Precision Targeting of Hippocampal Subfields with AAVs

About This Grant

In recent decades, we have gained a deep understanding of brain function in health and disease with the advent of techniques relying on genetic manipulations such as opto- and chemogenetics. These methods allow the isolated investigation of well-delineated cell populations. Although the hippocampus is one of the most extensively studied brain regions, research progress has been severely hindered by the lack of genetic access to hippocampal subfields, thereby restricting the applicability of these trailblazing methodologies. Several adeno- associated virus (AAV) vectors utilizing neuron-type-specific regulatory transcriptional sequences (enhancer- AAVs) were developed recently. We propose to develop hippocampal cell type-specific enhancer-AAV viruses for highly efficient and convenient targeting of hippocampal excitatory cell types by evaluating the potential of several candidate enhancers for neuron-type-specific targeting in the hippocampus using a publicly available hippocampal RNA sequencing (RNA-seq) dataset. First, we will develop enhancer-AAVs for selective targeting of dentate gyrus granule cells. Our preliminary results show highly specific granule cell labeling, which we will leverage to develop cell type-specific optogenetic and chemogenetic virus variants. Second, we will expand these efforts to other hippocampal excitatory cell types: CA3, CA2, and CA1 pyramidal cells and hilar mossy cells. The development of these selective methods will allow the research community to gain unprecedented insight into hippocampal function in healthy and pathophysiological conditions.