Skip to main content
SpringerLink
Log in

Disruption of cortical-limbic interaction as a substrate for comorbidity

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

The prefrontal cortex exerts a potent regulatory influence over subcortical systems that are involved in the regulation of affective states. In particular, the amygdala is a region that is known to play a prominent role in the expression of emotions, and this function is believed to be disrupted in affective disorders and drug abuse. In addition, dysfunction of the prefrontal cortex is believed to be a common element in many psychiatric disorders such as schizophrenia. Using electrophysiological recordings in rodents, we examined the interactions of the prefrontal cortex with the amygdala. Our studies showed that these areas are strongly interdependent, with the prefrontal cortex showing conditioned responses that depend on amygdala inputs, and in turn exerting a potent attenuation of activity within the amygdala. In particular, the ability of the prefrontal cortex to modulate amygdala activity is likely to play an important role in our ability to cope with stressors. We propose that a dysfunction within the prefrontal cortex disrupts the ability of this region to effectively modulate the amygdala, leaving the organism susceptible to detrimental effects of stressors. This would appear to be a common underlying process that may leave the individual susceptible to drug abuse and to the onset or exacerbation of psychiatric disorders such as schizophrenia and depression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abercrombie ED and BL Jacobs (1987) Single-unit response of noradrenergic neurons in the locus coeruleus of freely moving cats. I. Acutely presented stressful and nonstressful stimuli.J. Neurosci. 7, 2837–2843.

    PubMed  CAS  Google Scholar 

  • Amat J, MV Baratta, E Paul, ST Bland, LR Watkins and SF Maier (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus.Nature Neurosci. 8, 365–371.

    Article  PubMed  CAS  Google Scholar 

  • Angrist BM and S Gershon (1970) The phenomenology of experimentally induced amphetamine psychosis — preliminary observations.Biol. Psychiatry 2, 95–107.

    PubMed  CAS  Google Scholar 

  • Angrist B, G Sathananthan, S Wilk and S Gershon (1974) Amphetamine psychosis: behavioral and biochemical aspects.J. Psychiatric Res. 11, 13–23.

    Article  CAS  Google Scholar 

  • Baare WF, CJ van Oel, HE Hulshoff Pol, HG Schnack, S Durston, MM Sitskoorn and RS Kahn (2001) Volumes of brain structures in twins discordant for schizophrenia.Arch. Gen. Psychiatry 58, 33–40.

    Article  PubMed  CAS  Google Scholar 

  • Bouret S, A Duvel, S Onat and SJ Sara (2003) Phasic activation of locus ceruleus neurons by the central nucleus of the amygdala.J. Neurosci. 23, 3491–3497.

    PubMed  CAS  Google Scholar 

  • Coco ML, CM Kuhn, TD Ely and CD Kilts (1992) Selective activation of mesoamygdaloid dopamine neurons by conditioned stress: attenuation by diazepam.Brain Res. 590, 39–47.

    Article  PubMed  CAS  Google Scholar 

  • Correll CM, JA Rosenkranz and AA Grace (2005) Chronic cold stress alters prefrontal cortical modulation of amygdala neuronal activity in rats.Biol. Psychiatry 58, 382–391.

    Article  PubMed  Google Scholar 

  • Dunn AJ (1988) Stress-related activation of cerebral dopaminergic systems. Ann.NYAcad. Sci. 537, 188–205.

    Article  CAS  Google Scholar 

  • Finlay JM and MJ Zigmond (1997) The effects of stress on central dopaminergic neurons: possible clinical implications.Neurochem. Res. 22, 1387–1394.

    Article  PubMed  CAS  Google Scholar 

  • Finlay JM, MJ Zigmond and ED Abercrombie (1995) Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam.Neuroscience 64, 619–628.

