Effects of social isolation and enrichment on communication impairment in a translational model of PD

摘要 帕金森病（Parkinson disease，PD）是一种复杂的神经退行性疾病，以肢体运动、感觉运动、 和非运动特征，包括焦虑、抑郁和认知功能障碍。90%的PD患者 经历严重的沟通缺陷，降低生活质量。发声功能，认知能力， 焦虑/抑郁的调节对于有意义的社会互动至关重要;因此，PD患者通常 经历了令人衰弱的社会孤立。社交孤立的生活条件如何影响语音交流， 然而，PD患者的认知能力和健康状况尚不清楚，特别是在早期和中期疾病中。 此外，调节这些行为的潜在大脑病理学没有得到充分描述。因为这些 知识的关键差距，沟通，认知和焦虑/抑郁方面的缺陷在很大程度上仍然不足- 治疗。我们建议研究社会互动如何与发声功能，认知，幸福感， 使用早发性PD（Pink 1-/-）的经验证的大鼠模型的神经病理学进展。该模型 再现了发病后喉和脑干病理的声音沟通缺陷， 类似于人类的渐进式时间轴。我们的中心假设是，社会隔离进一步有助于 发声退化，通过社会充实干预增加发声机会将减缓 声音沟通缺陷的发作和进展，改善认知功能，减少焦虑， 快感缺乏是抑郁症的标志此外，我们假设，神经化学成分的关键领域， 言语运动和认知/情绪控制（腹侧被盖区，内侧前额叶皮层， 黑质）将被社会条件改变。我们提出了两个具体目标：目标1将量化 社会条件对Pink 1-/-和Pink 2-/-儿童言语交流、认知、焦虑和快感缺乏影响 WT大鼠。将Pink 1-/-和野生型（WT）对照大鼠随机分配至3个实验处理组 条件：（1）控制，（2）隔离，和（3）社会丰富（每周实施5次，以促进社会和 与同类的发声机会）。使用已建立的大鼠行为测试，声音交流，认知， 焦虑和快感缺乏将在以下疾病阶段进行量化和统计学比较：前驱期 （2、4月龄）、早期（6月龄）和中期（8、10月龄）。此外，目标2将确定如何社会 条件影响腹侧被盖区，内侧前额叶皮层， Pink 1-/-和WT大鼠的黑质。将对这些区域的脑组织进行多巴胺检测， 在10个月时使用高压液相色谱法测定去甲肾上腺素和5-羟色胺浓度。这项工作 是及时和重要的，因为它将导致更好地了解社会隔离如何有助于 PD相关沟通功能障碍的复杂病理学，并提供如何 丰富的社会生活可以减轻这些缺陷，改变大脑神经化学。我的首要目标是 培训的目的是为开展直接影响人类健康的研究奠定基础。

Abstract Parkinson disease (PD) is a complex, neurodegnerative disorder characterized by limb motor, sensorimotor, and non-motor features including anxiety, depression, and cognitive dysfunction. 90% of individuals with PD experience significant communication deficits that diminish quality of life. Vocal function, cognitive skill, and regulation of anxiety/depression are essential for meaningful social interactions; thus, individuals with PD often experience debilitating social isolation. How socially-isolating living conditions impact vocal communication, cognitive abilities, and well-being in PD, however, is not known, especially in early and mid-stage disease. Further, the underlying brain pathology that modulates these behaviors is not fully described. Because of these critical gaps in knowledge, deficits in communication, cognition, and anxiety/depression remain largely under- treated. We propose to study how social interaction relates to vocal function, cognition, well-being, and neuropathological progression using a validated rat model of early-onset PD (Pink1-/-). This model recapitulates vocal communication deficits with laryngeal and brainstem pathology that follows an onset and progressive timeline analogous to humans. Our central hypotheses are that social isolation further contributes to vocal degradation, and enhancing vocal opportunities with a social enrichment intervention will slow the onset and progression of vocal communication deficits, improve cognitive function, and decrease anxiety and anhedonia, a marker for depression. Further, we hypothesize that neurochemical content in areas critical for speech motor and cognitive/emotional control (the ventral tegmental area, medial prefrontal cortex, and substantia nigra) will be altered by social condition. We propose two specific aims: Aim 1 will quantify the impact of social condition on vocal communication, cognition, anxiety, and anhedonia in Pink1-/- and WT rats. Pink1-/- and wildtype (WT) control rats will be randomly assigned to 3 experimental treatment conditions: (1) control, (2) isolation, and (3) social enrichment (implemented 5x per week to facilitate social and vocal opportunities with conspecifics). Using established rat behavior tests, vocal communication, cognition, anxiety, and anhedonia will be quantified and statistically compared at the following disease stages: prodromal (2, 4 mo of age), early (6 mo), and mid-stage (8,10 mo). Additionally, Aim 2 will determine how social condition affects catecholamine concentrations in the ventral tegmental area, medial prefrontal cortex, and substantia nigra of Pink1-/- and WT rats. Brain tissue from these regions will be assayed for dopamine, norepinephrine, and serotonin concentrations using high pressure liquid chromatography at 10 mo. This work is timely and significant as it will lead to a better understanding of how social isolation contributes to the complex pathology of PD-related communication dysfunction and provide foundational knowledge of how social enrichment may attenuate these deficits and change brain neurochemistry. The overarching goal of my training is to provide a foundation to conduct research that has a direct translation to human health.