Synaptic and Neuronal Plasticity in Cortical Circuits

We use several model systems to study developmental plasticity in the cortex and its mechanisms. The first, which we pioneered, involves rewiring the brain: we induce projections from the eye to innervate nonvisual centers, such as the auditory thalamus, early in life. Visual inputs cause the auditory pathway to develop with a very different pattern of activity than normal. We have demonstrated that visual inputs profoundly alter neuronal circuits and connectivity in the rewired auditory cortex. Furthermore, visual projections to auditory cortex mediate visual behavior, and visual projections via the auditory thalamus to the amygdala mediate visual fear learning.

The second model system involves the formation and maintenance of ocular dominance columns in visual cortex. Here, the lab examines molecular mechanisms and dynamics of structural and functional changes in synapses. Several screens that we have carried out reveal changes in expression of scores of molecules that are regulated by activity. Specific sets of molecules are required for hebbian, and other sets for homeostatic, changes in neurons. Our work has shown that molecules such as Arc, CaMKII and STAT1 are key players that link feedforward and feedback changes in neuronal connectivity due to changes in electrical activity.

Cortical circuits are comprised of specific cell-types that each have unique patterns of connections and contribute in specific ways to function. We use a wide range of approaches to analyze the role of inhibitory and excitatory neuron subtypes, along with astrocytes, in cortical plasticity. The goal of these studies is to establish the conceptual basis for understanding activity-dependent plasticity in the cortex.

Many disorders of brain development arise from dysfunction in cortical synapses and circuits. We use animal models of subsets of autism, such as Rett Syndrome, to discover mechanisms by which the underlying genes influence synaptic function and plasticity. Novel therapeutics arising from these insights have entered clinical trials.