    Article  PubMed  CAS  Google Scholar 

  • Finlay JM, HP Jedema, AD Rabinovic, MJ Mana, MJ Zigmond and AF Sved (1997) Impact of corticotropin-releasing hormone on extracellular norepinephrine in prefrontal cortex after chronic cold stress.J. Neurochem. 69, 144–150.

    PubMed  CAS  Google Scholar 

  • Fiore M, L Talamini, F Angelucci, T Koch, L Aloe and J Korf (1999) Prenatal methylazoxymethanol acetate alters behavior and brain NGF levels in young rats: a possible correlation with the development of schizophrenia-like deficits.Neuropharmacology 38, 857–869.

    Article  PubMed  CAS  Google Scholar 

  • Flagstad P, A Mork, BY Glenthoj, J van Beek, AT Michael-Titus and M Didriksen (2004) Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens.Neuropsychopharmacol. 29, 2052–2064.

    Article  CAS  Google Scholar 

  • Goldman-Rakic PS (1999) The physiological approach: Functional architecture of working memory and disordered cognition in schizophrenia.Biol. Psychiatry 46, 650–661.

    Article  PubMed  CAS  Google Scholar 

  • Goto Y and AA Grace (2005) Dopamine-dependent interactions between limbic and prefrontal cortical synaptic plasticity in the nucleus accumbens: disruption by cocaine sensitization.Neuron 47, 255–266.

    Article  PubMed  CAS  Google Scholar 

  • Goto Y and AA Grace (2006) Alterations in prefrontal cortical activity and plasticity in adult rats with disruption of cortical development.Biol. Psychiatry (in press).

  • Gourevitch R, C Rocher, G Le Pen, MO Krebs and TM Jay (2004) Working memory deficits in adult rats after prenatal disruption of neurogenesis.Behav. Pharmacol. 15, 287–292.

    Article  PubMed  CAS  Google Scholar 

  • Grace AA (1995) The tonic/phasic model of dopamine system regulation: its relevance for understanding how stimulant abuse can alter basal ganglia function.Drug & Alcohol Depend. 37, 111–129.

    Article  CAS  Google Scholar 

  • Grace AA (2000a) Psychostimulant action on dopamine and limbic system function: relevance to the pathophysiology and treatment of ADHD, In:Stimulant Drugs and ADHD: Basic and Clinical Neuroscience (Solanto MV, AFT Arnsten and FX Castellanos, Eds.) (Oxford University Press:New York, NY).

    Google Scholar 

  • Grace AA (2000b) The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving.Addiction 95, S119-S128.

    PubMed  Google Scholar 

  • Grace AA (2004) Developmental dysregulation of the dopamine system and the pathophysiology of schizophrenia, In:Neurodevelopment and Schizophrenia (Keshavan MS, JL Kennedy and RM Murray, Eds.) (Cambridge University Press: Cambridge, UK), pp 273–294.

    Google Scholar 

  • Grace AA and H Moore (1998) Regulation of information flow in the nucleus accumbens: a model for the pathophysiology of schizophrenia, In:Origins and Development of Schizophrenia: Advances in Experimental Psychopathology (Lenzenweger MF and RH Dworkin, Eds.) (American Psychological Association Press:Washington DC), pp 123–157.

    Chapter  Google Scholar 

  • Grant SJ and DE Redmond Jr (1984) Neuronal activity of the locus ceruleus in awakeMacaca arctoides.Exp. Neurol. 84, 701–708.

    Article  PubMed  CAS  Google Scholar 

  • Grant SJ, G Aston-Jones and DE Redmond Jr (1988) Responses of primate locus coeruleus neurons to simple and complex sensory stimuli.Brain Res. Bull. 21, 401–410.

    Article  PubMed  CAS  Google Scholar 

  • Gray TS (1999) Functional and anatomical relationships among the amygdala, basal forebrain, ventral striatum, and cortex.An integrative discussion.Ann. NY Acad.Sci. 877, 439–444.

