The function of the nervous system is dependent on complex interactions between networks of neurons composed of multiple neuron types. Understanding how these networks function both in health and disease is dependent on understanding the precise connectivity between specific neuron types and their functional interactions in the intact brain. It is therefore apparent that, in order to have an adequate understanding of the nervous system, it is necessary to have detailed descriptions of neuronal connectivity with the same level of precision at which these systems operate and to selectively manipulate and measure the activity of specific cell types in the context of the normal functioning network. Such studies would be greatly facilitated by the ability to target gene expression to specific cell types in the context of AAV vectors. The research proposed here is aimed at developing and using a novel high throughput strategy and PCR-activated cell sorting for identification of cell type specific enhancer elements. The approach used will identify enhancers that can drive transgene expression in specific types of cortical neurons. Further studies will valdiate these enhancers in a real-use context for ability to facilitate imaging with genetically-encoded calcium indicators and to facilitate optogenetic inactivation. These reagents will allow future studies testing the functional contributions of specific inhibitory neuron types to perception,cognition and behavior.
Understanding the detailed organization of cortical circuits involving specific neuron types is necessary to obtain a mechanistic understanding of the function of the cerebral cortex. Understanding the specific roles of genetically accessed neuron types in cortical function has important implications for human health, as these cell types and their activities are implicated in the cortical mechanisms that regulate attention and their disruption is implicated in schizophrenia and autism.
