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

描述（由申请人提供）：本提案的目的是研究神经毒性损伤黑质纹状体多巴胺能系统对血清素能系统的影响，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患者明显比其他类似残疾的患者更抑郁。在分子水平上，血清素能和多巴胺能系统之间的相互作用有助于情绪障碍，包括焦虑和抑郁，并可能是PD中情绪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）损伤小鼠将被用作模型，因为纹状体DA随时间的恢复和多巴胺能系统的内在可塑性。在提出的研究中，我们将测试假设，即在mptp损伤小鼠的血清素能系统中存在动态行为，分子和形态学改变。小鼠将接受MPTP或生理盐水，并在损伤后第5天（MPTP诱导的细胞完全死亡的早期急性耗竭）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）高效液相色谱法检测纹状体多巴胺和血清素，（iii）致密黑质多巴胺能神经元和中脑背5-羟色胺能神经元的细胞计数，（iv）中脑、纹状体、边缘系统和额叶皮层5-羟色胺受体1a、1b、2a和2c的mRNA表达。我们假设在mptp损伤后血清素能系统急剧增加，然后下调以促进多巴胺能神经传递。DA回归后5-羟色胺神经传导恢复正常。此外，5-羟色胺系统的增加或减少驱动焦虑和抑郁的变化。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。我们假设阉割会增加mptp损伤小鼠的焦虑和抑郁。伍德博士将与南加州大学凯克医学院（Keck School of Medicine of USC）神经内科的Michael Jakowec博士合作，接受血清素及其受体测量分子技术的培训。此外，她还将在斯克里普斯研究所（the Scripps Research Institute）的乔治·f·库布（George F. Koob）博士的实验室里学习研究小鼠焦虑和抑郁的其他方法。

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.