    Article  PubMed  CAS  Google Scholar 

  • Gresch PJ, AF Sved, MJ Zigmond and JM Finlay (1994) Stress-induced sensitization of dopamine and norepinephrine efflux in medial prefrontal cortex of the rat.J. Neurochem. 63, 575–583.

    PubMed  CAS  Google Scholar 

  • Hariri AR, VS Mattay, A Tessitore, F Fera and DR Weinberger (2003) Neocortical modulation of the amygdala response to fearful stimuli.Biol. Psychiatry 53, 494–501.

    Article  PubMed  Google Scholar 

  • Jackson ME and B Moghaddam (2004) Stimulus-specific plasticity of prefrontal cortex dopamine transmission.J. Neurochem. 88, 1327–1334.

    PubMed  CAS  Google Scholar 

  • Jedema HP and AA Grace (2003) Chronic exposure to cold stress alters electrophysiological properties of locus coeruleus neurons recordedin vitro.Neuropsychopharmacology 28, 63–72.

    Article  PubMed  Google Scholar 

  • Jedema HP, AF Sved, MJ Zigmond and JM Finlay (1999) Sensitization of norepinephrine release in medial prefrontal cortex: effect of different chronic stress protocols.Brain Res. 830, 211–217.

    Article  PubMed  CAS  Google Scholar 

  • Jedema HP, JM Finlay, AF Sved and AA Grace (2001) Chronic cold exposure potentiates CRH-evoked increases in electrophysiologic activity of locus coeruleus neurons.Biol. Psychiatry 49, 351–359.

    Article  PubMed  CAS  Google Scholar 

  • Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia.Am. J. Psychiatry 160, 13–23.

    Article  PubMed  Google Scholar 

  • Kretteck JE and JL Price (1978) A description of the amygdaloid complex in the rat and cat with observations on intra-amygdaloid axonal connections.J. Comp. Neurol. 178, 255–280.

    Article  Google Scholar 

  • Kroner S, JA Rosenkranz, AA Grace and G Barrionuevo (2005) Dopamine modulates excitability of basolateral amygdala neuronsin vitro.J. Neurophysiol. 93, 1598–1610.

    Article  PubMed  CAS  Google Scholar 

  • Laviolette SR and AA Grace (2006) Cannabinoids dramatically potentiate neuronal emotional learning in the medial prefrontal cortex through basolateral amygdala inputs.J. Neurosci.,26, 6458–6468.

    Article  PubMed  CAS  Google Scholar 

  • Laviolette SR, WJ Lipski and AA Grace (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.J. Neurosci. 25, 6066–6075.

    Article  PubMed  CAS  Google Scholar 

  • LeDoux JE (2000) Emotion circuits in the brain.Annu. Rev. Neurosci. 23, 155–184.

    Article  PubMed  CAS  Google Scholar 

  • Mana MJ and AA Grace (1997) Chronic cold stress alters the basal and evoked electrophysiological activity of rat locus coeruleus neurons.Neuroscience 81, 1055–1064.

    Article  PubMed  CAS  Google Scholar 

  • Maren S and GJ Quirk (2004) Neuronal signalling of fear memory.Nat. Rev. Neurosci. 5, 844–852.

    Article  PubMed  CAS  Google Scholar 

  • Maroun M and G Richter-Levin (2003) Exposure to acute stress blocks the induction of long-term potentiation of the amygdalaprefrontal cortex pathwayin vivo.J. Neurosci. 23, 4406–4409.

    PubMed  CAS  Google Scholar 

  • Meaney MJ, DH Aitken, C van Berkel, S Bhatnagar and RM Sapolsky (1988) Effect of neonatal handling on age-related impairments associated with the hippocampus.Science 239, 766–768.

    Article  PubMed  CAS  Google Scholar 

  • Milad MR and GJ Quirk (2002) Neurons in medial prefrontal cortex signal memory for fear extinction.Nature 420, 70–74.

