Invitation til

GÆSTEFORELÆSNING

2600 Glostrup.

Chair:

Lundbeck Foundation

Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research

(CINS)

Københavns Universitetshospital, Psykiatrisk Center Glostrup

Titel:

Stress, drug abuse, and schizophrenia: Common pathophysiological variables underlying dopamine system dysregulation

For many years, schizophrenia has been considered to be a disorder related to hyper-responsivity within the dopamine system. We have developed an animal model of schizophrenia based on administration of the mitotoxin methyl azoxymethanol acetate (MAM) to rats at gestational day 17 and testing them as adults. These rats show a number of characteristics expected for an animal model of schizophrenia, including disruption of paired-pulse inhibition, disruption of latent inhibition and executive behaviors, and hyper-responsivity to amphetamine. The hyper-responsivity to amphetamine is also found in humans, and has been linked to an over-responsive dopamine system. We found that, in the MAM model, hyper-responsivity of the dopamine system can be traced to overactivity within the ventral hippocampus leading to an increase in the proportion of dopamine neurons firing spontaneously. As a result, there are a larger number of neurons that can respond to phasic events, thereby amplifying the dopamine signal. This hippocampal overactivity is correlated with decreased parvalbumin interneurons and decreased conditioned stimulus-evoked gamma rhythms, consistent with what has been reported in schizophrenia. Moreover, stress and amphetamine sensitization, which are risk factors for schizophrenia and lead to a hyperdopaminergic state, also act via the ventral hippocampus circuit. As a result, normalization of activity within the ventral hippocampus may be a more effective therapeutic approach to the treatment of schizophrenia than would blockade of dopamine at its receptors

A. Positions and Honors.

1985-91 Assistant Professor of Behavioral Neuroscience & Psychiatry, Univ. Pittsburgh, Pittsburgh, PA

1991-96 Associate Professor of Neuroscience and Psychiatry, University of Pittsburgh, Pittsburgh, PA

1996-2003 Professor of Neuroscience and Psychiatry, University of Pittsburgh, Pittsburgh, PA

2003- Professor of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh,

Other Experience and Professional Memberships

1993-96 NIMH Study Section Member

1995 Election to membership in ACNP

2000 Promotion to Fellow, American College of Neuropsychopharmacology

2001 National Alliance for Research on Schizophrenia and Depression Scientific
Advisory Board

2003 National Alliance for the Mentally Ill - Scientific Council

2005 Schizophrenia Research Forum Scientific Advisory Board

2005 Schizophrenia International Research Society Board of Directors

2008 ACNP council

Honors

1987 Sloan Foundation Research Fellowship

1990 Sigma Xi Assistant Professor Award

1993 Chancellor's Distinguished Research Award

1994 NAMI Judith Silver Award for Schizophrenia Research

1998 NARSAD Distinguished Investigator Award

1999 Daniel H. Efron Award, American College of Neuropsychopharmacology

2000 Kearny Visiting Professor, Mental Health Research Institute, Univ. Melbourne,
Australia

2000 Chancellor’s Distinguished Research Award-Senior Scholar

2000 Dr. Paul Janssen Schizophrenia Research Award (CINP)

2008 Lilly Basic Scientist Award (CINP)

B. Selected peer-reviewed publications (in chrolological order)

(Publications since 2003 selected from 144 peer-reviewed publications)

Jedema, H.P. and Grace, A.A. (2003) Chronic exposure to cold stress alters electrophysiological properties of locus coeruleus neurons recorded in vitro. Neuropsychopharmacology 28:63-72.

Floresco, S.B. and Grace, A.A. (2003) Gating of hippocampal-evoked activity in prefrontal cortical neurons by inputs from the mediodorsal thalamus and ventral tegmental area. Journal of Neuroscience 23: 3930-3943.

Charara, A. and Grace, A.A. (2003) Dopamine receptor subtypes selectively modulate excitatory afferents from the hippocampus and amygdala to rat nucleus accumbens neurons. Neuropsychopharmacology 28: 1412-1421.

Floresco, S.B., West, A.R., Ash, B., Moore, H. And Grace, A.A. (2003) Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nature Neuroscience 6: 968-973..

Rosenkranz, J.A., Moore, H. And Grace, A.A. (2003) The prefrontal cortex regulates lateral amygdala neuronal plasticity and response to previously conditioned stimuli. Journal of Neuroscience 23: 11054-11064.

Jedema, H.P. and Grace, A.A. (2004) Corticotropin-releasing hormone directly activates noradrenergic neurons of the locus coeruleus recorded in vitro. Journal of Neuroscience 24: 9703-9713.

