The cerebral cortex is the seat of higher brain function, responsible for sensory perception, cognitive processes, voluntary movement, and consciousness. Abnormalities of the human cerebral cortex cause neurological and psychiatric disorders, such as epilepsy, schizophrenia, and autism. A key feature of the functional anatomy of the human cerebral cortex is its organization into functionally distinct regions along its tangential dimension. During brain development, highly heterogeneous cell types must precisely assemble into unique neural circuits both within and between these areas to control complex behaviors and cognitive processes. The molecular mechanisms that encode cortical projection neuron subtype identity and synaptic specificity remain poorly understood. This proposal details a 3 year plan for postdoctoral research and professional development under the mentorship of Dr. Nenad Sestan, Professor of Neurobiology at Yale University. The fellow will investigate the mechanisms that form the molecular basis for intra-cortical projection neuron heterogeneity and projection identity. The fellow will build on his existing expertise in neurodevelopmental biology, microscopy, histology, and cell biology. He will further develop new expertise in the structure and function of the developing cerebral cortex, neural circuit tracing, transcriptional profiling, single-cell sorting, and advanced mouse genetic technologies by pursuing the following specific aims: 1.) Characterization of intra-cortical projections in association areas of auditory cortex (A2), 2.) Transcriptional profiling and characterization of intra-cortical projection neuron subtypes in A2, and 3.) Deciphering the molecular mechanisms that establish intra-cortical projection neuron heterogeneity in A2. The expertise of Dr. Sestan in cortical development and genomics, mouse genetics, and studies of long-range projection circuitry will provide the scientific guidance and technical capabilities necessary to ensure successful completion of these aims. The fellow and the sponsor have also developed a detailed plan for professional skills development. The research and training plan proposed here, along with the fellow's choice of mentor, will provide excellent training towards the fellow's goal of an academic career studying the developmental neurobiology of the cerebral cortex and its dysfunction in disease.
The cerebral cortex is responsible for higher brain function and is divided into regions with distinct roles in brain function, which must communicate with each other to produce complex behaviors and cognitive processes. Dysfunction of communication between cortical regions leads to disorders including autism and schizophrenia. This project explores the mechanisms that determine how connections between different functional regions of the cerebral cortex are made during development in order to determine how these connections might be abnormal in disease.
| Silbereis, John C; Pochareddy, Sirisha; Zhu, Ying et al. (2016) The Cellular and Molecular Landscapes of the Developing Human Central Nervous System. Neuron 89:248-68 |
| Olmos-Serrano, Jose Luis; Kang, Hyo Jung; Tyler, William A et al. (2016) Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination. Neuron 89:1208-1222 |