    Article  PubMed  CAS  Google Scholar 

  • Morgan MA, LM Romanski and JE LeDoux (1993) Extinction of emotional learning: contribution of medial prefrontal cortex.Neurosci. Lett. 26, 109–113.

    Article  Google Scholar 

  • Moore H, D Giracello, AA Grace and M Geyer (1999) Sensory gating deficits in rats with early disruption of limbic cortical development: relevance to schizophrenia.Soc. Neurosci. Abstr. 25, 1580.

    Google Scholar 

  • Moore H, HJ Rose and AA Grace (2001) Chronic cold stress reduces the spontaneous activity of ventral tegmental dopamine neurons.Neuropsychopharmacology 24, 410–419.

    Article  PubMed  CAS  Google Scholar 

  • Nisenbaum LK, MJ Zigmond, AF Sved and ED Abercrombie (1991) Prior exposure to chronic stress results in enhanced synthesis and release of hippocampal norepinephrine in response to a novel stressor.J. Neurosci. 11, 1478–1484.

    PubMed  CAS  Google Scholar 

  • Pantelis C, D Velakoulis, J Suckling, PD McGorry, L Phillips, A Yung, S Wood, E Bullmore, W Brewer, B Soulsby and P McGuire (2000) Left medial temporal volume reduction occurs during the transition from high-risk to first-episode psychosis.Schizophr. Res. 41, 35.

    Article  Google Scholar 

  • Pantelis C, D Velakoulis, PD McGorry, SJ Wood, J Suckling, LJ Phillips, AR Yung, ET Bullmore, W Brewer, B Soulsby, P Desmond and PK McGuire (2003) Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison.Lancet 361, 281–288.

    Article  PubMed  Google Scholar 

  • Perotti LI, Y Hadeishi, PG Ulery, M Barrot, L Monteggia, RS Duman and EJ Nestler (2004) Induction of deltaFosB in reward-related brain structures after chronic stress.J. Neurosci. 24, 10594–10602.

    Article  CAS  Google Scholar 

  • Quirk GJ, GK Russo, JL Barron and K Lebron (2000) The role of ventromedial prefrontal cortex in the recovery of extinguished fear.J. Neurosci. 20, 6225–6231.

    PubMed  CAS  Google Scholar 

  • Ramsooksingh MD, HP Jedema and AA Grace (2004) Stimulation of the central nucleus of the amygdala increases single unit activity of locus coeruleus neurons.Soc. Neurosci. Abstr. 29, Prgm. No. 282.210.

  • Rasmussen K, DA Morilak and BL Jacobs (1986) Single unit activity of locus coeruleus neurons in the freely moving cat. I. During naturalistic behaviors and in response to simple and complex stimuli.Brain Res. 371, 324–334.

    Article  PubMed  CAS  Google Scholar 

  • Rocher C, M Spedding, C Munoz and TM Jay (2004) Acute stressinduced changes in hippocampal-prefrontal circuits in rats: effects of antidepressants.Cerebral Cortex 14, 224–229.

    Article  PubMed  Google Scholar 

  • Rosenkranz JA and AA Grace (2001) Dopamine attenuates prefrontal cortical suppression of sensory inputs to the basolateral amygdala of rats.J. Neurosci. 21, 4090–4103.

    PubMed  CAS  Google Scholar 

  • Rosenkranz JA and AA Grace(2002a) Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neuronsin vivo.J. Neurosci. 22, 324–337.

    PubMed  CAS  Google Scholar 

  • Rosenkranz JA and AA Grace (2002b) Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning.Nature 417, 282–287.

    Article  PubMed  CAS  Google Scholar 

  • Rosenkranz JA and AA Grace (2003) Affective conditioning in the basolateral amygdala of anesthetized rats is modulated by dopamine andprefrontal cortical inputs.Ann. NYAcad. Sci. 985, 488–491.

