Highly evolved brain circuits in primates: molecular vulnerabilities for disease

灵长类动物高度进化的大脑回路：疾病的分子脆弱性

• 批准号: 8558580
• 负责人: AMY F.T. ARNSTEN
• 金额: $ 83.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8558580
• 关键词: Affect; Alzheimer' s Disease; Area; Brain; Caring; Cognition Disorders; Cyclic AMP; Data; Disease; Disease Resistance; Elderly; Employee Strikes; Frontotemporal Dementia; Functional disorder; Genetic; Impaired cognition; Link; Medical; Molecular; Mus; Patients; Potassium Channel; Primates; Process; Proteins; Psyche structure; Regulation; Research; Resources; Risk; Schizophrenia; Signal Pathway; Signal Transduction; Societies; Testing; association cortex; base; fascinate; flexibility; mouse model; sensory cortex; tau phosphorylation

DESCRIPTION (provided by applicant): Cognitive disorders such as Alzheimer's Disease (AD), Fronto-Temporal Dementia and schizophrenia are a tremendous burden on our society, as patients are often unable to care for themselves, and require extensive resources for many years. These disorders will be an even greater burden as our society grows older in the next decades. Current treatments are inadequate, and research in this arena continues to focus on mouse models. However, AD, schizophrenia, and related cognitive disorders primarily afflict the highly evolved association cortices which are poorly developed in mice, while the primary sensory cortices are little affected in these disorders. What makes the association cortices so vulnerable? And why are more basic cortical areas, such as the sensory cortices, more resistant to disease? These are fascinating evolutionary questions with immediate medical relevance. The proposed research will test the hypothesis that the highly evolved primate association cortices are more vulnerable to disease because they are regulated by Ca2+-cAMP signaling pathways in a fundamentally different manner than the evolutionarily older, sensory cortices, and that dysregulation of Ca2+-cAMP signaling following genetic or environmental insults predisposes these higher circuits to dysfunction and degeneration, e.g. through hyper-phosphorylation of tau. Our data have revealed that primate prefrontal association circuits contain high levels of cAMP-regulated K+ channels near their network connections that normally serve to gate inputs and provide mental flexibility. However, this process requires precise regulation, and even small insults to regulatory processes impair cognition and may increase risk for degeneration. A striking number of these proteins are genetically linked to schizophrenia, and show changes with advancing age. We hypothesize that primate cortical circuits will have differing sensitivities to Ca2+-cAMP signaling based on their evolutionary st

描述（由申请人提供）：认知障碍，如阿尔茨海默病（AD），额颞叶痴呆症和精神分裂症是我们社会的巨大负担，因为患者往往无法照顾自己，并需要多年的广泛资源。在未来几十年里，随着我们社会的老龄化，这些疾病将成为更大的负担。目前的治疗是不够的，在这个竞技场的研究继续集中在小鼠模型。然而，AD、精神分裂症和相关的认知障碍主要困扰小鼠中发育不良的高度进化的联合皮层，而初级感觉皮层在这些障碍中几乎不受影响。是什么让联合皮层如此脆弱？为什么更基本的皮层区域，如感觉皮层，更能抵抗疾病？这些都是有趣的进化问题，与医学有直接的关联。这项拟议的研究将检验这样一个假设，即高度进化的灵长类动物联合皮层更容易受到疾病的影响，因为它们受到Ca 2 +-cAMP信号通路的调节，其方式与进化上较老的感觉皮层根本不同，并且遗传或环境损伤后Ca 2 +-cAMP信号通路的失调使这些高级回路易于功能障碍和退化。例如通过tau的过度磷酸化。我们的数据显示，灵长类前额叶联合回路在其网络连接附近含有高水平的cAMP调节的K+通道，这些通道通常用于门控输入并提供心理灵活性。然而，这一过程需要精确的调节，即使是对调节过程的微小损害也会损害认知，并可能增加变性的风险。这些蛋白质中有惊人数量与精神分裂症有遗传联系，并随着年龄的增长而发生变化。我们假设灵长类动物皮层回路对Ca 2 +-cAMP信号的敏感性因其进化过程不同而不同。