Our lab is interested in the mechanisms that underlie synaptic competition between neurons that innervate the same target cell. Such competitive interactions are responsible for sharpening the patterns of neural connections during development and may also be important in learning and memory formation. The Lichtman laboratory studies synaptic competition by visualizing synaptic rearrangements directly in living animals using modern optical imaging techniques. We have concentrated on neuromuscular junctions in a very accessible neck muscle in mice where new transgenic animals and other labeling strategies allow individual nerve terminals and postsynaptic specializations to be monitored over hours or months. In addition, we have developed several new methods to improve our ability to resolve synaptic structure. 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).

Lichtman’s research focuses on the study of neural connectivity and how it changes as animals develop and age. With his colleagues he has developed a number of tools that permit synaptic level analysis of neural connections. These include activity dependent uptake of fluorescent dyes, transgenic approaches to label individual nerve cells, and “combinatoric” methods (e.g., DiOlistics, Brainbow, and NPS) to label many nerve cells in the same tissue. In addition, he has helped develop automated electron microscopy approaches for large scale neural circuit reconstruction. These connectomic methods seek to make it routine to acquire neural circuit data in any nervous system. The central focus of his work is to describe the ways in which developing nervous systems change to accommodate information that is acquired by experience. Much of this work has centered on the mammalian peripheral nervous system which undergoes profound activity-dependent circuit reorganizations in early life. These alterations allow axons to prune most of their synaptic branches while strengthening a small subset of synapses in a competitive process called synapse elimination. Study of the dynamic changes that occur in circuits has required not only describing circuits in great detail at single time points but also visualizing how connections change over minutes, months and even years using in situ imaging approaches in living animals.

Click here to read about the Lichtman lab’s research in the Conte Center, focused on developmental origins of mental illness.

Conte Center at Harvard