    Article  Google Scholar 

  • Rosenkranz JA, DM Buffalari and AA Grace (2006) Opposing influence of basolateral amygdala and footshock stimulation on neurons of the central amygdala.Biol. Psychiatry 59, 801–811.

    Article  PubMed  Google Scholar 

  • Sapolsky RM (1996) Stress, glucocorticoids, and damage to the nervous system: the current state of confusion.Stress 1:1–19.

    Article  PubMed  CAS  Google Scholar 

  • Sapolsky RM, LC Krey and BS McEwen (1985) Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging.J. Neurosci. 5, 1222–1227.

    PubMed  CAS  Google Scholar 

  • Sapolsky RM, H Uno, CS Rebert and CE Finch (1990) Hippocampal damage associated with prolonged glucocorticoid exposure in primates.J. Neurosci. 10, 2897–2902.

    PubMed  CAS  Google Scholar 

  • Thompson JL, MF Pogue-Geile and AA Grace (2004) The interactions among developmental pathology, dopamine, and stress as a model for the age of onset of schizophrenia symptomatology.Schizophr. Bull. 30, 875–900.

    PubMed  Google Scholar 

  • Valenti O and AA Grace (2005) Chronic stress affects medial prefrontal cortex neuron activity.Neuropharmacology 49 (suppl. 1), 1–288.

    Google Scholar 

  • Van Bockstaele EJ, K Commons and VM Pickel (1997) Delta-opioid receptor is present in presynaptic axon terminals in the rat nucleus locus coeruleus: relationships with methionine5-enkephalin.J. Comp. Neurol. 388, 575–586.

    Article  PubMed  Google Scholar 

  • Van Bockstaele EJ, EE Colago and RJ Valentino (1998) Amygdaloid corticotropin-releasing factor targets locus coeruleus dendrites: substrate for the co-ordination of emotional and cognitive limbs of the stress response.J. Neuroendocrinol. 10, 743–757.

    Article  PubMed  Google Scholar 

  • Van Zoeren JG and EM Stricker (1977) Effects of preoptic, lateral hypothalamic, or dopamine-depleting lesions on behavioral thermoregulation in rats exposed to cold.J. Comp. Physiol. Psychol. 91, 989–999.

    Article  Google Scholar 

  • Veening JG, LW Swanson and PE Sawchenko (1984) The organization of projections from the central nucleus of the amygdala to brainstem sites involved in central autonomic regulation: a combined retrograde transport-immunohistochemical study.Brain Res. 303, 337–357.

    Article  PubMed  CAS  Google Scholar 

  • Walker EF and D Diforio (1997) Schizophrenia: a neural diathesis-stress model.Psychol. Rev. 104, 667–685.

    Article  PubMed  CAS  Google Scholar 

  • Weinberger DR, KF Berman, R Suddath and EF Torrey (1992) Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins.Am. J. Psychiatry 149, 890–897.

    PubMed  CAS  Google Scholar 

  • Weinberger DR, MS Aloia, TE Goldberg and KF Berman (1994) The frontal lobes and schizophrenia.J. Neuropsychiatry 6, 419–427.

    CAS  Google Scholar 

  • Yerkes RM and JD Dodson (1908) The relation of strength of stimulus to rapidity of habit formation.J. Comp. Neurol. Psychol. 18, 459–482.

    Article  Google Scholar 

  • Zhang TY, P Chretien, MJ Meaney and A Gratton (2005) Influence of naturally occurring variations in maternal care on prepulse inhibition of acoustic startle and the medial prefrontal cortical dopamine response to stress in adult rats.J. Neurosci. 25. 1493–1502.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, 15260, Pittsburgh, PA, USA

    Anthony A. Grace

Authors
  1. Anthony A. Grace
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony A. Grace.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grace, A.A. Disruption of cortical-limbic interaction as a substrate for comorbidity. neurotox res 10, 93–101 (2006). https://doi.org/10.1007/BF03033238

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033238

Keywords

Search

Navigation