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

项目摘要 认知缺陷是SCD的一个令人衰弱的并发症。就整体生活质量而言，它影响着生活的各个阶段， 从儿童的学业表现，到年轻人的教育成就，以及就业能力和工作 成人的滞留。在人类和老鼠研究中积累的证据表明， SCD认知功能障碍的病理生物学研究值得注意的是，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有助于认知缺陷的发展 SCD。其中一个受衰老影响的变化是成人的神经发生。在非SCD人群中的研究已经发现 衰老是成人神经发生的负面调节因素，与认知能力下降和认知能力增强同时发生 发炎。尽管SCD具有加速衰老的特征，但与系统性疾病 炎症和神经炎症的细胞证据，这些常见的疾病并发症如何 影响成人海马区神经发生或其是否参与认知功能障碍尚不清楚。我们的团队 最近发现，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神经胶质发生 镰状细胞小鼠与年龄匹配的对照组进行比较。然而，这对功能集成的影响 成年出生的神经元进入镰状细胞小鼠的神经回路尚不清楚。这一多样性补充试图填补 这种病理生物学上的知识缺口参与了SCD认知缺陷的发展。我们假设 SCD的衰老和炎症改变了成年出生的齿状回神经元的功能回路和 可能在一定程度上导致了认知缺陷的发展。我们推测衰老和炎症会影响 将成年出生的神经元整合到先前存在的神经回路中，并有助于 镰状细胞小鼠的认知障碍。我们将探讨衰老和炎症对成人的影响 用单突触GFP标记的逆转录病毒标记方法在SCD中进行神经再生。我们的目标是：(1) 研究成年后再生障碍性贫血小鼠和镰状细胞神经元功能整合的程度。 认知衰退的发生及其与基于海马体的记忆和学习的表现相关 试验；(2)我们还将用米诺环素(抗神经炎症)治疗另一组小鼠，确定功能 成年出生的神经元的整合，并记录神经炎症的细胞证据 免疫组织化学。这将与接受治疗和未接受治疗的小鼠的认知缺陷有关。这个 从这个项目中获得的知识的意义将增进我们的理解，并使我们能够确定 预防或减轻SCD认知损害的潜在新靶点。

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.