John Huguenard

Current Research Interests

What are the neuronal mechanisms that underlie network oscillatory synchrony in the thalamocortical system? Such oscillations are related to cognitive processes, normal sleep activities and certain forms of epilepsy. Our approach is an analysis of the cells and microcircuits that make up thalamic and cortical circuits. We also use computational approaches to build physiologically constrained network models to test and improve our understanding of the circuit. Accordingly, we have been able to identify genes whose products, mainly ion channels, play key roles in the regulation of thalamocortical network responses.

Currently, projects focus on: Development of excitatory connections in neocortex, with an emphasis on AMPA receptor alterations in the early postnatal period -- Molecular pharmacology of inhibitory GABA-A receptors in the thalamus -- and the role of receptor phosphorylation in regulating inhibitory function -- Analysis of progression and destabilization of widespread thalamic network activity using large microelectrode arrays -- The roles of neuropeptides, especially NPY, SST, and VIP in regulating thalamic and cortical function -- Reorganization of neocortical connectivity following injury -- Roles of specific GABA-B receptors in regulating pre- and postsynaptic function.

The laboratory uses experimental techniques ranging from biophysical studies of single ion channels to in vivo recording to purely theoretical studies of network synchrony. Our toolbox includes: --Use of mutant mouse models for analysis of gene function in circuit behavior. For example, knockout and knockin mice have been used to identify the specific GABA-A receptor isoforms that are critical for the therapeutic actions of benzodiazepines in thalamus -- patch clamp recording methods for single channels and whole cell currents, with both isolated neurons and those in situ in brain slices -- multi-unit, multi-site extracellular recording techniques -- immunohistochemical techniques for cell identification and protein localization -- molecular & genetic approaches for in situ hybridization of specific transcripts -- targeted antisense oligodeoxynucleotide knockdown of specific gene products -- microscopic techniques for computerized neuronal reconstruction (Neurolucida) -- laser uncaging of photo-labile glutamate derivatives for circuit analysis -- single cell intracellular perfusion for modification of e.g., phosphorylation state -- paired intracellular recordings for analysis of single-axon synaptic connections -- fluorometric detection of calcium indicator dyes in cells and circuits -- local perfusion within slice micro-regions for pharmacological analysis -- computer-based modeling of single cell and circuit behaviors.