1 (TRα1). Consequently, mice heterozygous for a dominant-negative mutation in TRα1 display profound neuroanatomical abnormalities including deranged development of parvalbumin neurones. However, the exact timing and orchestration of TH signalling during parvalbumin neurone development remains elusive. In the present study, we dissect the development of parvalbumin neurones in the anterior hypothalamic area (AHA) in male mice using different mouse models with impaired pre- and postnatal TH signalling in combination with bromodeoxyuridine birth dating and immunohistochemistry. Our data reveal that hypothalamic parvalbumin neurones are born at embryonic day 12 and are first detected in the AHA at postnatal day 8, reaching their full population number at P13. Interestingly, they do not require TH postnatally because their development is not impaired in mice with impaired TH signalling after birth. By contrast, however, these neurones crucially depend on TH through TRα1 signalling in the second half of pregnancy, when the hormone is almost exclusively provided by the mother. For the first time, our findings directly link a maternal hormone to a neuroanatomical substrate in the foetal brain, and underline the importance of proper TH signalling during pregnancy for offspring mental health. Given the role of hypothalamic parvalbumin neurones in the central control of blood pressure, the present study advocates the inclusion of cardiovascular parameters in the current discussion on possible TH substitution in maternal hypothyroxinaemia.
甲状腺激素 (TH) 对大脑发育和功能至关重要。这在未经治疗的先天性甲状腺功能减退症中最为明显，导致不可逆转的智力迟钝。同样，母亲甲状腺功能减退症，即怀孕期间缺乏 TH，与后代的神经功能障碍有关，如自闭症和智力下降。在大脑中，TH 主要通过 TH 受体 α1 (TRα1) 发挥作用。因此，TRα1 显性负突变杂合子小鼠表现出明显的神经解剖异常，包括钙结合蛋白 32 (parvalbumin) 神经元发育紊乱。然而，TH 信号在 parvalbumin 神经元发育过程中的确切时间和协调仍然难以捉摸。在本研究中，我们使用不同的小鼠模型，结合溴脱氧尿苷标记和免疫组织化学技术，研究了雄性小鼠前下丘脑区域 (AHA) parvalbumin 神经元的发育。我们的数据显示，下丘脑 parvalbumin 神经元在胚胎第 12 天产生，并在出生后第 8 天首次在 AHA 中检测到，在 P13 时达到其全部数量。有趣的是，它们在出生后 TH 信号受损的小鼠中不需要 TH，因为它们的发育没有受损。相比之下，然而，这些神经元在妊娠后半期非常依赖 TH 通过 TRα1 信号，此时激素几乎完全由母亲提供。我们的研究结果首次将一种母体激素与胎儿大脑中的神经解剖学基质直接联系起来，并强调了怀孕期间适当的 TH 信号对后代心理健康的重要性。鉴于下丘脑 parvalbumin 神经元在血压的中枢控制中的作用，本研究主张在当前关于母体甲状腺功能减退症中可能的 TH 替代的讨论中纳入心血管参数。
