The progress in understanding how neuronal dysfunction can lead to nervous system disorders has drawn attention to the central role played by trophic factors in modulating brain function. Cognitive deficits, which are widely prevalent in neuropsychiatric disorders, are known to be regulated by trophic factors. The hippocampal actions of neurotrophic factors have been shown to be particularly important, influencing cellular pathways and mechanisms to produce behavioral effects. Erythropoietin (EPO), a naturally occurring hormone and trophic factor, widely prescribed to treat anemia, exerts robust neurotrophic actions in the brain. Moreover, peripheral administration is sufficient to elicit CNS effects in several preclinical and clinical psychiatry studies. Multiple human studies have demonstrated that EPO produces cognitive enhancing effects. The regulation of behavior is considered to be a result of neurotrophic activity that is independent of EPO’s physiological and hemostatic role in regulating hematopoiesis. However, the specific trophic mechanisms in the brain have not been characterized. Furthermore, the use of an inherently erythropoietic molecule to produce therapeutic neurotrophic effects can lead to elevated blood viscosity and increase the risk for adverse vascular events. We therefore utilize chemically engineered EPO derivatives that are non-erythropoietic but retain neurotrophic activity, to investigate the role of its hippocampal actions in cognition. Employing a combination of conditional, region-specific, receptor knockout mice and viral-mediated gene manipulation we will determine the role of hippocampal neurotrophic factor-driven mechanisms at the molecular, cellular and behavioral levels. Our studies are expected to provide new insight into trophic factor-mediated modulation of cognitive behavior and also inform the development of novel trophic factor based therapeutic agents.