Cortical Development, Plasticity and Dynamics
Mriganka Sur, PhD, Principal Investigator
Plasticity, or the adaptive response of the brain to changes in inputs, is essential to brain development and function. The developing brain requires a genetic blueprint but is also acutely sensitive to the environment. The adult brain constantly adapts to changes in stimuli, and this plasticity is manifest not only as learning and memory but also as dynamic changes in information transmission and processing. Many neurological disorders can be traced to specific dysfunctions in mechanisms of signaling or network formation in the brain. The goal of our laboratory is to understand long-term plasticity and short-term dynamics in networks of the developing and adult cortex, and how disruption of any of these network properties leads to brain disorders.
Cortical development starts with genes that demarcate different areas, and subsequently genes that prompt the formation of a scaffold of connections between neurons in each area. Each area of cortex is organized into functional layers specialized for receiving, integrating, and forwarding inputs. The connections among and within these layered areas are fine-tuned during development, through the interaction of extrinsic sensory and intrinsic genetic influences. Proper cortical wiring depends on precise timing of genetic translation, routing of sensory inputs, and gradation of molecular cues. To better understand this process, we couple methods of RNA, protein, and genetic analysis with behavioral and functional imaging assays. By applying these methods to genetically modified or sensory-deprived model animals, we probe the roles of individual factors in the development of normal and impaired cortical function.
In the adult brain, cortical networks underlie the internal representation of the world that allows our predictable interaction with it. The cortex is made up of a number of diverse cell types suited to particular subtasks of information processing. The basic division between excitatory and inhibitory neurons has been further refined as these classes have become better defined in our understanding. Recently astrocytes have been recognized as active signal-processing cells as well. Development of high-speed imaging, activity-sensitive dyes, and light-sensitive ion channels are currently fueling our exploration of the varied and plastic networks these cells form. Imaging the activity of networks and their constituent cells in real time during stimulation informs us about rates of plasticity, attention effects, the routing of sensory inputs, and the roles played by specific cell classes in these networks. We apply these methods to induced or genetically specified animal models of disorders such as Rett Syndrome to pinpoint the factors that lead to cortical dysfunction, and to test therapeutic approaches for efficacy against these underlying factors. Thus classification of cell types and their roles leads to identification of disease mechanisms, and in turn to the informed development of interventions targeting the bases of disorders, rather than their symptoms.
To carry out our experimental program, which stretches from identification of mRNAs to functional characterization of cells and networks to analysis of behavior, the Sur laboratory uses and develops state-of-the-art techniques. These include functional imaging and optogenetic perturbation of single neurons and entire networks in vitro and in vivo using two-photon microscopy, multiple-electrode single unit recording in cortex, high-resolution optical imaging of activity from an expanse of cortex, whole-cell intracellular recording and calcium imaging in slices and in the intact brain, and microarrays and computational tools to identify genes in specific tissues and at specific points in development. We are uniquely equipped to identify patterns of abnormality at any level from protein expression to behavior, and to follow those patterns back to their roots.