Schizophrenia is a devastating disorder in which the nature of changes occurring in the brain remains unclear. Extensive research has shown that a number of brain regions and systems are involved in schizophrenia or in its treatment; these include the prefrontal cortex, temporal lobe (hippocampus), ventral striatum and dopamine systems. Our research is directed to understanding the neurobiology of schizophrenia and related neuropsychiatric disorders focusing on the interactions among these systems. The primary approach involves the use of electrophysiological techniques, looking particularly at the modulation of information flow through the neural circuits linking these brain regions. Both in vivo and in vitro intracellular recordings from neurons in the prefrontal cortex and nucleus accumbens are employed to study these interactions. We are focusing on the role of biogenic amines on the control of such information flow through the ventral basal ganglia circuit. Experiments involving stimulation of the source and application of agonists/antagonists are being carried out, with emphasis on understanding the role of the dopaminergic and serotonergic innervation of these structures. We have shown that neurons in the prefrontal cortex and ventral striatum alternate between active and inactive states, as defined by changes in their membrane potential. The hippocampus and other limbic inputs may gate prefrontal cortical throughput in the ventral striatum by enabling active states; this phenomenon is also controlled by dopamine, a transmitter implicated in schizophrenia.
We are studying these interactions in a developmental animal model of schizophrenia. A neonatal hippocampal lesion produces behavioral alteration that resemble phenomena observed in schizophrenia, which emerge after puberty. A number of electrophysiological changes, primarily in the response of the ventral basal ganglia circuit to activation of the mesolimbic projections, have been observed. We are also performing many of these studies combining electrophysiology with electrochemical detection of dopamine release. Our goal is to understand the function and interactions among systems involved in higher cognitive functions, that are known to be disturbed in a number of neuropsychiatric disorders.
Another set of experiments are aimed at elucidating changes in information processing in the same circuit following repeated administration of psychostimulants. This treatment elicits enhanced behavioral responses, and has been proposed to be related to the craving addicted people exhibit for drugs.
Tseng KY, O'Donnell P. Prefrontal cortical interneurons acquire modulation by D2 dopamine receptors during adolescence. Cerebral Cortex (in press).
Kasanetz F, Riquelme LA, O'Donnell P, Murer MG. Turning off cortical ensembles stops striatal up states and elicits phase perturbations in cortical and striatal slow oscillantions in rat in vivo. Journal of Physiology 577 (2006) 97-113..
Tseng KY, Snyder-Keller A, O'Donnell P. Dopaminergic modulation of striatal plateau depolarizations in corticostriatal organotypic cocultures. Psychopharmacology (in press).
Tseng KY, Amin F, Lewis BL, O'Donnell P. Altered prefrontal cortical metabolic response to mesocortical activation in adult animals with a neonatal ventral hippocampal lesion. Biological Psychiatry 60 (2006) 585-590.
Tseng KY, Mallet N, Toreson K, Le Moine C, Gonon F, O'Donnell P. Excitatory response of prefrontal cortical fast-spiking interneurons to ventral tegmental area stimulation in vivo. Synapse 59 (2006) 412-417.
Wolf JA, Moyer JT, Lazarewicz MT, Contreras D, Benoit-Marand, M, O’Donnell P, and Finkel LH. NMDA/AMPA ratio impacts state transitions and entrainment to oscillations in a computational model of the nucleus accumbens medium spiny projection neuron. Journal of Neuroscience 25 (2005) 9080-9095.
O’Donnell, P. Mesolimbic-mesocortical loops may encode saliency, not just reward. Behavioral & Brain Sciences – commentary 28 (2005) 360-361.
Brady, AM, Glick, SD, and O’Donnell, P. Selective disruption of nucleus accumbens gating mechanisms in rats behaviorally sensitized to methamphetamine Journal of Neuroscience 25 (2005) 6687-6695.
Peters, Y.M. and O'Donnell, P. Social isolation rearing affects prefrontal cortical response to ventral tegmental area stimulation. Biological Psychiatry 57 (2005) 1205-1208.
Peters, Y.M., O'Donnell, P. and Carelli, R.M. Prefrontal cortical cell firing during maintenance, extinction and reinstatement of goal-directed behavior for natural reward. Synapse 56 (2005) 74-83.
Tseng, K.Y. and O'Donnell, P. Post-pubertal emergence of prefrontal cortical oscillations induced by D1-NMDA co-activation. Cerebral Cortex 15 (2005) 49-57.
Tseng, KY and O'Donnell, P. Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. Journal of Neuroscience 24 (2004) 5131-5139.
Peters, Y., Barhnardt, N.E. and O'Donnell, P. Prefrontal cortical up states are synchronized with ventral tegmental area activity. Synapse 52 (2004) 143-152.
