Understanding How Experience Controls Brain Development

My laboratory is interested in the role of sensory experience in controlling the development, function and plasticity of the visual circuit and how circuit development and function become disrupted in neurodevelopmental disorders. We conduct state of the art experiments in visual circuit development using molecular genetic manipulations, electrophysiological methods, in vivo time-lapse imaging, electron microscopy and behavior. Over the past 20 years we have demonstrated roles for a variety of activity-dependent mechanisms in controlling structural plasticity of neuronal dendrites and axons, synaptic maturation and topographic map formation. This body of work has helped to generate a comprehensive understanding of the role of experience in shaping brain development. Two key points to emerge from our research is that circuit formation in vivo is a dynamic process throughout development that is continuously guided by experience, and that the basic mechanisms governing brain development, plasticity, information processing and organizational principles of brain circuits are highly conserved across vertebrates. More recently we have begun to address the role of activity-dependent mechanisms in the development of the functional visual circuit, assessed by in vivo recordings of visual responses in intact animals and behavioral assays. This series of studies has revealed critical molecular/genetic players required for the integration of neurons into functional circuits in vivo.

Research Projects

The Dynamic Connectome

A thorough understanding of circuit development and brain function requires knowledge of the connectivity of brain networks. In vivo time-lapse imaging of dendritic and axonal structures have shown that they are dynamic over the timecourse of hours and days. Importantly the structural dynamics are the physical substrate of synaptic dynamics and therefore dynamics in the connectivity map. We have begun to assess the dynamics in the connectivity map of the optic tectum by combining in vivo time lapse imaging with serial section electron microscopy and three-dimensional reconstruction of optic tectal neuronal dendrites and axons. We use 2 photon time lapse imaging of GFP expressing neurons in living animals to identify dynamic branches within neurons and serial section electron microscopy (EM) to generate 3 dimensional reconstructions of labeled neurons and their synaptic partners. By comparing the live imaging data and the serial section EM data, we determine the synaptic connectivity and ultrastructural synaptic features of dynamics and stable dendritic and axonal branches. This type of analysis will allow us to identify stable and dynamic components of the connectome and to determine how connectivity changes with experience and under conditions that model human neurodevelopemental diseases.

Regulation of Neurogenesis

The development of brain networks depends of the spatial and temporal control of cell proliferation and differentiation. We have recently begun several projects to investigate the control of neurogenesis in the tadpole brain. A significant advantage of studying neurogenesis in tadpoles is that the animals develop externally so the entire process from progenitor cell proliferation to neuronal differentiation and integration into brain circuits can be easily visualized and manipulated in the intact animal. We have recently found that visual experience controls neurogenesis and we have conducted microarray analysis to identify candidate molecular genetic pathways through which sensory experience controls neurogenesis.

Balanced Inhibition in Visual Circuit Function and Behavior

The retinotectal system processes and integrates visual and mechanosensory information and controls behavioral responses to sensory inputs. The interaction between excitatory and inhibitory synaptic inputs is essential for these brain functions. Excitatory synaptic activity is balanced by inhibitory synaptic input throughout the CNS. Despite the widespread expectation that balanced inhibition to excitation is essential for circuit function and information processing, the consequences of manipulating the ratio of inhibition to excitation on information processing and behavior have not been directly tested. We are using in vivo imaging, electrophysiological methods and behavior combined with molecular genetic manipulations to determine the function of inhibition in visual system function. These projects will the mechanisms controlling the development of inhibitory and excitatory neurons and explore the consequences of disrupting the balance of inhibition to excitation in the intact brain, akin to deficits in information processing seen in neurodevelopmental disorders such as autism spectrum disorders.