The central mission of my laboratory is to develop new strategies to rejuvenate and protect the brain. Towards this end, we are pioneering inhibitory neuron transplantation approaches to discover principles for the reactivation of juvenile brain plasticity. In addition, we have created new microglial transplant technology to correct the brain’s self-protection mechanisms. Lastly, we are developing new 3D histological imaging methods to precisely map recent activity and inflammation across the whole brain.

Rejuvenation of Brain Plasticity. The brain has the remarkable capacity to rewire its connections and thereby reorganize its function. In the young brain, the plasticity of neuronal connections mediates the fine-tuning of a wide range of behaviors, from visual perception to language acquisition to social recognition. What mechanism regulates the plasticity of young brains? How might we reactivate this plasticity in adulthood? We discovered that transplanted inhibitory interneurons restore juvenile plasticity in the adult visual system. In addition to the transplantation of interneuron precursors, we employ a combination of techniques including two-photon functional imaging; rabies viral tracing; whole brain clearing and light sheet imaging of neural circuits; and mouse genetic tools that identify, stimulate and silence defined circuits. Understanding how neural plasticity is regulated may open new therapeutic avenues for the rejuvenation of brain function.

New Technology for Understanding Human Microglia. We have established a new research program to develop tools for the study of neuroinflammation in the brain. As the resident immune cells of the brain, microglia protect against insult and injury. Increasingly, these cells are implicated in a wide array of brain disorders. Human microglial biology has been primarily studied in vitro. Together with collaborators, we are devising new xenotransplantation approaches to understand human microglial function using recipient mouse brains. By engineering patient-derived microglia to express various fluorescent reporters of microglial activity, we will study how human microglia survey the brain and respond to insults. Our intent is to uncover how these patient-derived mutations impair microglial response so that we can design new strategies to better protect the brain from disease.

Next-Generation Brain Histology. For over three hundred years, scientists and physicians have plumbed the anatomical mysteries of the body by slicing tissues into thin sections and viewing these sections under the microscope. In the last five years, new technologies have emerged that fundamentally upend conventional tissue histology. Using new chemical procedures, complex biological tissue such as brains can be rendered optically transparent. When combined with new microscopes that excite fluorescent probes deep in the cleared tissue using a laser light sheet, large 3D dimensional structures can be reconstructed nearly 100 times faster than state-of-the-art thin section technology. Although these 3D methods are in their infancy, the potential for transformation of basic research and tissue diagnostics is immense. My research laboratory has developed new microscopy hardware and analysis software and devised new assays that support researchers who want to use these revolutionary new technologies for basic science and drug discovery. Eventually, we envision a 3D revolution in human tissue diagnostics that we call next-generation histology. We are creating platforms for mapping regional signatures of neural activity and inflammation at cellular resolution that will find application in diverse fields such as neurodevelopment, addiction, brain injury and neurodegeneration.