Intellectual deficits are common following intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Cognitive deficits often include anterograde and retrograde amnesia and deficits in spatial memory function which points towards hippocampal injury. In our preliminary data, we have developed a model of intraventricular blood (IVB) and intraventricular thrombin (IVT) which produces a significantly worse performance in the Morris water maze paradigm 5 weeks after the injection compared to sham surgery. We did not see obvious neuronal loss in the dentate gyrus or hippocampus at this time point. However, we saw a significant impairment in dentate neurogenesis as evidenced by vastly reduced numbers of dividing progenitor cells and failure of dentate progenitor cells to differentiate into new neurons. Spatial memory deficits after IVT could be inhibited by the src inhibitor PP2. This finding has led us to the hypothesis that the decrease in dentate progenitor cells is due to thrombin activation of the src pathway through protease-activated receptor 1 (PAR1). The grant will test this hypothesis and identify further members of the signaling cascade with RNA sequencing. We are especially interested in linking known regulators of the dentate progenitor cell maintenance and differentiation pathways such as WNT-3A or sonic hedgehog to our preliminary finding of src pathway activation. The grant is aimed to identify a pipeline of candidate genes which are implicated in the hemorrhage-induced decline of the pool of dentate progenitor cells. Identification of candidate genes will serve as the basis for an R01 application towards the end of the K08 period. My mentor Frank Sharp is ideal for this project due to his extensive experience with dentate neurogenesis in the setting of hemorrhage or ischemia as well as his experience with whole-genome transcriptome studies. This grant proposal is aimed to understand the genomic mechanism of memory dysfunction that we see after intraventricular hemorrhage to develop therapies to treat this important clinical problem.
Whole blood or thrombin will be injected into the ventricles of rats to produce a decline in the pool of dentate progenitor cells and memory deficits in order to model the cognitive deficits that occur in humans following intraventricular hemorrhage and subarachnoid hemorrhage. The mechanism of memory decline will be studied with protease-activating receptor blockers and PP2, and RNA sequencing will be performed to identify further genes involved in the signaling cascade leading to impairment in dentate neurogenesis.