Brady, A.M. and O'Donnell, P. Dopaminergic modulation of prefrontal cortical input to nucleus accumbens in vivo. Journal of Neuroscience 24 (2004) 1040-1049.
Goto, Y. and O'Donnell, P. Prefrontal lesion reverses abnormal mesoaccumbens response in an animal model of schizophrenia. Biological Psychiatry 55 (2004) 172-176.
O'Donnell, P. Dopamine gating of forebrain neural ensembles. European Journal of Neuroscience 17 (2003) 429-435.
Goto, Y. and O'Donnell, P. Delayed mesolimbic system alteration in a developmental animal model of schizophrenia. Journal of Neuroscience 22 (2002) 9070-9077.
Goto, Y. and O'Donnell, P. Timing-dependent limbic-motor synaptic integration in the nucleus accumbens. Proceedings of the National Academy of Sciences 99 (2002) 13189-13193.
O'Donnell, P., Lewis, B.L., Weinberger, D.R., and Lipska, B.K. Neonatal hippocampal damage alters electrophysiological properties of prefrontal cortical neurons in adult rats. Cerebral Cortex 12 (2002) 975-982.
Goto, Y. and O'Donnell, P. Network synchrony in the nucleus accumbens. Journal of Neuroscience 21 (2001) 4498-4504.
Goto, Y. and O'Donnell, P. Synchronous activity in the hippocampus and nucleus accumbens in vivo. Journal of Neuroscience 21 (2001) RC131.
Wang, J. and O'Donnell, P. D1 dopamine receptors potentiate NMDA-mediated excitability increase in rat prefrontal cortical pyramidal neurons. Cerebral Cortex 11 (2001) 452-462.
Lewis, B.L. and O'Donnell, P. Ventral tegmental area afferents to the prefrontal cortex maintain membrane potential 'up' states in pyramidal neurons via D1 dopamine receptors. Cerebral Cortex 10 (2000) 1168-1175.
O’Donnell, P., Greene, J., Pabello, N., Lewis, B.L. and Grace, A.A. Modulation of cell firing in the nucleus accumbens. Annals of the New York Academy of Sciences, vol. 877, (1999) 157-175.
O’Donnell, P. and Grace, A.A. Disruption of information flow within cortical-limbic circuits and the pathophysiology of schizophrenia. In: Schizophrenia in a Molecular Age. C.A. Tamminga, Ed. American Psychiatric Press, Washington, DC (1999) 109-140.
O’Donnell, P. Ensemble coding in the nucleus accumbens. Psychobiology 27 (1999) 187-197.
O’Donnell, P. and Grace, A.A. Dysfunction in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters. Schizophrenia Bulletin 24 (1998) 267-283.
Carr, D.B., O'Donnell, P., Card, J.P. and Sesack, S.R. Dopamine terminals in the rat prefrontal cortex synapse on pyramidal cells that project to the nucleus accumbens. Journal of Neuroscience 19 (1999) 11049-11060.
O'Donnell, P. and Grace, A.A. Phencyclidine interferes with the hippocampal gating of nucleus accumbens neuronal activity in vivo. Neuroscience 87 (1998) 823-830.
O'Donnell, P., Lavín, A., Enquist, L.W., Grace, A.A., and Card, J.P. Interconnected parallel circuits between rat nucleus accumbens and thalamus revealed by retrograde transynaptic transport of pseudorabies virus. Journal of Neuroscience 17 (1997) 2143-2167.
O'Donnell, P. and Grace, A.A. Cortical afferents modulate striatal gap junction permeability via nitric oxide. Neuroscience 76 (1997) 1-5.
O'Donnell, P. and Grace, A.A. Dopaminergic reduction of excitability in nucleus accumbens neurons recorded in vitro. Neuropsychopharmacology 15 (1996) 87-97.
O'Donnell, P. and Grace, A.A. Different effects of subchronic clozapine and haloperidol on dye coupling between neurons in the rat striatal complex. Neuroscience 66 (1995) 763-767.
O'Donnell, P. and Grace, A.A. Synaptic interactions among excitatory afferents to nucleus accumbens neurons: Hippocampal gating of prefrontal cortical input. Journal of Neuroscience 15 (1995) 3622-3639.
O'Donnell, P. and Grace, A.A. Tonic D2-mediated attenuation of cortical excitation in nucleus accumbens neurons recorded in vitro. Brain Research 634 (1994) 105-112.
O'Donnell, P. and Grace, A.A. Dopaminergic modulation of dye coupling between neurons in the core and shell region of the nucleus accumbens. Journal of Neuroscience 13 (1993) 3456-3471.
O'Donnell, P. and Grace, A.A. Physiological and morphological properties of accumbens core and shell neurons recorded in vitro. Synapse 13 (1993) 135-160.
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