MOLECULAR/ANATOMICAL BASIS OF ABNORMAL MOTOR BEHAVIOR

描述（改编自申请人摘要）：神经生物学 自闭症的基础，情绪障碍，精神病综合征，焦虑综合征， 痴呆、智力迟钝、运动功能障碍和学习障碍 是不确定的，但这些通常发生的结果，胎儿， 青少年和成人甲状腺激素水平紊乱。 马达 这些疾病的异常可能取决于发育 运动系统及其与海马连接的异常 和额叶，这是甲状腺影响的主要胎儿目标 激素（TH，T4，T3）通过不明确的机制。 二十亿人 全世界的人都有因碘而引起TH水平紊乱的危险 缺乏症、甲状腺毒素或发育不良。 在美国， 先天性甲状腺功能减退症（SCH），可能有胎儿甲状腺功能减退症， 发生率为1/4000活产。 尽管早期的新生儿诊断和 用T4治疗这种疾病，患者，特别是，但不是 仅限于出生时T4水平低的人，可能有运动障碍。 异常和学习障碍，也许与不可逆的 胎儿脑部异常 在人类和啮齿动物中，TH减少会导致 神经元突起生长和维持的神经病理学改变 和连通性。 这是通过影响细胞骨架结构而发生的， 微管、微丝和神经丝被选择性地 对转录、翻译、装配和轴突的影响 其分子组分的运输，即，微管蛋白亚型，MAPS， 肌动蛋白和神经丝。 hyt/hyt小鼠有胎仔发病，严重 和遗传性甲状腺功能减退症，是严重的人类SCH的模型。 小鼠在某些微管蛋白同种型mRNA中具有特异性减少， 蛋白质，即，在锥体神经元中发现的Mbeta 5、Mbeta 2和Malpha 1 胎儿大脑皮层（CC）。 这些减少可能有助于 微管和突起生长的变化以及观察到的改变 在与皮质脊髓束相关的反射性和复杂运动行为中 功能障碍 本提案的目的是使用hyt/hyt鼠标 与对照甲状腺功能正常的hyt/+同窝仔和祖品系相比 BALB/cBY小鼠：（1）表征皮质脊髓束的时间 (from第V层感觉运动皮层）生长到脊髓中， 小鼠新生儿的道示踪方法;（2）定义 Mbeta 5 mRNA在蛋鸡中的定位和潜在丰度差异 孕晚期大鼠V感觉运动皮质锥体神经元的原位观察 杂交;（3）利用过程生长的组织培养模型 和完整的CC与Mbeta 5微管蛋白亚型的分子研究 mRNA/蛋白质来定义TH如何调节CC马达的发育 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.