Molecular, cellular and physiological correlates of sustained attention in the locus coeruleus to anterior cingulate cortex circuit

蓝斑与前扣带皮层回路持续注意力的分子、细胞和生理相关性

• 批准号: 10753763
• 负责人: HENRY HALLOCK
• 金额: $ 44.37万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-13 至 2025-09-12
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753763
• 关键词: Alzheimer' s Disease; Anatomy; Animal Model; Anterior; Apolipoprotein E; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Autopsy; Behavior; Behavioral; Biological Markers; Brain; Brain Diseases; Brain Stem; Cells; Chromosome Mapping; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Coupled; Data; Diagnosis; Disease; Dorsal; Electrophysiology (science); Exhibits; Functional disorder; Gene Expression; Gene Transfer Techniques; Genes; Genetic; Genetic Transcription; Goals; Human; Immunohistochemistry; Individual; Knowledge; Label; Link; Major Depressive Disorder; Mediating; Mental disorders; Mission; Molecular; Molecular Genetics; Molecular Target; Mus; Neurobehavioral Manifestations; Neurodevelopmental Disorder; Neurons; Pathway interactions; Patients; Pattern; Performance; Physiological; Population; Prefrontal Cortex; Regulation; Research; Rodent; Role; Schizophrenia; Signal Pathway; Symptoms; System; Testing; Translations; United States National Institutes of Health; Variant; Viral; age related neurodegeneration; analog; brain tissue; cell type; cellular targeting; cingulate cortex; design; epigenome editing; experimental study; genetic variant; genome wide association study; in vivo; innovation; locus ceruleus structure; neural; neuropsychiatric disorder; novel; patient population; performance tests; recruit; response; single nucleus RNA-sequencing; single-cell RNA sequencing; sustained attention; therapeutic target; tool; touchscreen; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Sustained attention deficits are a prominent cognitive symptom in neuropsychiatric disorders such as schizophrenia, attention-deficit hyperactivity disorder, and major depressive disorder as well as in age-related neurodegenerative disorders, including Alzheimer’s disease. In humans, continuous performance tests (CPTs) are commonly used to assess sustained attention in patients with these neuropsychiatric diseases. The anterior cingulate cortex (ACC) is essential for normal CPT performance, and patient populations often exhibit aberrant ACC function during the CPT. These results are in line with an established role for the ACC in attention-guided behavior, and point to a role for the ACC in the pathophysiology of attentional deficits in complex brain disorders. However, the cellular and molecular mechanisms that underlie the role of the ACC to regulate sustained attention remain unclear. This lack of knowledge is important because identifying these mechanisms is critical for developing targeted treatments for attention deficits. This application investigates links between expression of novel molecular and cellular targets, neural activity patterns in ACC circuits and attentional performance. Our preliminary data suggest that projection-specific pathways between the locus coeruleus (LC) and the ACC regulate distinct aspects of attention-guided behavior during the CPT. Specifically, we identified the gene encoding Apolipoprotein E (Apoe), which has been implicated in attention and disorders associated with disorders featuring deficits in attention, as a potential molecular player underlying regulation of sustained attention in the LC-ACC circuit. We leverage genetic and circuit-specific tools to dissect the molecular, cellular and circuit underpinnings of sustained attention during a touchscreen-based rodent analog of the human CPT (rCPT) in mice. Specifically, we 1) test causal relationships between Apoe gene expression, physiological function in the LC-ACC circuit and attentional performance, and 2) identify cell types and circuit- specific molecular targets in the rodent and human ACC that are critical for sustained attention. To achieve these aims we integrate a variety of molecular and systems level approaches including in vivo electrophysiology, single-cell RNA-sequencing, and CRISPR-dCas9 mediated epigenome editing coupled with quantification of attention-guided behavior. For the sequencing studies, we capitalize on the power of molecular genetic tools to target and manipulate cell-specific populations within the LC-ACC circuit in the mouse and use these data to genetically identify circuit-specific cell types in data from postmortem human brain tissue. This cross-species analysis supports our long-term goal of identifying and prioritizing therapeutic targets for disorders that feature attentional deficits. The proposed research is significant because the results will significantly advance our understanding of the circuit and molecular mechanisms underlying sustained attention, as well as provide potential avenues for anatomically and genetically-localized therapeutic targeting in disorders featuring dysregulation of attention.

项目摘要 持续的注意力缺陷是神经精神障碍的一个突出的认知症状， 精神分裂症、注意力缺陷多动障碍和重度抑郁症以及与年龄相关的 神经退行性疾病，包括阿尔茨海默病。在人类中，持续性能测试（CPT） 通常用于评估这些神经精神疾病患者的持续注意力。的 前扣带皮层（ACC）对于正常CPT表现是必不可少的，并且患者群体通常表现出 CPT期间ACC功能异常。这些结果符合行政协调会的既定角色， 注意力引导行为，并指出ACC在注意力缺陷的病理生理学中的作用， 复杂的脑部疾病然而，ACC的作用背后的细胞和分子机制， 监管持续关注仍不清楚。这种知识的缺乏很重要，因为识别这些 机制对于开发针对注意力缺陷的靶向治疗至关重要。该应用程序调查 新的分子和细胞靶点的表达，ACC回路中的神经活动模式， 注意力表现。我们的初步数据表明，基因座之间的投射特异性通路 蓝斑核（LC）和前扣带回在CPT期间调节注意力引导行为的不同方面。具体地说， 我们发现了编码载脂蛋白E（ApoE）的基因，该基因与注意力和精神障碍有关 与以注意力缺陷为特征的疾病相关，作为潜在的分子参与者， LC-ACC电路中的持续注意力。我们利用遗传学和电路特定的工具来剖析 基于触摸屏的啮齿动物模拟过程中持续注意力的分子、细胞和电路基础 人CPT（rCPT）在小鼠中的作用。具体来说，我们1）测试Apoe基因表达之间的因果关系， LC-ACC回路中的生理功能和注意力表现，以及2）识别细胞类型和回路- 啮齿动物和人类ACC中的特异性分子靶点对持续关注至关重要。实现 为了达到这些目标，我们整合了多种分子和系统水平的方法， 电生理学、单细胞RNA测序和CRISPR-dCas 9介导的表观基因组编辑， 注意力引导行为的量化。对于测序研究，我们利用了 分子遗传工具用于靶向和操纵LC-ACC回路内的细胞特异性群体 并使用这些数据从基因上鉴定来自死后人类数据中的回路特异性细胞类型 脑组织这种跨物种分析支持我们的长期目标，即确定和优先考虑治疗性药物。 针对注意力缺陷的疾病这项研究意义重大，因为结果 这将极大地促进我们对持续性脑缺血背后的电路和分子机制的理解。 注意，以及提供解剖学和遗传学定位治疗靶向的潜在途径 注意力失调的疾病