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)等共核病都是阿尔茨海默病相关疾病(ADRD)，是世界上最常见和增长最快的痴呆症类型。此外，突触核蛋白病理越来越被认为是痴呆症(如阿尔茨海默病)混合病理的一部分。虽然与突触核蛋白相关的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的震颤、迟缓和僵硬，但在认知和情感脑网络中也可以看到蛋白质α-突触核蛋白纤维的积累，从而导致痴呆。患者和他们的家人正在与一系列认知和情感症状作斗争，这些症状通常被称为“非运动症状”，严重影响了他们的生活质量。到2040年，仅因突触核蛋白相关的ADRD，全球将有近2000万患者患有认知障碍、冲动、幻觉、焦虑和其他痴呆症特征，这些非运动症状几乎没有有效的治疗方法。所有与突触核蛋白相关的痴呆的一个共同特征是，年龄是最重要的风险因素。然而，尽管年龄是一种危险因素，但在认知和网络功能障碍中，年龄和α-突触核蛋白之间的具体相互作用仍未得到很大程度的研究，也是理解年龄依赖型痴呆和神经退行性变机制的一个重要需求。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，实验性种植突触核蛋白预形成的纤维(PFF)可以诱导幼年小鼠大脑皮质振荡的变化，影响中皮质边缘网络的突触核蛋白病理可以导致认知和情感障碍，在正常衰老中，中皮质边缘网络功能也受到损害。此外，在阿尔茨海默病小鼠模型中，非侵入性的伽马波段神经调节可以改善认知并延缓神经病理的进展。我们实验室建立的老龄大鼠模型和注射PFF在评估衰老和突触核蛋白病理之间相互作用的认知和情感效应方面具有特殊的价值。老鼠在评估认知和行为功能障碍方面有丰富的行为能力。将预先形成的突触核蛋白纤维注射到腹侧被盖区，可以在给定的时间点将快速进展的病理靶向已知的表现为突触核蛋白病理的中皮质边缘结构，这类似于人类LBD和PDD的非运动性疾病和进展。这项建议的目的是开发一种实验方法，概括LBD和PDD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痴呆相关的认知/动机和神经网络结果的交互影响，并测试基于伽玛波治疗对阿尔茨海默病小鼠模型有效的这些非运动症状的神经调节疗法。我们的理论基础是，这些实验将有助于确定中皮质边缘网络在年龄相关性突触核病认知症状中的作用，并在未来解决突触核蛋白相关痴呆的研究中确定治疗性神经调节的框架。

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.