MOLECULAR/ANATOMICAL BASIS OF ABNORMAL MOTOR BEHAVIOR

描述(摘自申请者的摘要)：神经生物学 自闭症的基础，情绪障碍，精神病症状，焦虑症状， 痴呆症、智力低下、运动功能障碍和学习障碍 很难确定，但这些通常是胎儿的结果， 青少年、成人甲状腺激素水平紊乱。马达 这些障碍中的异常可能是基于发育 运动系统的异常及其与海马体的联系 和额叶，这是受甲状腺影响的主要胎儿目标 激素(TH、T4、T3)的作用机制不明确。20亿人 全世界都有因碘引起的TH级疾病的风险 缺乏症、甲状腺毒素或发育不良。在美国，零星的 先天性甲状腺功能减退症(SCH)，可能有胎儿甲状腺功能减退， 发生在4000个活产儿中的1个。尽管早期的新生儿诊断和 用T4治疗这种疾病，特别是患者，但不是 仅限于出生时T4水平低的人，可能有运动 异常和学习障碍，可能与不可逆转有关 胎儿脑部异常。在人类和啮齿动物中，减少了这一原因 神经元突起生长和维持过程中的神经病理改变 和连通性。这是通过影响细胞骨架结构而发生的， 通过选择微管、微丝和神经丝 对转录、翻译、组装和轴突的影响 其分子成分的运输，即微管蛋白亚型，MAP， 肌动蛋白和神经丝。HYT/HYT小鼠有胎儿发病，严重 遗传性甲状腺功能减退症，是严重人类SCH的模型。这 小鼠在某些微管蛋白亚型的mRNAs和 锥体神经元中发现的蛋白质，即Mbeta5、Mbeta2和Malpha1 胎儿大脑皮层(CC)。这些削减可能有助于 微管和突起生长的变化以及观察到的变化 与皮质脊髓束相关的反射性和复杂运动行为 功能障碍。这项提案的目的是使用HYT/HYT鼠标 对照正常甲状腺HYT/+仔鼠和祖细胞株的比较 BALB/CBY小鼠：(1)皮质脊髓束的时序特征 (从V层感觉运动皮质)生长到脊髓。 (2)通过轨迹追踪方法确定小鼠新生的 蛋鸡Mbeta5基因的定位及潜在丰度差异 妊娠晚期V型感觉运动皮质锥体神经元的原位研究 杂交；(3)利用过程生长的组织培养模型 和完整CC与Mbeta5微管蛋白亚型的分子研究 确定TH如何调控CC马达发育的mRNA/蛋白质 神经元和运动行为。

DESCRIPTION (Adapted from applicant's abstract): The neurobiological basis of autism, mood disorders, psychotic syndromes, anxiety syndromes, dementia, mental retardation, motor dysfunction, and learning disability is poorly established, but these occur commonly as result of fetal, juvenile, and adult disorders of thyroid hormone level. The motor abnormalities in these disorders may be predicated on developmental abnormalities of the motor system and its connections with hippocampus and frontal lobe, which are primary fetal targets affected by thyroid hormone (TH,T4,T3) by poorly defined mechanisms. Two billion people worldwide are at risk for disorders of TH level because of iodine deficiency, thyroid gland toxins or maldevelopment. In the US, sporadic congenital hypothyroidism (SCH), which may have fetal hypothyroidism, occurs in 1/4000 live births. Despite early neonatal diagnosis and treatment of this disorder with T4, patients, particularly, but not limited to those with low T4 levels at birth, may have motor abnormalities and learning disabilities, perhaps related to irreversible fetal brain abnormalities. In humans and rodents, reduced TH causes neuropathological alterations in neuronal process growth and maintenance and connectivity. This occurs by affecting the cytoskeletal structures, the microtubules, microfilaments, and neurofilaments by selective effects on the transcription, translation, assembly, and axonal transport of their molecular components, i.e., tubulin isoforms, MAPS, actin, and neurofilaments. The hyt/hyt mouse has a fetal onset, severe and inherited hypothyroidism and is a model of severe human SCH. This mouse has specific reductions in certain tubulin isoform mRNAs and proteins, i.e., Mbeta5, Mbeta2, and Malpha1, found in pyramidal neurons of the fetal cerebral cortex (CC). These reductions may contribute to changes in microtubules and process growth and the observed alterations in reflexive and complex motor behavior related to corticospinal tract dysfunction. The aims of this proposal are to use the hyt/hyt mouse compared to control euthyroid hyt/+ littermates and progenitor strain BALB/cBY mice: (1) to characterize the timing of corticospinal tract (from layer V sensorimotor cortex) growth to the spinal cord in the mouse neonate by tract tracing methodology; (2) to define the localization and potential abundance differences of Mbeta5 mRNA to layer V sensorimotor cortex pyramidal neurons in later gestation by in situ hybridization; and (3) to utilize tissue culture models of process growth and intact CC with molecular studies of Mbeta5 tubulin isoform mRNA/protein to define how TH regulates the development of CC motor neurons and motor behavior.