Cognitive and Affective Network Dysfunction and Neuromodulation in Aging and Synucleinopathy

路易体痴呆（LBD）和帕金森病痴呆（PDD）等突触核蛋白病都是阿尔茨海默病相关疾病（ADRD），是世界上最常见且增长最快的痴呆类型之一。此外，突触核蛋白病理学越来越多地被理解为有助于痴呆症如阿尔茨海默病中的混合病理学。虽然突触核蛋白相关的ADRD通常被认为是由于黑质纹状体网络的运动结构退化而引起震颤、迟钝和僵硬，但在认知和情感脑网络中也观察到蛋白质α-突触核蛋白原纤维的积累，导致痴呆。患者及其家属与一系列认知和情感症状作斗争，通常被称为“非运动症状”，对他们的生活质量有重大影响。到2040年，全球将有近2000万患者患有认知障碍，冲动，幻觉和焦虑以及仅来自突触核蛋白相关ADRD的痴呆症的其他特征，对于这些非运动症状几乎没有有效的治疗方法。所有突触核蛋白相关痴呆的一个共同特征是年龄是最重要的风险因素。尽管年龄作为一个危险因素的作用，然而，在认知和网络功能障碍的年龄和α-突触核蛋白之间的特定的相互作用仍然在很大程度上未被研究，并在理解年龄依赖性痴呆和神经退行性变的机制的一个重要的未满足的需求。此外，用于研究LBD和PDD病理生理机制的突触核蛋白动物模型通常是年轻人，很少考虑年龄。已发表的和初步的数据表明，突触核蛋白预形成的原纤维（PFF）的实验播种诱导的变化，在年轻的成年小鼠的皮质振荡，突触核蛋白的病理影响mesocorticolimbic网络可以诱导认知和情感缺陷，和mesocorticolimbic网络功能也受到损害，在正常老化。此外，非侵入性的γ-波段神经调节改善了阿尔茨海默病小鼠模型的认知能力并延缓了神经病理学的进展。本实验室建立的老年大鼠模型和注射PFF对评估衰老与突触核蛋白病理学之间相互作用的认知和情感效应具有特别的价值。大鼠具有用于评估认知和行为功能障碍的丰富的行为库。将预先形成的突触核蛋白原纤维注射到腹侧被盖区中允许在给定时间点将快速进行性病理靶向至已知显示突触核蛋白病理的中皮质边缘结构，其类似于人LBD和PDD非运动疾病和进展。该提案的目的是开发一种实验方法，该方法概括了LBD和PDD中认知和情感功能障碍的行为、病理和神经网络特征，确定高龄和α-突触核蛋白病理对与突触核蛋白相关的痴呆相关的认知/动机和神经网络结果的相互作用，并基于在阿尔茨海默氏病小鼠模型中有效的γ-波段疗法来测试针对这些非运动症状的神经调节疗法。我们的理由是，这些实验将有助于建立中皮质边缘网络在年龄相关性突触核蛋白病的认知症状中的作用，并在未来的研究中确定治疗性神经调节的框架，以解决突触核蛋白相关性痴呆。

Synucleinopathies such as Lewy body dementia (LBD) and Parkinson’s disease dementia (PDD), both Alzheimer’s disease-related disorders (ADRD), are some of the most common and fastest growing types of dementia in the world. In addition, synuclein pathology is increasingly appreciated as contributing to mixed pathology in dementias such as Alzheimer’s disease. Although synuclein-associated ADRDs are commonly thought of as causing tremor, slowness, and stiffness from degeneration of the motor structures of the nigrostriatal network, the accumulation of the protein alpha- synuclein fibrils is also seen in cognitive and affective brain networks, leading to dementia. Patients and their families struggle with a host of cognitive and affective symptoms, usually referred to as ‘non-motor symptoms”, with significant impact on their quality of life. By 2040 there will be close to 20 million patients world-wide with cognitive impairment, impulsivity, hallucinations, and anxiety, and other features of dementia just from synuclein-associated ADRDs alone, with few effective therapies for these non-motor symptoms. A common feature of all synuclein-related dementias is that age is the most significant risk factor. Despite the role of age as a risk factor, however, the specific interactions between age and a-synuclein in cognitive and network dysfunction remain largely unstudied and an important unmet need in understanding the mechanisms of age-dependent dementia and neurodegeneration. Moreover, synuclein animal models used to study pathophysiologic mechanisms of LBD and PDD are usually young adults, and rarely take age into account. Published and preliminary data show that experimental seeding of synuclein preformed fibrils (PFF) induces changes in oscillations in the cortex of young adult mice, that synuclein pathology affecting the mesocorticolimbic network can induce cognitive and affective deficits, and that mesocorticolimbic network function is also compromised in normal aging. Moreover, non-invasive, gamma-band neuromodulation improves cognition and delays progression of neuropathology in mouse models of Alzheimer’s disease. The establishment of aged rat models and PFF injections in our lab have particular value in assessing the cognitive and affective effects of the interaction between aging and synuclein pathology. Rats have a rich behavioral repertoire for assessment of cognitive and behavioral dysfunction. The injection of preformed synuclein fibrils into the ventral tegmental area allows for the targeting of a rapidly progressive pathology at a given timepoint to a mesocorticolimbic structure known to show synuclein pathology, which is analogous to human LBD and PDD non-motor disease and progression. The objective of this proposal is to is to develop an experimental approach that recapitulates behavioral, pathological, and neural network signatures of cognitive and affective dysfunction in LBD and PDD, determine the interacting effects of advanced age and a-synuclein pathology on cognitive/motivational and neural network outcomes relevant for synuclein-related dementias, and test a neuromodulatory therapy for these non-motor symptoms based on gamma-band therapies efficacious in Alzheimer’s disease mouse models. Our rationale is that these experiments will help to establish the role of the mesocorticolimbic network in cognitive symptoms in age-related synucleinopathy, and identify a framework for therapeutic neuromodulation in future studies that addresses synuclein-associated dementias.