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

描述(申请人提供)：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5-羟色胺能系统的影响，以了解这些变化如何影响帕金森病(PD)的情感和运动功能障碍。越来越明显的是，帕金森氏症不仅仅是一种运动障碍。帕金森病患者明显比其他类似残疾的患者更抑郁。在分子水平上，5-羟色胺能系统和多巴胺能系统之间的相互作用导致了包括焦虑和抑郁在内的情感障碍，并可能是帕金森病患者情感障碍和运动功能障碍之间密切关系的基础。这里将使用1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)损伤的小鼠作为模型，因为随着时间的推移，纹状体DA的恢复和多巴胺能系统的内在可塑性。在拟议的研究中，我们将检验这一假设，即MPTP损伤小鼠的5-羟色胺能系统存在动态的行为、分子和形态变化。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时早期，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)纹状体多巴胺和5-羟色胺；(Iii)黑质致密部多巴胺能神经元和中缝背侧5-羟色胺能神经元的细胞计数；以及(Iv)5-羟色胺受体1a、1b、2a和2c在中脑、纹状体、边缘系统和额叶皮质的mRNA表达。我们假设，在MPTP损伤后，5-羟色胺能系统急剧增加，然后被下调，试图促进多巴胺能神经传递。随着DA的回归，5-羟色胺的神经传递恢复正常。此外，5-羟色胺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帕金森病情感障碍易感性中的作用。我们假设去势会增加MPTP损毁小鼠的焦虑和抑郁。伍德博士将与南加州大学凯克医学院神经病学系的迈克尔·雅科维克博士合作，接受测量5-羟色胺及其受体的分子技术方面的培训。此外，她还将在斯克里普斯研究所乔治·F·库布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.