Fronto-insular network in cognitive-affective interactions during decision-making

摘要 阿尔茨海默病(AD)是最常见的与年龄相关的神经退行性疾病之一， 对从记忆到决策等广泛的大脑功能产生毁灭性的影响。虽然众所周知 阿尔茨海默病会损害认知功能，神经精神症状在有AD风险或患有AD的人中很常见 预测认知障碍的发生率。人脑成像研究强调了大脑的网络 各区域，特别是内侧前额叶皮质(MPFC)、前岛叶皮质(AIC)和中脑 多巴胺(DA)区域，作为认知和情感加工之间的潜在接口。此外， 比较神经解剖学和发育遗传学已经在小鼠的大脑区域进化中确定 与人类mPFC、AIC和DA区相关。我们父母基金(R01MH127737)的总体目标是 阐明柔韧时认知-情感相互作用的额岛环路机制 小鼠的决策和压力对这种机制的影响。额叶皮质关联区 典型的表现为AD进展过程中淀粉样变的早期出现。然而，淀粉样蛋白病理如何 决策过程中调节认知-情感相互作用的长程皮质投射的影响没有 被调查过了。这一行政副刊扩展了我们对额岛的机械性调查 阿尔茨海默病小鼠遗传模型决策过程中认知-情感交互作用的网络研究。我们 假设mPFC-AIC-DA回路的平衡神经通讯功能进行性受损 由淀粉样变性，导致认知灵活性受损。使用淀粉样变小鼠(APP/PS1和 5xFAD)，我们提出了两个目标。目的1确定淀粉样变性如何影响mPFC-AIC的连接和功能； 目的2明确淀粉样变性对多巴胺调节mPFC和AIC功能的影响。有初步数据 通过这一补充，我们将申请国家投资局的资金，以进一步调查 额岛环内神经活动、突触形态和淀粉样蛋白病理进行性变化 AD小鼠模型的建立，并探讨额叶-岛叶电路调制范式对病理的保护作用 与阿尔茨海默病相关的进展和认知能力下降。

ABSTRACT Alzheimer’s Disease (AD) is one of the most prevalent age-related neurodegenerative disorders with devastating effects on a broad range of brain functions from memory to decision making. While it is well known that AD impairs cognitive functions, neuropsychiatric symptoms are common in those at risk of or with AD and predict the incidence of cognitive impairment. Human brain imaging studies have highlighted a network of brain regions, particularly the medial prefrontal cortex (mPFC), the anterior insular cortex (aIC), and midbrain dopamine (DA) regions, as the potential interface between cognitive and affective processing. Furthermore, comparative neuroanatomy and developmental genetics have identified in mice brain regions evolutionarily related to human mPFC, aIC, and DA regions. The overall objective of our parent grant (R01MH127737) is to elucidate the fronto-insular circuit mechanisms underlying cognitive-affective interactions during flexible decision-making and the impact of stress on such mechanisms in mice. Frontal cortical association areas typically show early appearance of amyloid pathology during AD progression. However, how amyloid pathology impacts long-range cortical projections mediating cognitive-affective interactions during decision-making has not been investigated. This administrative supplement extends our mechanistic investigation of fronto-insular network in cognitive-affective interactions during decision-making to mouse genetic models of AD. We hypothesize that the balanced neural communication in mPFC-aIC-DA circuits is progressively impaired by amyloidosis, leading to the impairment of cognitive flexibility. Using amyloidosis mice (APP/PS1 and 5xFAD), we propose two aims. Aim 1 determines how amyloidosis affects mPFC-aIC connectivity and function; Aim 2 defines the impact of amyloidosis on DA modulation of mPFC and aIC function. With preliminary data obtained through this supplement, we will apply for NIA funding to further investigate the mechanistic links among progressive changes in neural activity, synaptic morphology, and amyloid pathology in fronto-insular circuits in AD mouse models, and to explore fronto-insular circuit modulation paradigms to protect against the pathological progression and cognitive decline associated with AD.