Precise cellular identities are necessary to maintain a coherent network of communicating neurons. In the human brain, neural networks are constructed in a well-controlled manner and then subjected to multiple iterations of reinforcement and modulation, resulting in a system capable of adult cognition. Much of this refinement takes place during childhood and adolescence, in the context of interactions with the environment. Throughout this process, specific cells establish unique identities within the network;their roles are dependent both on the initial cell type, defined by an early developmental program, and on the modifications that occur as they become integrated into the nervous system as a whole. If a neuron cannot retain its initial, fundamental characteristics as it adapts itself to the network developing around it, its role in the system may be corrupted. This study aims to examine the molecular means by which a neuron maintains crucial aspects of its identity in a changing environment. Because multiple undefined inputs to a cell may be difficult to control and their effects may be difficult to track, this study makes use of a system in which stimuli are well defined, and markers of cell identity are easy to follow. The AWC olfactory neurons in the nematode C. elegans detect a defined set of volatile chemicals and can be identified by a specific set of molecular markers. The goal of this study is to identify and characterize molecules responsible for maintaining neural identity in the AWCs after differentiation, when the neurons are first exposed to external olfactory stimuli. Specifically, this study aims to: (1) determine the mechanism of action of the nuclear protein, NSY-7, which is required for one of the AWC neurons to retain aspects of its identity after differentiation;(2) characterize the expression and regulation of the nsy-7 gene in order to better understand its function, and (3) define interactions between nsy-7 and the molecular pathway responsible for sensory signal transduction in the AWCs. Examination of the mechanisms controlling maintenance of neural identity may serve to illuminate the factors involved in certain psychiatric disorders, such as schizophrenia, that appear to be partially under genetic control but that first manifest themselves at or after adolescence. The factors responsible for the failure of an apparently normal brain to attain stability late in development remain largely unidentified, but disorders in which an seemingly stable brain departs from its normal state are widespread. Elucidation of the genes that normally control this phenomenon, and their application in the treatment and prevention of psychiatric disease, would therefore be broadly beneficial to public health and to the community.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F03A-M (20))
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Vogel, Michael W
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Lesch, Bluma J; Bargmann, Cornelia I (2010) The homeodomain protein hmbx-1 maintains asymmetric gene expression in adult C. elegans olfactory neurons. Genes Dev 24:1802-15
Lee, Jin I; O'Halloran, Damien M; Eastham-Anderson, Jeffery et al. (2010) Nuclear entry of a cGMP-dependent kinase converts transient into long-lasting olfactory adaptation. Proc Natl Acad Sci U S A 107:6016-21
Lesch, Bluma J; Gehrke, Andrew R; Bulyk, Martha L et al. (2009) Transcriptional regulation and stabilization of left-right neuronal identity in C. elegans. Genes Dev 23:345-58