Highly evolved brain circuits in primates: molecular vulnerabilities for disease

描述(申请人提供)：认知障碍，如阿尔茨海默病(AD)，额-颞叶痴呆和精神分裂症是我们社会的巨大负担，因为患者经常无法照顾自己，并且需要多年的广泛资源。随着我们的社会在未来几十年变得更加老龄化，这些疾病将成为一个更大的负担。目前的治疗方法是不够的，这一领域的研究继续集中在老鼠模型上。然而，阿尔茨海默病、精神分裂症和相关的认知障碍主要影响高度进化的关联皮质，而初级感觉皮质在这些障碍中几乎没有受到影响。是什么让大脑皮层如此脆弱？为什么更基本的皮质区域，如感觉皮质，对疾病更具抵抗力？这些都是与医学直接相关的引人入胜的进化论问题。这项拟议的研究将检验一种假设，即高度进化的灵长类联合皮质更容易受到疾病的影响，因为它们受到钙-cAMP信号通路的调控，其方式与进化上较老的感觉皮质完全不同，并且遗传或环境侮辱后钙-cAMP信号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，灵长类前额叶联想回路在其网络连接附近含有高水平的cAMP调节的K+通道，通常用于门控输入和提供心理灵活性。然而，这一过程需要精确的监管，即使是对监管过程的微小侮辱也会损害认知，并可能增加退化的风险。这些蛋白质中有惊人数量与精神分裂症有基因联系，并随着年龄的增长而变化。我们假设灵长类皮质回路对钙-cAMP信号具有不同的敏感性，基于它们的进化阶段

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