Neural circuits are the basic computational units in the nervous system. Thus, our inability to anatomically label specific circuits and to manipulate their function is a major deficiency in our ability to study the brain. Imaging techniques, which have revolutionized our understanding of the functions of large brain structures, lack the resolution and precision needed for studying particular circuits. Molecular techniques, which have been extremely powerful in studying individual neurons, are currently limited to the confines of single cells. The development of a technology for circuit tracing and manipulation by selectively bridging across the synapses that connect neurons within a given circuit is still an unmet challenge. Here we propose to combine molecular biology and genetics to develop such a technology. At the core of our approach is a synthetic signaling pathway that is introduced into all neurons. Selective activation of this pathway within a particular circuit will be used to label the circuit, or to functionally manipulate it. To achieve this, we will selectively activate specifc neurons by optogenetic techniques. Glutamate release into the synapses of these neurons will activate the signaling pathway in post-synaptic neurons leading to expression of a marker protein that will label their projections. Since our system is modular, its use will be readily expanded to various neural circuits. Furthermore, our system can be configured for use in other model organisms including primates. Our technology for selective labeling and manipulation of circuits in vivo will therefore open new research avenues. In addition, it will be easily adapted t experiments in which the properties of particular circuits will be modified and the functional consequences will be studied. The type of studies of neural circuits afforded by our technology will lead to a deeper understanding of how the brain functions. Our technology will also be used in various mouse models for human diseases and help identify specific changes that occur in particular circuits in these model animals. Without a sensitive method for specific mapping and manipulation of particular circuits, the accessibility of these questions is rather limited. Our approach to circuit tracing and manipulation is totally different than any method attempted thus far, as molecular genetics has only been used to study neurons that express a given genetic marker. The system presented here will expand the use of molecular approaches to all the cells with which the neurons that express the genetic marker communicate. Thus, our technique will expand the utility of molecular biological approaches beyond the confines of a single neuron. Harnessing the enormous power of molecular genetics to study circuits will undoubtedly broaden our understanding of the brain and therefore have a major impact on the neuroscience community.

Public Health Relevance

We propose to develop a new technology for functional mapping and manipulation of neural circuits in mice. This technology will lead to a deeper understanding of normal brain function and will also enable the identification of specific changes that occur in particular neural circuits in mouse models of human diseases. Our technology will therefore reveal new insights into the mechanisms underlying psychiatric disorders, addiction, and the progression of neurodegenerative diseases.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZMH1)
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Freund, Michelle
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Brown University
Schools of Medicine
United States
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