The brain is an extremely complex network, consisting of billions of neurons connected by trillions of synapses. The details of these connections-which neurons form synaptic connections with which other neurons-are crucial in determining brain function. Malformation of these connections during prenatal and early postnatal development can lead to mental retardation, autism or schizophrenia;loss of specific connections later in life is associated with neurodegenerative diseases such as Alzheimer's. An efficient method for determining the brain's wiring diagram would transform neuroscience research. We propose to develop a method for exploiting high-throughput DNA sequencing to probe the connectivity of neural circuits at single-neuron resolution. PUBLIC HEALTH RELEVANCE: Many neuropsychiatric and neurodegenerative diseases, including autism, schizophrenia, mental retardation and Alzheimer's disease, result in the loss of specific connections in the brain. We propose to develop a method for identifying these connections in animal models of disease. Our method will have a profound impact on understanding the causes of these diseases.