Thompson, J.L., Pogue-Geile, M.F. and Grace, A.A. (2004) The interactions among developmental pathology, dopamine, and stress as a model for the age of onset of schizophrenia symptomatology. Schizophrenia Bulletin 30:875-900.

Kroner, S., Rosenkranz, J.A., Grace, A.A. and Barrionuevo, G. (2005) Dopamine modulates excitability of basolateral amygdala neurons in vitro. Journal of Neurophysiology 93: 1598-1610.

Lodge, D.L. and Grace, A.A. (2005) Acute and chronic Corticotropin Releasing Factor 1 receptor blockade inhibits cocaine-induced dopamine release: Correlation with dopamine neuron activity. Journal of Pharmacology and Experimental Therapeutics 314: 201-206

Goto, Y. and Grace, A.A. (2005) Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goal-directed behavior. Nature-Neuroscience 8: 805-812.

Correll, C.M., Rosenkranz, J.A. and Grace, A.A. (2005) Chronic cold stress alters prefrontal cortical modulation of amygdala neuronal activity in rats. Biological Psychiatry Biological Psychiatry 58: 382-391..

Lisman, J. and Grace, A.A. (2005)The hippocampal-VTA loop: control of entry into long-term memory. Neuron 46:703-713.

Laviolette, S.R., Lipski W.J. and Grace, A.A. (2005) A subpopulation of neurons in the medial prefrontal cortex encode emotional learning with burst and frequency codes through a dopamine D4 receptor-dependent basolateral amygdala input. Journal of Neuroscience 25: 6066-6075.

Goto, Y. and Grace, A.A. (2005) Dopamine-dependent interactions between limbic and prefrontal cortical synaptic plasticity within the nucleus accumbens: Disruption by cocaine sensitization. Neuron 47: 255-266.

Floresco, S.B., Geyer, M.A., Gold, L.H., and Grace, A.A. (2005) Developing predictive models and establishing a preclinical trials network for assessing treatment effects on cognition in animals. Schizophrenia Bulletin 31: 888-894.

Grace, A.A. (2006) Disruption of cortico-limbic interaction as a substrate for comormidity. Neurotoxicity Research 10: 93-101.

Laviolette, S.R. and Grace, A.A. (2006) The roles of cannabinoid and dopamine receptor systems in neural emotional learning circuits: Implications for schizophrenia and addiction. Cellular and Molecular Life Sciences 63: 1597-1613.

Onn, S.-P., Wang, X.-B., Lin M. and Grace, A.A. (2006) Dopamine D1 and D4 receptors differentially modulate recurrent excitatory synapses in prefrontal cortical pyramidal neurons. Neuropsychopharmacology 31: 318-338.

Miner, L.H., Jedema, H.P., Moore, F.W., Blakely, R.D., Grace, A.A. and Sesack, S.R. (2006) Chronic stress increases the plasmalemmal distribution of the norepinephrine transporter and the co-expression of tyrosine hydroxylase in norepinephrine axons in the prefrontal cortex. Journal of Neuroscience 26: 1571-1578.

Lodge, D.J. and Grace, A.A. (2006) The laterodorsal tegmental nucleus is essential for burst firing of dopamine neurons in the rat VTA. Proceedings of the National Academy of Sciences, USA 1004 (13) 5167-5172.

Rosenkranz, J.A., Buffalari, D.M. and Grace, A.A. (2006) Opposing influence of basolateral amygdala and footshock stimulation on neurons of the central amygdala. Biological Psychiatry 59: 801-811.

Lodge, D.J. and Grace, A.A. (2006) The hippocampus modulates dopamine neuron responsivity by regulating the intensity of phasic neuron activation. Neuropsychopharmacology 31: 1356-1361.

Moore, H.,Ghajarnia, M.E. Jentsch, J.D.,Geyer, M.A & Grace, A.A. (2006) A A Neurobehavioral Systems Analysis of Adult Rats Exposed to Methylazoxymethanol Acetate on E17: Implications for the Neuropathology of Schizophrenia. Biological Psychiatry 60: 253-264.

Goto, Y. and Grace, A.A. (2006) Alterations in prefrontal cortical activity and plasticity in adult rats with disruption of cortical development. Biological Psychiatry doi:10.1016/j.biopsych.2006.05.046..

Laviolette, S.R. and Grace, A.A. (2006) Cannabinoids dramatically potentiate neuronal emotional learning in the medial prefrontal cortex through basolateral amygdala inputs Journal of Neuroscience 26:6458-6468.

