Project Abstract Cognitive and behavioral (anxiety and depression) deficits are two potentially life-altering complications of sickle cell disease (SCD). Loss of full-scale intelligence quotient (IQ), interference with employability, navigation of healthcare resources and overall quality of life are some of the consequences of cognitive deficit in SCD patients. The molecular and cellular factors that mediate the development of these complications are still largely unknown. This proposal aims to define the role of neuroinflammation in development of abnormal neuroplasticity and how the two are temporally related to onset of cognitive and behavioral deficit in SCD. We will also attempt to identify some small molecules and treatment strategies that could have utility in prevention and/or treatment of SCD- associated cognitive and behavioral deficit. Our preliminary studies have shown that sickle cell mice developed cognitive and behavioral deficit that occur with age and neuroinflammation and thus our central hypothesis is that the development of cognitive deficits in SCD is due to neuroinflammation and abnormal neuroplasticity defined by decreased density of dendritic arbors, dendritic spines and, the proportion of immature dendritic spines. We will also examine the potential role or contribution from cerebral infarcts and microvasculopathy. This will be rigorously tested with the following aims (1) Determine the temporal relationship between presence of cognitive (learning and memory) deficit in SCD, and abnormal neuroplasticity and/or the burden of cerebral infarcts and microvasculopathy. This will enable us to establish a temporal relationship between the onset of cognitive and behavioral deficit, and onset of abnormal neuroplasticity as well as the burden of cerebral microinfarct. (2) Demonstrate the role of neuroinflammation, as well as the therapeutic benefit of minocycline in treating cognitive deficits in SCD. This will be done by establishing baseline relationship between onset and progression of cellular and molecular evidence of neuroinflammation and onset and progression of abnormal neuroplasticity as well as development of cognitive and behavioral deficit. Additionally, we will examine whether blocking neuroinflammation could be a potential target for the treatment or prevention of SCD associated cognitive and behavioral deficit. (3) Determine whether treatment with a neurotrophin agonist treatment or anti-neuroinflammatory mediators reverses neuroinflammation, abnormal neuroplasticity and cognitive deficit in SCD. These studies are design to enable us identify small molecule(s) and/or small molecule target(s) and provide the preclinical information that could support a clinical trial geared towards identifying treatment and prevention strategies for cognitive and behavioral deficit in SCD.