Dissecting circuit mechanisms by genetic manipulation of specific neural pathways

The major issue in neuroscience is to delineate the structure and function of the neural circuits that mediate a variety of brain functions. One useful approach to resolve this issue is the genetic manipulation of the activity of specific neural circuits, which enables the study of the behavioral and physiological consequences of the manipulation. A novel type of lentiviral vector showing highly efficient retrograde gene transfer (HiRet) can introduce a transgene into neurons that innervate a certain brain region at the vector injection site and confer a fundamental tool for genetically manipulating specific neural pathways. Here, we describe the strategy for the selective targeting of neural pathways by using this HiRet vector, combined with immunotoxin (IT)-mediated cell targeting, which eliminates particular neuronal types genetically engineered to express a receptor for the recombinant IT. Our strategy provides a powerful technology to investigate the framework underlying brain functions and to develop animal models for the dissection of neurological and neuropsychiatric diseases.