Area of Research
Models of Psychiatric Disorders, Neurogenetics, Synapses and Circuits, Cognitive/Systems Neuroscience
Systems neurophysiology in mouse models of neuropsychiatric illness.
Cloning of genes which predispose to neuropsychiatric illness is proceeding rapidly of late. Yet identifying such predisposition genes is but a first step in understanding the pathophysiology of mental illnesses. We study genetic models of these diseases from an integrative neuroscience perspective, focused on understanding how a given disease mutation leads to a behavioral phenotype in disease-related mouse models. To this end, we employ a range of systems neuroscience techniques, including in vivo anesthetized and awake behaving recordings.
A major effort in the laboratory involves recording neural activity from mice carrying induced mutations in genes or chromosomal regions that predispose to schizophrenia. We focus in particular on spatial working memory behaviors, which in rodents rely on functional connectivity between the hippocampus and medial prefrontal cortex. Using multielectrode arrays, we record multiple single units and local field potentials from these brain regions while mice perform a spatial working memory task. We measure neural activity in each area as well as functional synchronization between the two brain regions in wild type mice as well as mice carrying schizophrenia-predisposing mutations. These projects involve collaboration with laboratories at Columbia and at other institutions, including the laboratories of Joseph Gogos (Columbia University), Maria Karayiorgou (Columbia University), and Lorna Role (SUNY-Stonybrook).
A second major effort in the laboratory is aimed at identifying the effects of a deletion in the serotonin 1A-receptor (5-HT1AR) that lead to a phenotype of increased anxiety-related behavior. Data from lesion and tissue-specific, inducible rescue experiments suggest that the phenotype arises due to a lack of hippocampal 5-HT1ARs during development. Accordingly, we have identified cell anatomical and functional abnormalities in the hippocampus of 5-HT1AR knockouts. Of note, we find an increase in the power of theta (4-12 Hz) oscillations in the hippocampi of these animals during exposure to an anxiety-provoking environment. We also have accumulated evidence demonstrating that the increase in hippocampal activity is accompanied by an increase in theta-frequency oscillations in the medial prefrontal cortex, and have further shown that the functional synchronization between the ventral hippocampus and the medial prefrontal cortex predicts anxiety-like behavior. These data argue that hippocampal dysfunction plays a role in the anxiety-related phenotype in 5-HT1AR-deficient mice. Current efforts include further characterization of the nature of hippocampal activity differences using multiple single-unit recordings, as well as attempts to prove causality by artificially altering theta oscillations directly in wild-type mice and examining the effects of these alterations on anxiety-related behaviors.
Adhikari, A., M.A. Topiwala, and J.A. Gordon (2011). Single units in the medial prefrontal cortex with anxiety-related firing patterns are preferentially influenced by ventral hippocampal activity. Neuron. 71:898-910.
Gordon, J.A. Oscillations and hippocampal-prefrontal synchrony (2011) Curr. Opin. Neurobiol. 21:584-491.
Sigurdsson, T., K.L. Stark, M. Karayiorgou, J.A. Gogos, and J.A. Gordon. (2010) Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature, 464:763-767.
Adhikari, A., M.A. Topiwala, and J.A. Gordon (2010). Synchronized activity between the
ventral hippocampus and the medial prefrontal cortex during anxiety. Neuron, 65:257-269.
Lacefield, C.O., V. Itskov, T. Reardon, R. Hen, and J.A. Gordon (2010). Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus. Hippocampus Epub DOI: 10.1002/hipo.20860.