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Sex differences in norepinephrine action in striatal neurons

纹状体神经元去甲肾上腺素作用的性别差异

基本信息

批准号：
8057614
负责人：
John Meitzen
金额：
$ 5.22万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-31 至 2012-01-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8057614
关键词：
Accounting Adrenergic Receptor Adult Affect Animal Behavior Area BDNF gene Behavior Behavioral Brain Brain-Derived Neurotrophic Factor Complement Corpus striatum structure Cyclic AMP-Responsive DNA-Binding Protein Data Dopamine Dorsal Drug Addiction Drug abuse Electrophysiology (science)Event Family Female Gene Expression Genetic Techniques Goals Hormones Institution Laboratories Life Link Long-Term Effects MAP Kinase Gene Messenger RNA Molecular National Research Service Awards Neurobiology Neuroendocrinology Neuromodulator Neuronal Plasticity Neurons Neurosciences Norepinephrine Nucleus Accumbens Pathology Pathway interactions Phosphorylation Physiological Physiology Play Principal Investigator Rattus Receptor Activation Receptor Protein-Tyrosine Kinases Research Role Sex Characteristics Signal Transduction Signal Transduction Pathway Structure Structure/Function Nuclei System Techniques Testing Training Universities addiction base career cost dimorphism drug of abuse experience immunocytochemistry interest mRNA Expression male meetings monoamine novel professor programs research study sex sexual dimorphism skills transcription factor

项目摘要

DESCRIPTION (provided by applicant): Drug addiction has an enormous toll on personal, family and public life. Understanding the physiological mechanisms underlying drug addiction pathologies and normal striatal function will ultimately reduce the societal and personal cost of drug abuse, making the neurobiology of drug abuse a relevant line of research. While the neuromodulator dopamine is the focus of most research in this area, evidence is accumulating that norepinephrine also plays an essential role in aspects of drug addiction. Our pilot data indicates that norepinephrine acts directly on striatal neurons cultured from the nucleus accumbens and dorsal striatum to phosphorylate cAMP Response Element Binding Protein (CREB), a transcription-factor directly implicated as a molecular switch underlying long-term effects of drug abuse on the brain. We will build on this result in the first aim of our proposal, where we will elucidate the underlying signal transduction pathway that norepinephrine activates, and test whether this pathway induces gene expression. One of the most interesting aspects of drug addiction is that it is sexually dimorphic. There is currently not a clear mechanism to account for sex differences in drug abuse behavior. Interestingly, we find that the ¿1- adrenergic receptor is sexually dimorphic in adult striatum. In the second aim of our proposal we test the extent of this sexual dimorphism in NE action and whether it is induced via early hormone exposure. Finally, this proposal contains a significant training component. My ultimate career goal is to be a principal investigator at a research university. As a professor at such an institution, I want my research program to investigate phenomena of societal importance and to encompass techniques ranging from the molecular to the behavioral. The training that I will receive from this NRSA will help provide necessary background to meet these career goals. I will be trained in the usage of molecular and cellular neurobiological techniques, and broaden my research portfolio into mechanisms underlying drug abuse, sex differences, and the molecular physiology of mammalian striatal neurons. PUBLIC HEALTH RELEVANCE: Drug addiction is believed to be triggered by alterations in striatal monoamine signaling. Most research has focused on the role of dopamine, but accumulating evidence also suggests a strong norepinephrine component. In this proposal, we will test whether norepinephrine can directly affect molecular events related to drug addiction. Preliminary data suggest that norepinephrine action is sexually dimorphic. We will determine the extent of this dimorphism and test whether it is induced via early hormone exposure. The sex difference in norepinephrine signaling provides a potential mechanism underlying sexual dimorphisms in drug addiction behavior.

描述(申请人提供)：吸毒成瘾对个人、家庭和公共生活造成巨大损失。了解药物成瘾病理和正常纹状体功能的生理机制将最终降低药物滥用的社会和个人成本，使药物滥用的神经生物学成为相关的研究方向。虽然神经调节剂多巴胺是这一领域大多数研究的焦点，但越来越多的证据表明，去甲肾上腺素在药物成瘾方面也发挥着重要作用。我们的初步数据表明，去甲肾上腺素直接作用于从伏隔核和背侧纹状体培养的纹状体神经元，使cAMP反应元件结合蛋白(CREB)磷酸化，CREB是一种转录因子，直接被认为是药物滥用对大脑长期影响的分子开关。我们将在这一结果的基础上提出我们的建议的第一个目标，我们将阐明去甲肾上腺素激活的潜在信号转导途径，并测试该途径是否诱导基因表达。吸毒成瘾最有趣的方面之一是它具有两面性。目前还没有一个明确的机制来解释药物滥用行为中的性别差异。有趣的是，我们发现成年纹状体中的1-肾上腺素能受体是性二态的。在我们建议的第二个目标中，我们测试去甲肾上腺素活动中这种性二态的程度，以及它是否是通过早期激素暴露而诱导的。最后，该提案包含一个重要的培训部分。我的最终职业目标是成为一所研究型大学的首席研究员。作为这样一家机构的教授，我希望我的研究项目能够研究具有社会重要性的现象，并涵盖从分子到行为的各种技术。我将从NRSA获得的培训将有助于为实现这些职业目标提供必要的背景知识。我将接受分子和细胞神经生物学技术的使用方面的培训，并扩大我对药物滥用、性别差异和哺乳动物纹状体神经元的分子生理学的潜在机制的研究组合。与公共健康相关：药物成瘾被认为是由纹状体单胺信号的改变引发的。大多数研究都集中在多巴胺的作用上，但越来越多的证据也表明，去甲肾上腺素是一种很强的成分。在这项提案中，我们将测试去甲肾上腺素是否可以直接影响与药物成瘾相关的分子事件。初步数据表明，去甲肾上腺素的作用是性二态的。我们将确定这种二型性的程度，并测试它是否是通过早期激素暴露而诱导的。去甲肾上腺素信号的性别差异为药物成瘾行为中的性二型性提供了一个潜在的机制。