Effects of a null mutation of the gene beta catenin in dopamine neurons

多巴胺神经元中β连环蛋白基因无效突变的影响

基本信息

批准号：
8553297
负责人：
Cristina Backman
金额：
$ 14.28万
依托单位：
NATIONAL INSTITUTE ON DRUG ABUSE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8553297
关键词：
Ablation Adult Affect Age Animals Behavior Behavioral Body Weight Brain Brain region Cell Count Cell Nucleus Cell Polarity Cells Circadian Rhythms Commit Corpus striatum structure Development Dopamine Down-Regulation Environment Excision Gene Targeting Generations Genes Genetic Transcription Laboratories Maintenance Mediating Mediator of activation protein Messenger RNA Midbrain structure Molecular Motor Activity Mus Neurons Pathway interactions Pattern Play Process Radial Radio Role Scanning Signal Transduction Signal Transduction Pathway Slice Staging Substantia nigra structure Synapses Synaptic plasticity Tissues Transgenic Model Tyrosine 3-Monooxygenase Ventral Tegmental Area Vesicle beta catenin dopaminergic neuron hippocampal pyramidal neuron migration mouse model neurogenesis neuron development neurotransmission novel null mutation overexpression preproenkephalin prodynorphin progenitor recombinase response segregation

项目摘要

In our laboratory, we recently developed a Cre-loxP transgenic model to specifically inactivate β-catenin in DA neurons of the ventral midbrain (β-catenin KO mice). β-catenin KO mice are born at expected Mendelian radios. Adult mice present lower body weight compared with age-matched controls. Stereological cell counts do not reveal differences in the number of tyrosine hydroxylase positive neurons in the substantia nigra and ventral tegmental area of β-catenin KO mice. However, behavioral studies showed that β-catenin deficient mice are hyperactive in a novel environment, although no changes were found in the circadian locomotor activity pattern. To assess the dynamics of DA release in the striatum, fast-scan cyclic voltammetric recordings were performed in brain slices obtained from β-catenin KO mice and WT controls. Preliminary studies showed an increase of DA release in the striatum of KO animals when compared to controls. Striatal prodynorphin (PDyn) mRNA levels were significantly elevated in KO animals, suggesting an enhancement in neuronal activity associated with the striatonigral projection pathway, while preproenkephalin (PPE) mRNA levels remained unchanged. These results suggest β-catenin plays an essential role in the development and maintenance of dopaminergic neurotransmission. Our lab is currently focused on elucidating what molecular mechanisms, mediated by β-catenin ablation, result in the observed changes in behavior and dopaminergic neurotransmission.

在我们的实验室中，我们最近开发了一种Cre-loxP转基因模型，以在腹中脑（β-钙蛋白KO小鼠）的DA神经元中特异性灭活β-catenin。 β-catenin ko小鼠出生于预期的孟德尔收音机。与年龄匹配的对照相比，成年小鼠的体重较低。立体细胞计数并未揭示β-catenin ko小鼠的黑质和腹侧段区域中酪氨酸羟化酶阳性神经元数量的差异。然而，行为研究表明，β-catenin缺乏小鼠在新的环境中过度活跃，尽管在昼夜节律运动模式中未发现变化。为了评估纹状体中DA释放的动力学，在从β-catenin ko小鼠和WT对照中获得的大脑切片中进行了快速扫描的伏安记录。初步研究表明，与对照组相比，KO动物纹状体的DA释放增加。 KO动物的纹状体促肾上非（PDYN）mRNA水平显着升高，这表明与纹状体投射途径相关的神经元活性增强，而preproenkephalin（PPE）mRNA水平保持不变。这些结果表明β-catenin在多巴胺能神经传递的发展和维持中起着至关重要的作用。目前，我们的实验室集中于阐明β-catenin消融介导的分子机制导致观察到的行为和多巴胺能神经传递的变化。