Kawashima, H., Izaki, Y., Grace, A.A., and Takita, M. (2006) Cooperativity between hippocampal-prefrontal short-term plasticity through associative long-term potentiation. Brain Research 1109: 37-44.

Wong, D.F., Kuwabara, H., Schretlin, D., Bonson, K., Zhou, Y., Nandi, A., Brasic, J., Kimes, A.S., Maris M.A., Kumar, A., Contoreggi, C., Links, J., Ernst, M., Rousset, O., Zukin, S., Grace, A.A., Rohde, C., Jasinski, D.R., Gjedde, A. and London, E.D. (2006) Increased occupancy of dopamine receptors in human striatum during cue-elicited cocaine craving. Neuropsychopharmacology 31: 2716-2727..

Grace, A.A., Floresco, S.B., Goto, Y. and Lodge, D.J. (2007) The regulation of dopamine neuron firing and the control of goal-directed behaviors. Trends in Neurosciences 30:220-227.

Lodge, D.J. and Grace, A.A. (2007) Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. Journal of Neuroscience 27: 11424-11430.

Goto, Y. and Grace, A.A. (2007) The Yin and Yang of Dopamine Release: A New Perspective. Neuropharmacology 53: 583-587.

Buffalari, D.M. and Grace, A.A. (2007) Noradrenergic modulation of basolateral amygdala neuronal activity: Opposing influences of alpha-2 and beta receptor activation. Journal of Neuroscience 27: 12358-12366.

McCracken, C.B. and Grace, A.A. (2007) High-frequency deep brain stimulation of the nucleus accumbens region suppresses neuronal activity and selectively modulates afferent drive in rat orbitofrontal cortex in vitro. Journal of Neuroscience 27: 12601-12610.

Bissière, S., Plachta, N., McAllister, K.H., Hoyer, D., Olpe, H.-R., Grace, A.A. and Cryan, J.F. (2008) The rostral anterior cingulate cortex modulates the efficiency of amygdala-dependent fear learning. Biological Psychiatry 63: 821-831.

Onn, S.-P., Lin, M., Liu, J. and Grace, A.A. (2008) Dopamine DARPP-32-dependent modulation of prefrontal cortical input and intercellular coupling in mouse accumbens spiny and aspiny neurons. Neuroscience 151: 802-816.

Wong, D.F., Brasic, J., Singer, H., Schretlen, D., Kuwabara, H., Zhou, Y., Nandi, A., Maris, M., Alexander, M., Ye, W., Rousset, O., Kumar, A., Szabo, Z., Gjedde, A. and Grace, A.A. (2008) Mechanisms of dopamine and serotonin in Tourette syndrome: Clues from an in vivo neurochemistry study with PET. Neuropsychopharmacology 33: 1239-1251.

Goto, Y. and Grace, A.A. (2008) Dopamine modulation of hippocampal-prefrontal cortical interaction drives memory-guided behavior. Cerebral Cortex 18: 1407 - 1414.

Lisman, J.E., Coyle, J.T., Greene, R.W., Javitt, D.C., Benes, F.M., Heckers, S. and Grace, A.A. (2008) Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia Trends in Neurosciences 31: 234-242.

Jedema, H.P., Gold, S.J., Sved, A.F. and Grace, A.A. (2008) Chronic cold exposure increases RGS7 expression and decreases α_{2-autoreceptor-mediated inhibition of noradrenergic locus coeruleus neurons. European Journal of Neuroscience 27: 2433-2443.}

Belujon, P. and Grace, A.A. (2008) Critical role of the prefrontal cortex in the regulation of hippocampus-accumbens information flow. Journal of Neuroscience 28: 9797-9805.

Goto, Y, and Grace, A.A. (2008) Limbic and Cortical Information Processing in the Nucleus Accumbens. Trends in Neurosciences 31: 552-558.

McGinty, V.B. and Grace, A.A. (2008) Selective activation of medial prefrontal-to-accumbens projection neurons by amygdala stimulation and pavlovian conditioned stimuli. Cerebral Cortex 18: 1961-1972

Lodge, D.J. and Grace, A.A. (2008) Augmented hippocampal drive of mesolimbic dopamine neurons: A mechanism of psychostimulant sensitization. Journal of Neuroscience 28 7876-7882.

Sengupta, S.M., Grizenko, N., Schmitz, N., Schwartz, G., Bellingham, J., Polotskaia, A., Ter Stepanian, M., Goto, Y., Grace, A.A. and Joober, R. (2008) COMT Val 108/158Met polymorphism modulates task-oriented behaviour in children with ADHD Neuropsychopharmacology 33: 3069-3077.

