The goal of this work is to obtain a full account of all the nerve cells providing input to, and all the nerve cells providing output from, a particular inhibitory neuron (the PV cell) in the cerebral cortex. In addition the location and number of synaptic connections will be delineated. Such a complete map of the connections to and from a neuron has not previously been attempted in the cerebral cortex. In order to do this we will need to use four different newly developed approaches that include both new optical and new electron microscopy strategies. It is my belief that it is likely that subtle changes in neural circuits may underlie abnormalities that are expressed outwardly as mental illness. Until we have methods to trace the connections at the finest level, such abnormalities will be inaccessible to scientific scrutiny. We have chosen as a first test a particularly interesting neuron that is likely to be located at pivotal regulatory point in the controlling neural wiring plasticity during development and perhaps disease. The particular goal will be to look at changes in the pattern of connections during development and in the present of certain gene deletions that are likely to be related to the way these cells function.

Public Health Relevance

Mental illness remains intractable in part because the physical underpinnings of these disorders cannot be scrutinized with sufficient resolution. This proposal seeks to provide an analysis of the cells and synapses that are the sources to and output of, individual PV cells at unprecedented resolution. These inhibitory neurons are likely to be crucial in generating neural circuits therefore studying their connectivity in a variety of situations should be informative.

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National Institute of Mental Health (NIMH)
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Harvard University
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Fang, Tao; Lu, Xiaotang; Berger, Daniel et al. (2018) Nanobody immunostaining for correlated light and electron microscopy with preservation of ultrastructure. Nat Methods 15:1029-1032
Berger, Daniel R; Seung, H Sebastian; Lichtman, Jeff W (2018) VAST (Volume Annotation and Segmentation Tool): Efficient Manual and Semi-Automatic Labeling of Large 3D Image Stacks. Front Neural Circuits 12:88
Takesian, Anne E; Bogart, Luke J; Lichtman, Jeff W et al. (2018) Inhibitory circuit gating of auditory critical-period plasticity. Nat Neurosci 21:218-227
Babcock, Hazen P; Zhuang, Xiaowei (2017) Analyzing Single Molecule Localization Microscopy Data Using Cubic Splines. Sci Rep 7:552
Steullet, P; Cabungcal, J-H; Coyle, J et al. (2017) Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia. Mol Psychiatry 22:936-943
Lee, H H C; Bernard, C; Ye, Z et al. (2017) Genetic Otx2 mis-localization delays critical period plasticity across brain regions. Mol Psychiatry 22:680-688
Sheu, Shu-Hsien; Tapia, Juan Carlos; Tsuriel, Shlomo et al. (2017) Similar synapse elimination motifs at successive relays in the same efferent pathway during development in mice. Elife 6:
Cameron, Judy L; Eagleson, Kathie L; Fox, Nathan A et al. (2017) Social Origins of Developmental Risk for Mental and Physical Illness. J Neurosci 37:10783-10791
Morgan, Josh L; Lichtman, Jeff W (2017) Digital tissue and what it may reveal about the brain. BMC Biol 15:101
Quadrato, Giorgia; Nguyen, Tuan; Macosko, Evan Z et al. (2017) Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545:48-53

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