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 阿尔茨海默氏病（AD）是与年龄有关的神经退行性疾病之一 从记忆到决策的各种大脑功能的毁灭性影响。虽然众所周知 广告会损害认知功能，神经精神症状在有AD的风险或患有AD的患者中很常见 预测认知障碍的事件。人脑成像研究突出了大脑网络 区域，尤其是内侧前额叶皮层（MPFC），前岛皮层（AIC）和中脑 多巴胺（DA）区域是认知和情感处理之间的潜在接口。此外， 比较神经解剖学和发育遗传学在小鼠脑区域已经鉴定 与人类MPFC，AIC和DA区域有关。我们父母赠款（R01MH127737）的总体目标是 阐明柔性期间认知影响相互作用的前界电路机制 决策和压力对小鼠这种机制的影响。额叶皮质协会区域 通常在AD进展过程中显示淀粉样病理的早期出现。但是，淀粉样病理如何 在决策过程中影响介导认知影响互动的远程皮质项目尚未 被调查。这种行政补充扩展了我们对额头的机械投资 在决策与AD的小鼠遗传模型期间，认知影响相互作用的网络。我们 假设MPFC-AIC-DA电路中平衡的神经元通信逐渐受损 通过淀粉样变性，导致认知灵活性受损。使用淀粉样变性小鼠（APP/PS1和 5xfad），我们提出了两个目标。 AIM 1确定淀粉样变性如何影响MPFC-AIC连通性和功能； AIM 2定义了淀粉样变性对MPFC和AIC功能调制的影响。使用初步数据 通过此补充剂获得，我们将申请NIA资金，以进一步研究 神经元活性，突触形态和淀粉样病理学的渐进性变化 AD鼠标模型，并探索额 - 互联电路调制范例以防止病理 与AD相关的进展和认知下降。