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

摘要 阿尔茨海默病（AD）是最常见的年龄相关性神经退行性疾病之一， 对从记忆到决策的广泛大脑功能产生破坏性影响。虽然众所周知 AD损害认知功能，神经精神症状在有AD风险或患有AD的患者中很常见， 预测认知障碍的发生率。人类大脑成像研究强调了大脑的网络 区域，特别是内侧前额叶皮质（mPFC），前岛皮质（aIC）和中脑 多巴胺（DA）区域，作为认知和情感处理之间的潜在界面。此外，委员会认为， 比较神经解剖学和发育遗传学已经在老鼠的大脑区域中发现了进化 与人类mPFC、aIC和DA区域相关。我们的母基金（R 01 MH 127737）的总体目标是 阐明了在灵活的过程中认知情感相互作用的额岛电路机制 决策和压力对小鼠这种机制的影响。额叶皮质联合区 通常在AD进展期间显示淀粉样病变的早期出现。然而，淀粉样蛋白病理学 在决策过程中，影响远距离皮层投射介导的认知情感互动， 被调查了这一行政补充扩展了我们对前岛的机械调查， 网络在决策过程中的认知情感相互作用，以小鼠遗传模型的AD。我们 假设mPFC-aIC-DA回路中的平衡神经通信逐渐受损 淀粉样变性导致认知灵活性受损使用淀粉样变性小鼠（APP/PS1和 5xFAD），我们提出两个目标。目的1确定淀粉样变性如何影响mPFC-aIC连接和功能; 目的2明确淀粉样变性对DA调节mPFC和aIC功能的影响。有了初步数据 通过这一补充，我们将申请NIA资金，以进一步调查之间的机械联系， 在额-岛回路中神经活动、突触形态和淀粉样蛋白病理学的进行性变化， AD小鼠模型，并探讨额-岛电路调制范式对AD小鼠的病理保护作用 与AD相关的进展和认知下降。

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.