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Anxiety, depression, and serotonergic dysregulation in Parkinson's Disease

帕金森病的焦虑、抑郁和血清素失调

基本信息

批准号：
7333987
负责人：
RUTH I. WOOD
金额：
$ 17.58万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-16 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7333987
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Acute Affective Animal Model Anxiety Autopsy Basal Ganglia Behavior Disorders Behavioral Biological Models Brain Injuries Castration Cell Count Cell Death Characteristics Corpus striatum structure Depressed mood Development Disabled Persons Disease Dopamine Dorsal Estrogens Functional disorder Goals Gonadal Steroid Hormones High Pressure Liquid Chromatography Human Hysterectomy Incidence Injury Laboratories Learning Lesion Limbic System Literature Measurement Menopause Mental Depression Midbrain structure Modeling Molecular Mood Disorders Motor Mus Neurology Neurons Numbers Parkinson Disease Patients Personal Satisfaction Predisposition Purpose Quality of life Recovery Reporting Research Institute Role Saline Serotonin Staging Substantia nigra structure Synapses System Techniques Testing Thinking Time Training Woman Wood material Work day dopaminergic neuron frontal lobe functional disability insight mRNA Expression medical schools motor deficit motor disorder motor impairment mouse model neural circuit neurochemistry neurotoxic neurotransmission neurotransmitter biosynthesis pars compacta receptor receptor expression response serotonin receptor steroid hormone

项目摘要

DESCRIPTION (provided by applicant): The purpose of this proposal is to investigate the effects of neurotoxic injury to the nigrostriatal dopaminergic system on the serotonergic system to understand how these alterations influence affective and motor dysfunction in Parkinson's Disease (PD). It is becoming evident that PD is not simply a motor disorder. Patients with PD are significantly more depressed than other similarly-disabled patients. At the molecular level, interactions between the serotonergic and dopaminergic systems contribute to affective disorders including anxiety and depression, and may underlie the close relationship between affective and motor dysfunction in PD. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse will be used here as a model since there is return of striatal DA and intrinsic plasticity of the dopaminergic system over time. In the proposed studies, we will test the hypothesis that there are dynamic behavioral, molecular, and morphological alterations in the serotonergic system in the MPTP-lesioned mouse. Mice will receive MPTP or saline and analyzed at post-lesioned days 5 (early, acute depletion when MPTP-induced cell death is complete), and 35 (partial DA recovery). Analyses will include (i) depression and anxiety; (ii) striatal dopamine and serotonin by HPLC, (iii) cell counts of dopaminergic neurons in substantia nigra pars compacta and serotonergic neurons in the dorsal raphe, and (iv) mRNA expression of 5-HT receptors 1a, 1b, 2a, and 2c in midbrain, striatum, limbic system, and frontal cortex. We hypothesize that there is an acute increase in the serotonergic system after MPTP-lesioning that is then down-regulated in an attempt to facilitate dopaminergic neurotransmission. As DA returns 5-HT neurotransmission normalizes. Furthermore, increases or decreases in the 5-HT system drive changes in anxiety and depression. A secondary goal of our studies is to determine the role of steroid hormones in susceptibility to affective disorders in PD. We hypothesize that castration will increase anxiety and depression in the MPTP-lesioned mouse. Working with Dr. Michael Jakowec of the Department of Neurology at the Keck School of Medicine of USC, Dr. Wood will receive training in molecular techniques for measurement of serotonin and its receptors. In addition, she will spend time in the laboratory of Dr. George F. Koob at The Scripps Research Institute to learn additional approaches to study anxiety and depression in mice.

描述（由申请方提供）：本提案的目的是研究黑质纹状体多巴胺能系统的神经毒性损伤对多巴胺能系统的影响，以了解这些改变如何影响帕金森病（PD）的情感和运动功能障碍。越来越明显的是，PD不仅仅是一种运动障碍。PD患者比其他类似残疾患者更抑郁。在分子水平上，多巴胺能和多巴胺能系统之间的相互作用有助于情感障碍，包括焦虑和抑郁，并可能成为PD中情感和运动功能障碍之间密切关系的基础。1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）损伤的小鼠将在此用作模型，因为随着时间的推移，纹状体DA和多巴胺能系统的内在可塑性恢复。在拟议的研究中，我们将测试的假设，有动态的行为，分子和形态学的改变，在MPTP损伤的小鼠的多巴胺能系统。小鼠将接受MPTP或盐水，并在损伤后第5天（当MPTP诱导的细胞死亡完成时的早期急性消耗）和第35天（部分DA恢复）进行分析。分析将包括（i）抑郁和焦虑;（ii）通过HPLC测定的纹状体多巴胺和5-羟色胺;（iii）黑质丘脑部多巴胺能神经元和中缝背核多巴胺能神经元的细胞计数;（iv）中脑、纹状体、边缘系统和额叶皮质中5-HT受体1a、1b、2a和2c的mRNA表达。我们推测MPTP损伤后多巴胺能神经系统有急性增加，然后下调，试图促进多巴胺能神经传递。随着DA的恢复，5-HT神经传递正常化。此外，5-HT系统的增加或减少会导致焦虑和抑郁的变化。我们研究的第二个目标是确定类固醇激素在PD患者情感障碍易感性中的作用。我们假设去势会增加MPTP损伤小鼠的焦虑和抑郁。与南加州大学凯克医学院神经病学系的Michael Jakowec博士合作，Wood博士将接受测量血清素及其受体的分子技术培训。此外，她还将在乔治F博士的实验室度过一段时间。Koob在斯克里普斯研究所学习其他方法来研究小鼠的焦虑和抑郁。