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

摘要 帕金森病(PD)是一种复杂的神经退行性疾病，以肢体运动、感觉运动、 以及非运动性特征，包括焦虑、抑郁和认知功能障碍。90%的帕金森病患者 经历严重的沟通障碍，降低生活质量。发声功能、认知技能和 焦虑/抑郁的调节对于有意义的社会互动是必不可少的；因此，帕金森病患者通常 经历令人衰弱的社会孤立。与世隔绝的生活环境如何影响语音交流， 然而，帕金森病的认知能力和幸福感尚不清楚，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还没有完全描述。正因为如此 知识方面的严重差距、沟通、认知方面的缺陷以及焦虑/抑郁在很大程度上仍然低于- 治疗过了。我们建议研究社会互动如何与发声功能、认知、幸福感和 使用经过验证的早发性帕金森病大鼠模型(PINK1-/-)进行神经病理进展。这款车 摘要声带沟通障碍与喉部和脑干病理后，起病和 类似于人类的渐进时间线。我们的中心假设是，社会孤立进一步推动了 声音退化，通过社会丰富干预增加发声机会将减缓 发声沟通障碍的发生和发展，改善认知功能，降低焦虑和 快感缺乏，这是抑郁症的标志。此外，我们假设关键区域的神经化学含量对 语言运动和认知/情绪控制(腹侧被盖区、内侧前额叶皮质和 黑质)会因社会条件而改变。我们提出了两个具体目标：目标1将量化 社会条件对PINK1-/-和PINK1-/-患者发声交流、认知、焦虑和快感缺失的影响 WT大鼠。PINK1-/-和野生型(WT)对照组大鼠将随机分为3个实验处理组 条件：(1)控制，(2)隔离，(3)社会充实(每周实施5次，以促进社会和 具有相同细节的发声机会)。利用已建立的老鼠行为测试，发声交流，认知， 焦虑和快感缺乏将在以下疾病阶段进行量化和统计比较：前驱症状 (2、4个月龄)、早期(6个月)、中期(8、10个月)。此外，《目标2》将决定如何社交 疾病影响腹侧被盖区、内侧前额叶皮质、 PINK1-/-和WT大鼠黑质。这些区域的脑组织将被检测多巴胺， 去甲肾上腺素和5-羟色胺浓度在10个月时用高压液相色谱仪测定。这部作品 是及时和重要的，因为它将导致更好地理解社会孤立是如何导致 帕金森病相关沟通障碍的复杂病理，并提供有关如何 社会财富可能会减轻这些缺陷，并改变大脑的神经化学。我的首要目标是 培训是为了提供一个基础，以进行对人类健康有直接影响的研究。

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.