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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
United States
Zip Code
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
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
Babcock, Hazen P; Zhuang, Xiaowei (2017) Analyzing Single Molecule Localization Microscopy Data Using Cubic Splines. Sci Rep 7:552
Morgan, Josh L; Lichtman, Jeff W (2017) Digital tissue and what it may reveal about the brain. BMC Biol 15:101
Morgan, Josh Lyskowski; Berger, Daniel Raimund; Wetzel, Arthur Willis et al. (2016) The Fuzzy Logic of Network Connectivity in Mouse Visual Thalamus. Cell 165:192-206
Mierau, Susanna B; Patrizi, Annarita; Hensch, Takao K et al. (2016) Cell-Specific Regulation of N-Methyl-D-Aspartate Receptor Maturation by Mecp2 in Cortical Circuits. Biol Psychiatry 79:746-54
Perez, Julio D; Rubinstein, Nimrod D; Dulac, Catherine (2016) New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain. Annu Rev Neurosci 39:347-84
Morishita, Hirofumi; Cabungcal, Jan-Harry; Chen, Ying et al. (2015) Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons. Biol Psychiatry 78:396-402
Richardson, Douglas S; Lichtman, Jeff W (2015) Clarifying Tissue Clearing. Cell 162:246-257
Kasthuri, Narayanan; Hayworth, Kenneth Jeffrey; Berger, Daniel Raimund et al. (2015) Saturated Reconstruction of a Volume of Neocortex. Cell 162:648-61

Showing the most recent 10 out of 27 publications