Harvard University - Department of Molecular & Cellular Biology

NEW RESEARCH CENTER AIMS TO MAP BRAIN'S NERVE CIRCUITS IN SEARCH FOR CAUSES OF MENTAL ILLNESS

by Richard Saltus

November 22nd, 2011


(L-R) T. Hensch, C. Dulac, J. Cuff, J. Lichtman, X. Zhuang

Scientists in the Department of Molecular and Cellular Biology (MCB) and Center for Brain Science (CBS) have launched a high-tech effort to map the brain’s “wiring diagram” and how it is shaped by early experience, seeking the causes of – and potential treatments for – schizophrenia, autism, retardation and other disorders. Researchers in a new Silvio O. Conte Center funded by the National Institute of Mental Health (NIMH) are focusing on critical periods in brain development, when the effects of abnormal genes and environmental stresses can lead to miswired connections in key areas of the brain.

The project takes advantage of powerful computational, genome sequencing and imaging tools, including electron microscopes and a high-resolution optical imaging platform based on technologies known as “Brainbow” and “STORM,” which enable scientists to visualize nerve pathways in mice by tagging them with scores of different fluorescent colors and imaging them with nanometer-scale resolution. With these and other resources, the scientists say they will able to identify the thousands of individual connections made onto and from a single cell. They have chosen for these studies a particular type of neuron that orchestrates the wiring of nerves during brain development.

The center is also probing the effects of “genomic imprinting” on brain development – the phenomenon of a gene having different effect depending on whether it was inherited from the father or mother. Many such imprinted genes, when mutated, appear to contribute to mental retardation and other brain disorders.

Takao K. Hensch, PhD, the grant’s principal investigator and center director, explains: “Our aim is to use new methods of analyzing brain circuits to attain a rather simple, but heretofore unattainable goal - the complete connectional diagram and imprinted gene expression profile of a pivotal cell type implicated in many cognitive developmental disorders.”

Hensch, a professor of Molecular and Cellular Biology, studies the critical periods in development when the brain “wires itself up.” During those periods the brain is “plastic” and able to learn new information, but is also most susceptible to rewiring that occurs under physical and environmental stresses.

For example, a study of adults who were born during a severe famine in Holland near the end of World War II had double the average risk of schizophrenia; this connection was confirmed in a much larger study of individuals born during Chinese famine of 1959 to 1961 when millions died of starvation.

The center was established in September with a $9 million Silvio O. Conte Centers grant from NIMH, which provides a funding framework for basic neuroscience research on well-defined scientific questions, and a mission of translating these discoveries for application to mental health issues.

Collaborators in the center include Jeff Lichtman, MD, Ph.D. , professor of Molecular and Cellular Biology, and Catherine Dulac, PhD, professor of Molecular and Cellular Biology and a Howard Hughes Medical Institute (HHMI) investigator.

Also, Xiaowei Zhuang, PhD, the inventor of STORM, a super-resolution system of optical microscopy, who is professor of Chemistry and Chemical Biology and of Physics, as well as an HHMI investigator; and James Cuff, D.Phil., director of Research Computing for the Faculty of Arts and Sciences.

Lichtman is a leader in the field of “connectomics” – mapping interconnections of nerve cells within the brain to better understand its function in health and disease. (It’s estimated that the human brain is made up of some 120 billion neurons that make connections via many trillions of junctions known as synapses.)

Connectomics research got a major boost in 2007 when Lichtman and a colleague, Joshua Sanes developed the Brainbow technique. It allows individual neurons within mouse brains to be distinguished from each other by labeling them with as many as 100 differently colored fluorescent proteins. Processed by computer software, a Brainbow image resembles an abstract painting with neon-bright networks of filigree representing individual cells making connections.

Brainbow is one of the tools the Harvard scientists will use to study a particular brain cell type, known as the parvalbumin (PV)-positive GABA neuron, in the frontal lobe. Hensch’s research has pointed to this neuron as playing a pivotal role in orchestrating normal brain development, but it’s also particularly vulnerable to the effects of stress, making this cell a prime candidate for studying mental disorders.

The effects on brain development of imprinted genes will be the focus of Dulac’s work. Until recently, about 100 such genes – which have different effects depending on their parent of origin – had been identified, and some of them linked to mental retardation, autism and other conditions. Dulac, however, has reported as many as 1,300 genes are imprinted in the developing and adult brain, providing additional targets for study. The sensitivity of imprinted genes to early environmental factors such as stress will be of particular interest in this study.

Zhuang’s super-resolution microscope technology – declared Method of the Year by the scientific journal Nature Methods– will help the investigators trace the connectivity diagram. Able to image cells at the molecular level, the instruments will home on the input and output connections of the parvalbumin (PV)-positive GABA neuron, as well as resolving the thin processes (“wires”) stemming from these cells.

The avalanche of data produced in the project must be managed and sorted and assembled, and Cuff’s bioinformatics core resource will be indispensible. “Among other things, he’ll be applying algorithms from astrophysics and the study of galaxies to create connectivity and sequencing maps,” Hensch explains.

The NIMH Conte Center grants require a commitment to training the next generation of mental health researchers, involving even high school students in the project, and to make efforts to build awareness of mental illness across the community.

In this respect, Hensch says, “I’ve been fortunate to be part of Harvard’s Center on the Developing Child, which brings together people from all the schools – medicine, public health, education, business, law, and others – to think about investment in early childhood, since childhood is the critical time for building the intellectual capital of our country.”

Read more in HARVARD gazette

[November 22nd, 2011]

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