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 持续的注意力缺乏是神经精神疾病的重要认知症状，例如 精神分裂症，注意力缺陷多动障碍和主要抑郁症以及与年龄有关的 神经退行性疾病，包括阿尔茨海默氏病。在人类中，连续绩效测试（CPTS） 通常用于评估这些神经精神疾病患者的持续关注。这 前扣带回皮层（ACC）对于正常的CPT表现至关重要，患者种群经常表现出来 CPT期间的异常ACC函数。这些结果符合ACC中确定的作用 注意引导的行为，并指出ACC在注意力缺陷的病理生理中的作用 复杂的脑部疾病。但是，ACC作用为基础的细胞和分子机制 调节持续的关注尚不清楚。缺乏知识很重要，因为识别这些知识 机制对于为注意力缺陷开发有针对性的治疗至关重要。该申请正在调查 新分子和细胞靶标表达之间的联系，ACC电路中的神经活动模式和 注意力表现。我们的初步数据表明该基因座之间的投影特异性途径 Coeruleus（LC）和ACC调节CPT期间注意引导行为的不同方面。具体来说， 我们确定了编码载脂蛋白E（APOE）的基因，该基因已在注意力和疾病中暗示 与引起关注定义的疾病相关，是一个潜在的分子参与者的基础调节 在LC-ACC电路中持续关注。我们利用遗传和电路特异性工具来剖析 基于触摸屏的啮齿动物类似物期间，分子，细胞和电路的持续关注的基础 小鼠人类CPT（RCPT）的具体而言，我们1）测试ApoE基因表达之间的因果关系， LC-ACC电路和注意力表现的生理功能，以及2）确定细胞类型和电路 - 啮齿动物和人类ACC中的特定分子靶标对于持续关注至关重要。实现 这些目标我们整合了各种分子和系统级方法，包括体内 电生理学，单细胞RNA序列和CRISPR-DCAS9介导的表观基因组编辑与 注意引导行为的量化。对于测序研究，我们利用了 分子遗传工具靶向和操纵LC-ACC电路内细胞特异性种群 鼠标并使用这些数据来识别来自死后人类的数据中的电路特异性细胞类型 脑组织。这种跨物种分析支持我们确定和优先级治疗的长期目标 具有注意力缺陷的疾病的目标。拟议的研究很重要，因为结果 将大大提高我们对持续的电路和分子机制的理解 注意，并为解剖和遗传定位的治疗靶向提供潜在的途径 在引起注意力失调的疾病中。