Understanding how neural circuits in the brain allow us to form a percept of our environment and elicit a behavioral response has been a long-standing goal in Neuroscience. An understanding of these complex processes will not be possible until we can elucidate which cells connect to one another in the central nervous system. Conventional tools to map neural circuits have limitations that have slowed progress in understanding which cells connect to one another;thus, we know relatively little about the development of neural circuits, particularly how neuronal circuit connections change in response to differences in sensory experience or synaptic input activity. Application of neurotropic viruses to map neural circuits will make a significant contribution to our understanding of neural circuit development. The overall goal of this research project is to understand how neural circuits develop and to elucidate the role of activity in this process by applying pseudotyped rabies virus-mediated tracing to a model system uniquely amenable to in vivo developmental studies. Furthermore, we can use pseudotyped rabies virus-mediated tracing to map the circuitry of a molecularly-defined neuron type, such as GABAergic neurons. GABAergic neurons comprise a relatively small proportion of neurons in the central nervous system, but they exquisitely balance out the excitation produced by the far more numerous excitatory neurons. Perturbation in this balance of excitation to inhibition in the central nervous system is thought to underlie neurodevelopmental disorders like autism and schizophrenia.
The specific aims of this proposal are to: (1) adapt the pseudotyped rabies virus trans-synaptic tracing method to Xenopus tadpoles, (2) to identify the presynaptic partners of optic tectal neurons using retrograde tracing with pseudotyped rabies virus and to test whether visual experience affects tectal cell connectivity maps, and (3) to test whether glutamatergic or GABAergic synaptic inputs affect the development of tectal cell connectivity maps using pseudotyped rabies virus trans-synaptic tracing. These experiments will allow us to both determine as yet unidentified presynaptic partners of tectal neurons, and also to test directly whether visual experience or synaptic transmission alters the number and type of presynaptic partners that a tectal neuron has. These experiments will help to elucidate the mechanisms regulating the development of neural circuits and this basic understanding of brain development is critical to developing new ways to treat brain illness and injury. Furthermore, these experiments will expand our knowledge of GABAergic circuit development and can have important implications for neurodevelopmental disorders like autism and schizophrenia.
An understanding of which cells in the brain connect to one another is critical to understanding brain function and to treating brain illness and injury. The experiments in this proposal will expand our knowledge of neuronal connectivity and can have important implications for our understanding and treatment of neurodevelopmental disorders such as autism and schizophrenia.