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

决策过程中认知情感交互的额岛网络

• 批准号: 10715606
• 负责人: Kuan Hong Wang
• 金额: $ 37.73万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-05 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715606
• 关键词: APP-PS1; Administrative Supplement; Affect; Affective; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloidosis; Anterior; Appearance; Area; Attention; Behavioral Paradigm; Brain; Brain imaging; Brain region; Calcium; Cognitive; Communication; Data; Decision Making; Development; Disease Progression; Dopamine; Electrophysiology (science); Equilibrium; Fiber; Functional disorder; Funding; Genetic Models; Human; Image; Impaired cognition; Impairment; Incidence; Investigation; Label; Link; Measures; Medial; Mediating; Memory; Midbrain structure; Modeling; Morphology; Mus; Neuroanatomy; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenicity; Pathologic; Pathway interactions; Pharmacogenetics; Photometry; Prefrontal Cortex; Process; Research; Rewards; Risk; Senile Plaques; Sensory; Signal Transduction; Sorting; Stimulus; Stress; Synapses; Testing; Update; Viral; Wisconsin; abeta deposition; age related neurodegeneration; amyloid pathology; cognitive function; common symptom; comparative; developmental genetics; dopaminergic neuron; effective therapy; excitatory neuron; extracellular; flexibility; fluorescence imaging; frontal lobe; imaging study; in vivo; in vivo imaging; inhibitory neuron; insight; mouse genetics; mouse model; nerve supply; neural; neural circuit; neurobiological mechanism; neuropsychiatric symptom; optogenetics; parent grant; response; sensor; tau aggregation; transmission process; two-photon

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.

抽象的 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 众所周知，它会对从记忆到决策等一系列大脑功能产生毁灭性影响。 AD 损害认知功能，神经精神症状在有 AD 风险或患有 AD 的人群中很常见， 预测认知障碍的发生率 人类大脑成像研究强调了大脑网络。 区域，特别是内侧前额皮质 (mPFC)、前岛叶皮质 (aIC) 和中脑 多巴胺（DA）区域，作为认知和情感处理之间的潜在接口。 比较神经解剖学和发育遗传学已经在小鼠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 (R01MH127737) 的总体目标是 阐明灵活过程中认知情感相互作用背后的额岛回路机制 决策以及压力对小鼠额叶皮层关联区域机制的影响。 通常在 AD 进展过程中早期出现淀粉样蛋白病理，然而，淀粉样蛋白病理如何发生。 影响长期皮层投射，在决策过程中调节认知情感相互作用，但尚未 该行政补充扩展了我们对额岛的机械调查。 AD 小鼠遗传模型决策过程中认知情感相互作用的网络。 研究发现 mPFC-aIC-DA 回路中的平衡神经通讯逐渐受损 淀粉样变性导致认知灵活性受损（APP/PS1 和 5xFAD），我们提出两个目标：目标 1 确定淀粉样变性如何影响 mPFC-aIC 连接和功能； 目标 2 通过初步数据定义了淀粉样变性对 mPFC 和 aIC 功能的 DA 调节的影响。 通过这个补充获得的，我们将申请NIA资助来进一步研究之间的机制联系 额岛环路中神经活动、突触形态和淀粉样蛋白病理学的渐进性变化 AD 小鼠模型，并探索额岛电路调制范例以防止病理性 与 AD 相关的进展和认知能力下降。