When Brain Development Goes Awry
New Research Center Seeks Answers on the Origins of Mental Health Disorders
By Parizad Bilimoria
Call it a Dream Team for neuroscientific research. Led by neurobiologist and Center on the Developing Child-affiliated faculty member Takao Hensch, Harvard scientists who are pioneers in the diverse fields of brain plasticity, connectomics, genomic imprinting, and super-resolution imaging are now collaborating with experts in bioinformatics to understand and communicate the changes in neural circuits that underlie disorders such as autism, schizophrenia, anxiety, and depression.
In the fall of 2011, the National Institute of Mental Health (NIMH) brought this team together with a $9 million grant to establish the Conte Center at Harvard, named in memory of the late Massachusetts congressman and champion of biomedical research funding, Silvio O. Conte. Awarded annually by the NIMH since 1993, Conte Center grants provide support for five years of multidisciplinary studies employing innovative methods to tackle “high-risk, high-impact questions” in basic or translational mental health research.
“The opportunity to connect with scientists of this caliber to do groundbreaking work is why I am here,” says Hensch, director of the Conte Center, professor of molecular and cellular biology at Harvard, and professor of neurology at Boston Children’s Hospital (BCH). “I truly believe this grant will catalyze new advances that could, one day, significantly improve the quality of people’s lives.”
Coming Together to Dig Deeper
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The Conte Center at Harvard supports projects led by five principal investigators, including Hensch. All of their work converges on a single type of brain cell, which is thought to be particularly vulnerable to genetic and environmental insults associated with cognitive disorders: the parvalbumin-positive inhibitory interneuron, or “PV-cell.”
Hensch is an international leader in the study of critical periods of brain development—the windows of time when brain circuits are most open to influence from experiences. His laboratory, in conjunction with the lab of Michela Fagiolini, another Center on the Developing Child-affiliated faculty member who is an assistant professor of neurology at BCH, is now applying a critical-period perspective to investigating how brain development is altered in disorders such as autism, Rett syndrome, and schizophrenia.
Their attention was first drawn to PV-cells upon realizing that the maturation of these neurons could control the timing of critical periods—timing which, they hypothesize, might be disrupted in many neurodevelopmental disorders. It was then that Hensch felt that he and Fagiolini were at a particularly exciting juncture in their research, where they could truly begin to think about using their basic research findings and methods to gain insights into psychiatric disorders. “Our critical-period research had reached a point where we might make inroads toward better understanding mental illness,” Hensch says.
To move toward this goal, Hensch began to consult with Catherine Dulac, who is the Higgins Professor of Molecular and Cellular Biology and the department chair, and Jeff Lichtman, who is the Jeremy R. Knowles Professor of Molecular and Cellular Biology, about complementing his own team’s abilities in cellular physiology and behavior with their cutting-edge methods in genomics and imaging, respectively.
Dulac’s laboratory is pioneering the study of genomic imprinting—a phenomenon in which the copies of genes inherited from an individual’s mother and father act differently. In 2010, when fewer than 100 imprinted genes were known overall, Dulac’s team published a list of over 1,300 candidates for imprinted genes specific to the brain alone. Many of these appeared to be important in brain disorders, but the phenomenon differed in various regions of the brain. To get a deeper understanding, they needed to zoom in on a single cell type.
Lichtman’s team, too, realized the need to focus on one type of brain cell, as part of its larger effort to map the complete wiring of neural connections in the brain, known as the “connectome.” Lichtman and many others believe that psychiatric illnesses may be “connectopathies,” or disorders of neural connectivity, and, over the years, his lab has developed novel imaging methods that now make it possible to begin to test this hypothesis.
Together, the trio decided to apply for a Conte Center grant. Joining them in the application were Xiaowei Zhuang, a professor of chemistry and chemical biology and a professor of physics, and James Cuff, who is director of research computing and chief technology architect in Harvard’s Faculty of Arts and Sciences. Zhuang’s laboratory has revolutionized the field of light microscopy with the invention of STORM (STOchastic Optical Reconstruction Microscopy)—a technique that is being used in the connectome project to see, as never before, how neurons connect with one another. Cuff is an expert in developing new ways to collect and analyze large and complex sets of biological data. His team will apply principles from astrophysics to the challenge of integrating and interpreting the large volumes of information generated by the Conte labs.
Reaching Beyond the University
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Faculty Spotlight: Takao HenschLearn more about Conte Center Director Takao Hensch’s research interests and his affiliation with the Center on the Developing Child in a Faculty Spotlight feature.Read more >> |
One unusual feature of the Conte grant that appealed to the Harvard group was that it required the collaborators to engage in education and outreach projects that could complement their basic research, and it even provided funding for those endeavors. The Conte Center is working closely on these ventures with the Center on the Developing Child as well as the Harvard Life Sciences Outreach Program, which supports high school and community life sciences education by leveraging Harvard’s research and teaching resources. Some of the components of this work include:
- In 2012, the launch of the Conte-Center for Brain Science (CBS) Colloquium on Mental Health, an interdisciplinary series of lectures focused on mental health research and held monthly throughout the academic year. The lectures, followed by small group discussion sessions with the speakers, bring together students, fellows, faculty, and staff from Harvard’s various schools as well as interested community members.
- During summer 2012, together with Life Sciences Outreach, hosting a two-day workshop for high school science teachers. This featured basic and clinical neuroscience lectures, lab tours, and laboratory sessions on brain imaging and neurophysiology. Upon completion of the workshop, teachers received specialized laboratory kits that will allow them to teach hands-on lessons about the electrical lives of neurons.
- Supporting summer undergraduate research and facilitating an effort led by the Center on the Developing Child to provide summer internship opportunities for students at various levels—high school to graduate school—to contribute to the connectome project by coloring electron microscope images of the brain to help reconstruct neural circuits in three dimensions.
- Launching the Conte Center web site, featuring investigator profiles, project descriptions for each of the laboratories, an events page, and a Twitter feed of news and updates. The site is also linked to a blog on mental health research, called E/I Balance, which takes its name from the excitatory (E) and inhibitory (I) activity in the brain.
Hensch has been involved in research collaborations facilitated or sponsored by the Center on the Developing Child since 2006 and has assumed leadership roles, including serving on its steering committee. More recently, he was named to the inaugural advisory group for the Center’s Science of Health and Development Initiative. He is particularly energized by the fact that the Center’s activities on the science of brain development extend all the way from supporting the creation of new knowledge and communicating that knowledge to the public to translating the science into improved public policies for children and families. “The opportunity for a bench scientist to potentially influence policy is quite rare,” he notes. “The Center on the Developing Child makes this possible.”
Parizad Bilimoria is the Communications and Outreach Director for the Conte Center at Harvard.
Top photo courtesy of Harvard Life Sciences Outreach Program. Sidebar photo by Fred Field.
