RESEARCH AREAS
DEVELOPMENTAL NEUROSCIENCE : Nervous System Development, Regeneration and Repair
A major goal of neuroscience is to regenerate and repair neural systems disabled by diseases that have a genetic origin. Solving this problem requires a deep understanding of genetic control of neural development and the cellular and molecular mechanisms underlying the generation of diverse cell types and their circuitry. Faculty in our department utilize molecular and genetic approaches, as well as state-of-the-art imaging techniques, to elucidate the mechanisms that shape the development of the visual and auditory system.
Tom Reh and Olivia Bermingham-McDonogh investigate the key transcription factors that control neurogenesis and cell fate in the mammalian retina and inner ear, respectively.
Rachel Wong‘s lab studies the developmental assembly of neuronal circuits, their disassembly during degeneration and reassembly upon cellular regeneration. Their studies are focus on synaptic circuits of the vertebrate retina of zebrafish, mice and primate, using transgenic methods, imaging and electrophysiological approaches, and correlated fluorescence imaging and serial electron microscopy (CLEM). Volume imaging and reconstructions using semiautomated serial electron microscopy is used routinely by the Dacey and Wong labs to study the development of the human retina.
On the right is a 3D reconstruction of a cone photoreceptor (yellow) and its connection with an ON (magenta) and an OFF (green) midget bipolar cell in the developing fovea of the human retina around mid-gestation. Synaptic ribbons are shown in red. This specialized “private-line” connection, critical for high resolution vision, is formed relatively early in development (from Zhang et al., 2020).
John Clark’s lab has used the living zebrafish to observe the development of the lens of the eye to advance understanding of how cataracts are formed. David Raible and Rachel Wong also take advantage of the regenerative capacity of the adult zebrafish to uncover the mechanisms controlling endogenous cell replacement and synaptic rewiring in sensory systems. The Bermingham-McDonogh lab investigates what prevents hair cell regeneration in the mammalian inner ear and probes the molecular pathways that regulate hair-cell regeneration in the vestibular system. Although the mammalian retina is normally unable to regenerate its neurons, cell replacement can be triggered by inducing endogenous glial cells to produce neurons, a strategy advanced by the Reh lab.
SYSTEMS NEUROSCIENCE : Neural Circuitry, Function and Behavior
Understanding the function of the nervous system and how it is altered by disease requires integrating knowledge across levels of organization and complexity, from the biophysical mechanisms of synaptic transmission, to local microcircuit connectivity, to the coordinated activity of hundreds or thousands of neurons across diverse brain regions. At each of these levels integrated anatomical, physiological and behavioral data are ultimately needed to advance understanding of how a neural system encodes information and drives behavior. Faculty in Biological Structure reflect this great challenge in systems neuroscience.
Dennis Dacey’s lab works at the first steps in the visual process, with an in vitro preparation of the functioning primate retina, to identify synaptic mechanisms, and local circuits responsible for initiating color and motion perception using optical imaging of local dendritic processing, intracellular physiology, neural modeling and connectomic reconstruction of synaptic pathways.
On the right, you see a 3D reconstruction from electron microscopic data of the circuitry that mediates visual acuity in the fovea of the human retina. These miniaturized “midget” circuits preserve the high resolution afforded by the densely packed cone photoreceptors at the foveal center. The video shows three neighboring midget bipolar cells and their “private-line” synaptic connections to three midget ganglion cells. The small red balls indicate the locations of the bipolar to ganglion cell synapses.
Deeper into the visual pathway Anitha Pasupathy’s lab seeks to discover the neural code for our visual perception of objects and shape by integrating physiological recording of neural activity in neocortex with computational modeling and behavior manipulation in trained primates. At a still higher level of organization Wyeth Bair’s lab, in addition to physiological studies, is creating large-scale neural network models to integrate theories of motion, color and form processing across the primate visual system.
At a still more all-encompassing level, the goal of Nick Steinmetz’s lab is to understand how neural mechanisms of visual perception merge with pathways for cognition and ultimately behavior using the mouse brain as their model. Nick’s approach is to measure and manipulate neural circuit activity on a large, distributed nearly brain-wide scale and to correlate this neural population code with precisely measured visually guided behaviors. Of course, the ultimate goal of systems neuroscience is to understand the neural basis of human behavior and how it is altered by disabling neuropsychiatric disorders.
Sam Golden’s lab, also working with preclinical rodent models, is particularly interested in how maladaptive behavior like aggression and addiction arise by dysfunction of healthy reward circuitry. Sam’s lab has pioneered the use of sophisticated optogenetic and chemogenetic tools to manipulate and measure circuit changes combined with machine learning-based techniques to quantify behavior in a natural setting. Their lab also uses whole brain tissue clearing and light sheet microscopy for anatomical circuit mapping and functional activity mapping.
On the left, you see a 3D volumetric render generated from an intact mouse brain using tissue clearing and light sheet fluorescent microscopy. Cortical and hippocampal glutamatergic projections are indicated in green, and behaviorally activated neurons in red. This approach allows for single-cell resolution whole brain activity mapping within genetically defined types of neurons.