Overall abstract Most mental illnesses emerge during vulnerable windows of brain development to impact cognitive function in humans. While hundreds of genes and/or environmental factors have been linked to mental illnesses, even neighboring point mutations on a single gene (eg. Shank3) can lead to `early' disorders such as autism or `late' schizophrenia. This poses a double challenge to understanding their etiology and potential treatment ? how to track the trajectory of circuit derailment and the relevance of such studies in animals like mice whose cognitive skills may be less well-characterized. Our proposed Conte Center renewal will tackle these problems directly by uniting four pioneering neurobiologists focused on the formation and refinement of neuronal circuits in two stages of development, fetal and pre-adolescent critical periods. Our central hypothesis is that whatever the predisposing environmental factors or genetic bases, the proximate cause of aberrant behavior in cognitive disorders will be found in distinct patterns of altered neuronal connectivity. First, to examine how excitatory- inhibitory balance is established in fetal life, Arlotta combines cutting edge stem cell, genomic, imaging and physiological recording technology for the longitudinal study of human brain organoids carrying specific gene mutation. Second, key conceptual insights from Hensch in the first phase of our Center identified the pivotal role of parvalbumin (PV+) cells in determining postnatal critical period timing. Because of their high metabolic activity, PV+ cells are vulnerable to oxidative stress in mental illness, as are the gamma oscillations which they generate (in association with cognition). Manipulations altering PV+ cell maturational profiles powerfully shift plastic windows in sensory cortex, indicating that malleability of critical periods themselves may contribute to cognitive disorders as well. Third, Hensch and Feng confirmed an impairment of multisensory integration in the insular cortex of mice carrying autism risk mutations in Shank3 and Mecp2. Notably, these lie on opposite ends of PV+ circuit hypo- or hyper-maturation. Here, we will take advantage of reversible and conditional genetic mutations in these genes to map critical periods for other higher functions of relevance: attention, cognitive flexibility, and social preference? all established in the Hensch lab. Moreover, for direct comparison to his mice, Feng will produce marmosets carrying Cre recombinase in PV+ cells or Shank3 deletion using CRISPR technology. His unique infrastructure will enable manipulation and analysis of the same circuits in this primate with better evolved frontal cortex and behaviors. Fourth, we capitalize on a sophisticated platform for complete 3D electron microscopic circuit reconstruction established by Lichtman during the first phase of our Center to compare and contrast the emergence of `connectopathies' from human organoids to mice and marmosets. Ultimately, reducing the stigma of mental illness through state-of-the-art neuroscience to train the next generation and conveying this knowledge through our strong, active Outreach program is the primary mission of the Conte Center at Harvard.

Public Health Relevance

When a complex machine such as a car malfunctions, the first thing a mechanic must do is identify the origin of the problem. It's hard to fix things without knowing what's broken. This challenge plagues the understanding and treatment of mental illness. The Conte Center at Harvard seeks to revolutionize therapy and prevention by addressing two necessarily basic questions: What does mental illness look like in the brain? When and how during development do these differences arise? In our first phase, we established state-of-the-art technologies to fully reconstruct brain circuits and made conceptual advances into the biological basis of critical periods of vulnerability. Now reconfiguring around the laboratories of Arlotta, Lichtman, Hensch and Feng, our world class team tightly integrates across levels from behavior to circuits, cells, synapses, and genes, to understand what is different about a brain that produces the symptoms of schizophrenia or autism, for instance, versus one that does not. Focusing on the potential to rescue Shank3 or Mecp2 mutations, we span diverse systems from human organoids to reversible gene-targeting in mice and transgenic marmosets to track the trajectory from fetal development to cognitive impairment. Further, by leveraging our highly regarded Outreach infrastructure established in the first phase, our trainees will increase public awareness and build a pipeline of future investigators as they engage in this unparalleled research themselves.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
2P50MH094271-06
Application #
9489982
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Panchision, David M
Project Start
2011-09-05
Project End
2023-03-31
Budget Start
2018-07-01
Budget End
2019-03-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
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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
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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

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