Cognitive and Affective Network Dysfunction and Neuromodulation in Aging and Synucleinopathy

突触核蛋白病，如路易体痴呆（LBD）和帕金森病痴呆（PDD），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，突触核蛋白病理在阿尔茨海默病等痴呆症的混合病理中也越来越受到重视。虽然突触核蛋白相关的不良反应通常被认为是由黑质纹状体网络运动结构退化引起的震颤、迟缓和僵硬，但在认知和情感脑网络中也可以看到α -突触核蛋白原纤维的积累，从而导致痴呆。患者及其家属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”，对他们的生活质量产生重大影响。到2040年，全世界将有近2000万患者仅因突触核蛋白相关的不良反应而出现认知障碍、冲动、幻觉、焦虑和其他痴呆特征，而对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危险因素。然而，尽管年龄是一个风险因素，但年龄和a-突触核蛋白在认知和网络功能障碍中的具体相互作用在很大程度上仍未被研究，这是理解年龄依赖性痴呆和神经退行性疾病机制的重要需求。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为青壮年，很少考虑年龄因素。已发表的和初步的数据表明，突触核蛋白预形成原纤维（PFF）的实验播种诱导了年轻成年小鼠皮层振荡的变化，突触核蛋白病理影响中脑皮质边缘网络可诱导认知和情感缺陷，并且中脑皮质边缘网络功能在正常衰老中也受到损害。此外，非侵入性γ波段神经调节可改善阿尔茨海默病小鼠模型的认知并延缓神经病理学进展。本实验室老龄大鼠模型的建立和PFF注射在评估衰老与突触核蛋白病理相互作用的认知和情感效应方面具有特殊价值。大鼠有丰富的行为剧目来评估认知和行为功能障碍。将预先形成的突触核蛋白原纤维注射到腹侧被皮层区，可以在给定的时间点将快速进展的病理靶向到已知显示突触核蛋白病理的中皮质边缘结构，这类似于人类LBD和PDD的非运动疾病和进展。本提案的目的是开发一种实验方法，概括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，确定老年和a-突触核蛋白病理对突触核蛋白相关痴呆的认知/动机和神经网络结果的相互作用。并在阿尔茨海默病小鼠模型中有效的伽马带疗法的基础上，测试对这些非运动症状的神经调节疗法。我们的基本原理是，这些实验将有助于确定中皮质边缘网络在年龄相关突触核蛋白病认知症状中的作用，并确定未来研究中治疗性神经调节的框架，以解决突触核蛋白相关痴呆。

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.