Highly evolved brain circuits in primates: molecular vulnerabilities for disease

描述（由申请人提供）：认知障碍如阿尔茨海默病（AD），额颞叶痴呆和精神分裂症是我们社会的巨大负担，因为患者通常无法照顾自己，并且需要多年的大量资源。随着未来几十年我们社会的老龄化，这些疾病将成为更大的负担。目前的治疗方法是不充分的，这一领域的研究仍然集中在小鼠模型上。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层，而这些皮层在小鼠中发育不良，而初级感觉皮层在这些疾病中几乎没有受到影响。是什么让联想皮层如此脆弱？为什么更基本的皮层区域，比如感觉皮层，对疾病的抵抗力更强？这些都是与医学直接相关的令人着迷的进化问题。拟议的研究将验证以下假设：高度进化的灵长类动物联想皮层更容易受到疾病的影响，因为它们受到Ca2+-cAMP信号通路的调节，其方式与进化上较老的感觉皮层完全不同，并且遗传或环境损伤后Ca2+-cAMP信号通路的失调易使这些高级回路功能障碍和退化，例如通过tau蛋白的超磷酸化。我们的数据显示，灵长类动物前额叶关联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轻微损害也会损害认知，并可能增加退化的风险。这些蛋白质中有相当一部分在基因上与精神分裂症有关，并且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Ca2+-cAMP信号的敏感性基于它们的进化过程

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