Sunday, January 29, 2023
1/29/2023
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.
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