Sickle cell disease and the functional circuit of adult-born neurons in the dentate gyrus

镰状细胞病和齿状回中成年神经元的功能回路

• 批准号: 10693540
• 负责人: Hyacinth Idu Hyacinth
• 金额: $ 23.51万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693540
• 关键词: Acceleration; Adult; Affect; Age; Age Months; Age of Onset; Aging; Anemia; Area; Autopsy; Biological Assay; Brain; Cerebral Infarction; Child; Cognitive; Cognitive deficits; Complex; Complication; Cross-Sectional Studies; Data; Development; Disease; Education; Exposure to; Glycoproteins; Green Fluorescent Proteins; Health; Hippocampus; Histology; Human; Immunohistochemistry; Impaired cognition; Individual; Inflammation; Inflammatory; Knowledge; Label; Learning; Life; Measures; Mediating; Memory; Minocycline; Mus; Neurobiology; Neurons; Occupations; Oncogenic Viruses; Parahippocampal Gyrus; Performance; Pharmaceutical Preparations; Plasma; Population; Prevention strategy; Process; Quality of life; Rabies; Reporting; Retroviridae; Risk Factors; School-Age Population; Services; Sickle Cell; Sickle Cell Anemia; Socioeconomic Factors; Special Education; Synapses; Syndrome; Testing; adult neurogenesis; age effect; age related; aged; aging brain; astrogliosis; blood-brain barrier crossing; cognitive function; cognitive testing; comparison control; conditioned fear; cytokine; dentate gyrus; gliogenesis; insight; lateral ventricle; leukemia; memory retention; morris water maze; mouse model; nerve stem cell; neural circuit; neurobehavioral; neurobehavioral test; neurogenesis; neuroinflammation; new therapeutic target; newborn neuron; novel; object recognition; prevent; receptor; sickling; subventricular zone; systemic inflammatory response; young adult

Project Abstract Cognitive deficit is a debilitating complication of SCD. It affects all stages of life in terms of overall quality of life, from academic performance in children, to educational attainment in young adults, and employability and job retention in adults. Accumulating evidence in both human and mouse studies points to a multifactorial pathobiology of cognitive deficits in SCD. Notably, cognitive impairments worsen with increasing age, suggesting that age-related neurobiological changes in the brain may contribute to the development of cognitive deficits in SCD. One such change affected by aging is adult neurogenesis. Studies in non-SCD populations have identified aging as a negative regulator of adult neurogenesis that occurs concurrently with cognitive decline and increased inflammation. Although SCD has features of accelerated aging, in conjunction with elevated systemic inflammation and cellular evidence of neuroinflammation, how these common complications of the disease may affect adult neurogenesis in the hippocampus or its involvement in cognitive impairment is not clear. Our group recently showed that age and neuroinflammation affect cognitive function in sickle cell mice in "aged" (13 months old) mice compared to aged-matched control mice, with neurogenesis skewed more towards gliogenesis in aged sickle cell mice compared to age-matched controls. However, the effect of this on the functional integration of adult-born neurons into the neurocircuitry in sickle cell mice is unknown. This diversity supplement seeks to fill this knowledge gap in pathobiology involved in the development of cognitive deficits in SCD. We hypothesized that aging and inflammation in SCD alter the functional circuitry of adult-born neurons in the dentate gyrus and may partly underlie the development of cognitive deficit. We postulate that aging and inflammation affect the integration of adult-born neurons into the pre-existing neurocircuitry and contribute to the development of cognitive impairment in sickle cell mice. We will explore the impact of aging and inflammation on adult neurogenesis in SCD by using a monosynaptic GFP-tagged retrovirus labeling approach. We aim to: (1) investigate the extent of functional integration of adult-born neurons in sickle cell and AA control mice at the onset of cognitive decline and correlate this with performance on hippocampus-based memory and learning tests; (2) we will also treat another group of mice with minocycline (anti-neuroinflammation), determine functional integration of adult-born neurons, and document cellular evidence of neuroinflammation with immunohistochemistry. These will be related to cognitive deficits in treated and non-treated mice. The significance of the knowledge gained from this project would advance our understanding and enable us to identify potential novel targets for preventing or attenuating cognitive impairment in SCD.

项目摘要 认知缺陷是SCD的一种使人衰弱的并发症。它影响到生命的各个阶段，影响到整体生活质量， 从儿童的学习成绩，到年轻人的教育程度，以及就业能力和工作 保留在成人。在人类和小鼠研究中积累的证据表明， SCD中认知缺陷的病理生物学。值得注意的是，认知障碍随着年龄的增长而恶化，这表明 大脑中与年龄相关的神经生物学变化可能导致认知缺陷的发展， SCD。受衰老影响的一种变化是成人神经发生。在非SCD人群中的研究已经确定 衰老作为成人神经发生的负调节因子，与认知能力下降同时发生， 炎症尽管SCD具有加速老化的特征，但与全身性 炎症和神经炎症的细胞证据，这些常见的疾病并发症如何可能 影响成年海马神经发生或其参与认知障碍尚不清楚。我们集团 最近的研究表明，年龄和神经炎症会影响“老年”（13个月）镰状细胞小鼠的认知功能 与年龄匹配的对照组小鼠相比，老年小鼠的神经发生更倾向于胶质细胞生成。 镰状细胞小鼠与年龄匹配的对照组相比。然而，这对功能整合的影响， 成年出生的神经元进入镰状细胞小鼠的神经回路是未知的。这种多样性补充旨在填补 这种病理生物学知识的空白与SCD认知缺陷的发展有关。我们假设 SCD中的衰老和炎症改变了齿状回中成年出生的神经元的功能回路， 可能是认知缺陷的部分原因。我们假设衰老和炎症会影响 成人出生的神经元整合到预先存在的神经回路，并有助于发展 镰状细胞小鼠的认知障碍。我们将探讨衰老和炎症对成年人的影响。 SCD中的神经发生，通过使用单突触GFP标记的逆转录病毒标记方法。我们的目标是：（1） 研究镰状细胞和AA对照小鼠中成年出生的神经元的功能整合程度， 认知能力下降，并将其与基于校园的记忆和学习表现相关联 测试;（2）我们还将用米诺环素（抗神经炎症）治疗另一组小鼠， 整合的成年出生的神经元，并记录神经炎症的细胞证据， 免疫组化这些将与治疗和未治疗小鼠的认知缺陷相关。的 从这个项目中获得的知识的重要性将促进我们的理解，使我们能够确定 预防或减轻SCD认知障碍的潜在新靶点。