Spinophilin function in regulating pathological responses to psychostimulant drug

Spinphilin 在调节精神兴奋药物病理反应中的作用

基本信息

批准号：
9892499
负责人：
Anthony J. Baucum
金额：
$ 5.46万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892499
关键词：
Amphetamines Animals Applications Grants Area Axon Behavior Behavioral Benchmarking Biochemical Biological Biological Assay Brain CRISPR/Cas technology Cells Chronic Cocaine Corpus striatum structure Coupled Cyclic AMP-Dependent Protein Kinases Dendritic Spines Disease Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dose Drug toxicity Electrons Ensure Enterobacteria phage P1 Cre recombinase Exons Exposure to G-Protein-Coupled Receptors Genes Glutamates Goals Histologic Human Illicit Drugs Ion Channel Knock-out Knockout Mice Lead LoxP-flanked allele Mediating Methamphetamine Modeling Molecular Movement Mus Neurons Neurosciences Nucleus Accumbens Parkinson Disease Pathologic Pathology Pathway interactions Pharmaceutical Preparations Phenotype Play Population Protein phosphatase Proteins Regimen Regulation Research Risk Rodent Role Signal Transduction Site Substantia nigra structure Synapses Tamoxifen Testing Toxic effect Transgenic Mice Ventral Striatum Vertebral column addiction behavioral sensitization cell type cocaine exposure density dopaminergic neuron drug of abuse exposed human population improved interest knockout animal methamphetamine abuse novel postsynaptic programs protein expression protein function psychostimulant public health relevance response scaffold spinophilin success synaptic function targeted treatment tool

项目摘要

DESCRIPTION: The brain is made up of many different types of neurons. For example, one class of neuron in the striatum is called the medium spiny neuron (MSN). These spiny neurons are so called because they contain dendritic spines that form connections, called synapses, with glutamate-containing axons from the cortex and dopamine containing axons from the substantia nigra. The dendritic spines on the MSNs contain signaling and scaffolding molecules in an electron dense area called the postsynaptic density. Psychostimulant drugs of abuse act to increase dopamine release from nigral dopaminergic neurons, which has downstream effects on proteins that are localized to MSN dendritic spines. One protein, spinophilin, is increased upon chronic exposure to psychostimulant drugs of abuse. Striatal MSNs can be subdivided into two classes, direct and indirect pathway neurons. Currently there are very few ways to evaluate the function of synaptic proteins in the different classes of MSNs. This is important because the two classes of MSNs have different responses to psychostimulant exposure. The goal of our proposal is to determine the function of spinophilin in the two classes of MSNs in regulating responses to chronic non-toxic and toxic regimens of psychomotor stimulants such as cocaine and amphetamines. Determining the cell-specific role of spinophilin in mediating pathologies associated with these drugs of abuse will identify new pathways that can be targeted for treatment of addiction and disorders associated with long-term methamphetamine abuse, such as Parkinson disease (PD). In this proposal, we hypothesize that spinophilin plays a unique role in the two MSN populations in mediating psychostimulant-induced pathologies. This hypothesis will be tested using the following specific aims: Aim 1. (R21). Generate and validate mouse lines expressing tamoxifen-inducible, iCre in direct and indirect pathway MSNs. We will generate mouse lines that express a tamoxifen-inducible, improved Cre (iCre) recombinase in direct or indirect pathway MSNs. Aim 2. (R21). Generate and validate floxed spinophilin (Spinofl/fl) mice. We will generate a novel transgenic mouse line that will be crossed with the iCre animals generated in aim 1 to create MSN-specific spinophilin KO animals. Aim 3. (R33). Determine the role of spinophilin in direct and indirect pathway MSNs on psychostimulant sensitization. We will use mice created in aims 1 and 2 to determine the function of spinophilin in the two MSN populations on the regulation of pathologies associated with psychostimulant-induced sensitization Aim 4. (R33). Determine the role of spinophilin in direct and indirect pathway MSNs on METH toxicity. We will use mice created in aims 1 and 2 to determine the function of spinophilin in the two MSN populations on the regulation of pathologies associated with methamphetamine-induced toxicity.

描述：大脑由许多不同类型的神经元组成，例如，纹状体中的一类神经元称为中型多棘神经元（MSN），这些多棘神经元之所以如此，是因为它们包含形成连接的树突棘。 MSN 上的树突棘包含来自皮质的含谷氨酸的轴突和来自黑质的含多巴胺的轴突。电子密集区域（称为突触后密度）中的信号传导和支架分子会增加黑质多巴胺能神经元的多巴胺释放，这对位于 MSN 树突棘的蛋白质产生下游影响。长期接触滥用精神兴奋药物的纹状体 MSN 可分为两类：直接通路神经元和间接通路神经元。这很重要，因为两类 MSN 对精神兴奋剂暴露有不同的反应，我们建议的目标是确定两类 MSN 中的亲旋蛋白在调节对慢性非兴奋剂的反应中的功能。确定可卡因和安非他明等精神运动兴奋剂在介导与这些滥用药物相关的病理学中的细胞特异性作用将确定可针对的新途径。用于治疗与长期甲基苯丙胺滥用相关的成瘾和疾病，例如帕金森病 (PD)。在该提案中，我们认为 Spinophilin 在调节精神兴奋剂引起的病理学中发挥着独特的作用。使用以下具体目标进行测试：目标 1. (R21). 生成并验证在直接和间接途径 MSN 中表达他莫昔芬诱导型 iCre 的小鼠系。直接或间接途径 MSN 中他莫昔芬诱导的改良 Cre (iCre) 重组酶。 (R21)。生成并验证 floxed spinophilin (Spinofl/fl) 小鼠。目标 1 中生成的 iCre 动物用于创建 MSN 特异性亲旋蛋白 KO 动物。目的 3. (R33) 确定亲旋蛋白在直接中的作用。和间接途径 MSN 对精神兴奋剂致敏的影响我们将使用目标 1 和 2 中创建的小鼠来确定亲旋素在两个 MSN 群体中对精神兴奋剂引起的致敏相关病理的调节作用。目标 4（R33）。直接和间接途径 MSN 中的嗜旋蛋白对 METH 毒性的影响我们将使用目标 1 和 2 中创建的小鼠来确定嗜旋蛋白在这两个途径中的功能。 MSN 群体对甲基苯丙胺引起的毒性相关病理的调节。