Our laboratory examines the structure and function of synapses in the mammalian neocortex and their contribution to complex circuit activity and behavior. We are particularly interested in applying an array of methodological approaches, including electrophysiology, 2-photon imaging and transmitter photo-uncaging, optogenetics, and viral tracing to both reduced preparations and intact behaving animals. In this way, we hope to bridge the gaps between molecular, cellular, and systems neuroscience.
Development, function, and plasticity of inhibitory GABAergic circuits.
The balance of synaptic excitation and inhibition is thought to be critical for normal brain function and is disrupted in a variety of neuropsychiatric disorders. In the neocortex, this balance is maintained by an intricate dance between excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons. A major challenge to understanding the role of GABAergic inhibition is the incredible diversity of interneurons, with different subtypes defined by molecular, electrophysiological, and anatomical features corresponding to distinct functions in local microcircuits. In our studies, we use acute brain slice preparations to dissect the organization of GABAergic synapses and their ability to regulate postsynaptic activity. We have focused particularly on inhibition targeting pyramidal neuron dendrites, which influences both electrical and biochemical signaling in the postsynaptic cell. We are also using in vivo approaches to explore the role of different interneuron populations in the control of learning and perception.
Cortical microcircuits underlying visually-guided behavior.
Visual information is encoded by neuronal activity in the primary visual cortex, whose diverse anatomical projections route these signals to various downstream locations that subserve different aspects of perception, learning, and motor output. Outputs from pyramidal neurons in Layer 5 form the major pathway by which cortical information is communicated to subcortical structures, including the basal ganglia, superior colliculus, and brain stem. We are using novel viral tracing approaches to understand the organization of these outputs, combined with 2-photon calcium imaging in vivo to track the activity of identified Layer 5 neurons during the performance of visually-guided behaviors.
Neuromodulation: providing functional flexibility to cortical circuits.
Adaptive behavior over the life of an organism requires a nervous system with sufficiently stable wiring to support long-term memory but plastic enough to adjust to rapid changes in environmental context. Much of this dynamic flexibility is provided by neuromodulators such as dopamine, norepinephrine, and acetylcholine, which influence neuronal excitability and synaptic transmission. We are using a combination of approaches to study the cellular mechanisms and functional actions of neuromodulation on identified microcircuits in the mouse visual cortex. Studies in both brain slices and intact behaving animals provide us with a rich array of data to understand how neuromodulation influences behavior.
Models of neuropsychiatric illness.
A large body of evidence now suggests that disruption of synaptic transmission and subsequent dysfunction of neuronal circuits contributes to the pathophysiology of neuropsychiatric disorders such as schizophrenia and autism. We are actively investigating how genetic mutations of disease-linked genes, including MeCP2 (Rett Syndrome) and TSC1 (Tuberous Sclerosis) alter the function and plasticity of cortical synapses and produce consequences for behavior.