Valenti, O. and Grace, A.A. (2009) Entorhinal cortex modulates the activity states of electrophysiologically characterized medial prefrontal cortical neurons. Cerebral Cortex 19: 658-674.

Lodge, D.J., Behrens, M.M. and Grace, A.A. (2009) A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. Journal of Neuroscience 29:2344-2354.

McGinty, V.B. and Grace, A.A. (2009) Timing-dependent regulation of evoked spiking in nucleus accumbens neurons by integration of limbic and prefrontal cortical inputs. Journal of Neurophysiology 101: 1823-1835.

McCracken, C.B. and Grace, A.A. (2009) Nucleus accumbens deep brain stimulation produces region-specific alterations in local field potential oscillations and evoked responses in vivo. Journal of Neuroscience 29: 5354-5363.

McGinty, V.B. and Grace, A.A. (2009) Activity-dependent depression of medial prefrontal cortex inputs to accumbens neurons by the basolateral amygdala. Neuroscience 162: 1429-1436.

Buffalari, D.M. and Grace, A.A. (2009) Anxiogenic modulation of spontaneous and evoked neuronal activity in the basolateral amygdala. Neuroscience (in press).

Valenti, O. and Grace, A.A. (2009) Antipsychotic drug-induced increases in ventral tegmental area dopamine neuron population activity via activation of the nucleus accumbens-ventral pallidal pathway. International Journal of Neuropsychopharmacology (in press).

R37 MH57440 MERIT award Grace (PI) 8/15/07 B 7/31/17

NIH/NIMH

Gating of Information Flow within the Nucleus Accumbens

The major goals of this project are to examine afferent interactions within the nucleus accumbens, their modulation by dopamine afferents, how they regulate dopamine neuron activity states, and how these functions are altered in a rat with a developmental disruption model of schizophrenia.

Role: PI

RO1 MH073111 Haber (PI) 7/1/2005-6/30/2010

NIH/NIMH

Deep Brain Stimulation for OCD

Grace, Specific Aim 3 PI: Electrophysiological correlates of DBS.

The major goals of this project is to examine the effects of low and high frequency stimula
tion, equivalent to that used therapeutically for OCD, on corticothalamic brain circuit activity.

Role: Co-I

RO1 DA15408 Grace (PI) 7/1/2009-6/29/2011

NIH/NIDA

Stress-induced alterations in amygdala-LC interactions.

The major goals of this project is to examine the impact of stress and amphetamine sensitization on dopamine neuron responsivity, and its modulation by the ventral subiculum of the hippocampus.

Role: PI

P50 Conte Center Grant Haber (PI) MH086400 8/01/2009-7/30/2014

NIH/NIMH

Neurocircuitry underlying DBS effects in OCD: A window into mechanisms of action

Project 5: "In vivo neurocircuitry of DBS response in rodents"

The goal of this project is to examine the effects of deep brain stimulation in awake animals on neurocircuitry and behaviors related to obsessive-compulsive disorder.

Role: Project Director

Lundbeck Pharmaceuticals Research Grant 1/1/2009-12/31/2011

Electrophysiology of Sertindole actions.

This grant examines the effects of sertindole on dopamine neuron activity.

Role: PI

Completed Research Support

R01 DA15408 Grace (PI) 4/1/03 B 3/31/08

NIH/NIMH

Stress-induced alterations in amygdala-LC interactions

The major goals of this grant are to examine the interaction between the amygdala and the locus coeruleus in vivo and in vitro, and chronic stress-induced alterations within this circuit leading to sensitization. Role: PI

R01 MH57440 Grace (PI) 8/15/02 B 7/31/07

NIH/NIMH Gating of Information Flow within the Nucleus Accumbens

The major goals of this project are to examine afferent interactions within the nucleus accumbens, their modulation by dopamine afferents, how they regulate dopamine neuron activity states, and how these functions are altered in a rat with a developmental disruption model of schizophrenia.

Role: PI

P50 MH45156 Lewis (PI) 7/1/03 B 6/30/08

NIH/NIMH

Cortical Circuitry and Cognition in Schizophrenia

Grace, Project 5 PI: Afferent regulation of identified PFC output neurons and its modulation during development.

The major goals of this project are to examine how specific afferents modulate the activity of prefrontal cortical pyramidal neurons identified by projection site, and how this system is modified during development. I am NOT a participant in the renewal.

Role: Project leader