I am interested in the way in which experience instantiates itself into the physical structure of neural circuits, that is the physical underpinning of long lasting memory. During mammalian development synaptic connectivity changes dramatically as axons trim many of the synaptic branches and target cells loose many of their synaptic partners while at the same time the subset of connections that remain become stronger. It is possible that these changes underlie the way experience selects from a broad range of synaptic connections a small subset to underlie a long lasting trace of an experience. Our work argues that competition between the neurons that co-innervate the same target cells in development may drive these changes in connectivity. The lab studies circuit formation and rearrangement by visualizing peripheral (motor and autonomic) synaptic circuits directly in living animals. These studies take advantage of transgenic animals in which we express different colored fluorescent proteins in each cell (Brainbow). In addition we have developed automated tools to map neural connections (connectomics) at nanometer resolution using a new method of serial electron microscopy. This latter approach gives of a means of revealing neural circuit motifs throughout the nervous system.

We are interested in understanding how information is physically encoded in the nervous system. One of our major goals is to generate, in collaboration with others, a complete map of the neural connections in the brain—known as the “connectome.” Like the Human Genome Project, we believe that connectome work is necessary from both a basic science and clinical standpoint. From the basic science perspective, studying how the connectome changes as our brains mature will address fundamental questions of brain development, learning and memory, and comparing the connectomes of different individuals will reveal to what degree the pattern of neural connections in each human brain is unique. From a clinical perspective, connectomics will allow us to thoroughly examine the hypothesis that many brain disorders are “connectopathies”—in other words, the idea that the pathology lies in miswiring of neural circuits.

The cerebral cortex of the human brain contains more than 160 trillion synaptic connections. Each neuron receives synaptic connections from hundreds or even thousands of different neurons, and each sends outputs to a similar number of target neurons, spread out over a large distance. Thus, establishing the complete wiring diagram of even one type of neuron in the cortex poses enormous challenges. In the past several years we have been developing novel imaging methods to overcome these challenges. One new method is the “Brainbow” mouse, in which combinations of distinct fluorescent proteins are stochastically expressed in neurons, resulting in labeling with over a hundred unique hues that allow neighboring neuronal processes to be clearly distinguished from one another. Another technique we have optimized is serial electron microscopy reconstruction. For this we have developed a new device that makes possible automated ultrathin sectioning of large volumes of brain tissue (several cubic millimeters), called an Automatic Tape-Collecting Lathe Ultramicrotome (ATLUM).

We will now apply these technologies, as well as viral tracing, to deciphering the connectome of a specific population of inhibitory interneurons in the mouse prefrontal cortex—a population believed to be particularly vulnerable in mental illness. Examining various time points in relation to critical periods of cortical development and comparing healthy mice to mouse models of early life stress, autism, or schizophrenia, we hope to gain broad insights into the developmental circuit basis of mental illness.

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Jeff Lichtman is Jeremy R. Knowles Professor of Molecular and Cellular Biology at Harvard. He received an AB from Bowdoin (1973), and an M.D. and Ph.D. from Washington University (1980) where he worked for 30 years before moving to Cambridge in 2004. He is a member of the Center for Brain Science. Lichtman’s research interest revolves around the question of how mammalian brain circuits are physically altered by experiences, especially in early life.  He has focused on the dramatic re-wiring of neural connections that takes place in early postnatal development when animals are doing most of their learning. This work has required development of techniques such as “Brainbow” transgenic mice to visualize neural connections and monitor how they are altered over time.  Recently his efforts have focused on developing new electron microscopy methods to map the entire wiring diagram of the developing and adult brain.  This "connectomics" approach has as one of its aims uncovering the ways information is stored in neural networks.