Brain Structure and Function

, Volume 217, Issue 2, pp 337–351 | Cite as

Differential neuronal changes in medial prefrontal cortex, basolateral amygdala and nucleus accumbens after postweaning social isolation

  • Yu-Chun Wang
  • Ue-Cheung Ho
  • Meng-Ching Ko
  • Chun-Chieh Liao
  • Li-Jen Lee
Original Article


The mesocorticolimbic system contains dopamine (DA)-producing neurons in the ventral tegmental area (VTA) and their projection targets, including the medial prefrontal cortex (mPFC), amygdala (AMY) and nucleus accumbens (NAc). Disruption of this system might attribute to mental illnesses. In the present study, we adopted the postweaning social isolation paradigm to model neuropsychiatric disorders and studied the functional and structural changes of the mesocorticolimbic system. After 8–9 weeks of isolation, rats exhibited hyperlocomotor activity and impaired sensorimotor gating compared to group-reared controls. However, the number of tyrosine hydroxylase-positive VTA neurons and the volume of VTA were not affected. Comparing with group-reared controls, the DA levels in the isolation-reared were not altered in the VTA, mPFC and NAc but decreased in the AMY. In the structural aspect, dendritic features of layer II/III pyramidal mPFC neurons; pyramidal neurons in the basolateral nucleus of amygdala (BLA) and medium spiny neurons in the core region of the NAc (NAcc) were examined. Interestingly, the neuronal changes were region-specific. The mPFC neurons had reduced dendritic complexity, spine density and elongated terminal branches. The BLA neurons had extensive dendritic arbors with short branches but unchanged spine density. The NAcc neurons had reduced total dendritic length but the segment length and spine density remained the same. Together, the results demonstrated the structural and functional changes in the mesocorticolimbic DA system of socially isolated rats. These changes may account for the behavioral impairments in these rats and attribute to the susceptibility to mental disorders related to schizophrenia and depression.


Prepulse inhibition Hyperlocomotor activity Tyrosine hydroxylase-positive neurons Dopamine level Dendritic arbors Dendritic spine 





Basolateral nucleus of amygdala


Coefficient of error




3,4-Dihydroxy-phenylacetic acid


High performance liquid chromatography


Medial prefrontal cortex


Nucleus accumbens


Core region of the nucleus accumbens


Postnatal day


Phosphate-buffered saline


Prepulse inhibition




Tyrosine hydroxylase


Ventral tegmental area



This work was supported by National Science Council of the Republic of China (Grant numbers: NSC 98-2410-H-002-033-, NSC 96-2628-B-002-053-MY3 and NSC 99-2628-B-002-052-MY3) and National Taiwan University.


  1. Agís-Balboa RC, Pinna G, Zhubi A et al (2006) Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci USA 103:14602–14607PubMedCrossRefGoogle Scholar
  2. Agís-Balboa RC, Pinna G, Pibiri F et al (2007) Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice. Proc Natl Acad Sci USA 104:18736–18741PubMedCrossRefGoogle Scholar
  3. Akwa Y, Purdy RH, Koob GF et al (1999) The amygdala mediates the anxiolytic-like effect of the neurosteroid allopregnanolone in rat. Behav Brain Res 106:119–125PubMedCrossRefGoogle Scholar
  4. Alquicer G, Morales-Medina JC, Quirion R et al (2008) Postweaning social isolation enhances morphological changes in the neonatal ventral hippocampal lesion rat model of psychosis. J Chem Neuroanat 35:179–187PubMedCrossRefGoogle Scholar
  5. Alvarez VA, Sabatini BL (2007) Anatomical and physiological plasticity of dendritic spines. Annu Rev Neurosci 30:79–97PubMedCrossRefGoogle Scholar
  6. Arnsten AF (2009) Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 10:410–422PubMedCrossRefGoogle Scholar
  7. Bertolucci-D’Angio M, Serrano A, Driscoll P et al (1990) Involvement of mesocorticolimbic dopaminergic systems in emotional states. Prog Brain Res 85:405–416PubMedCrossRefGoogle Scholar
  8. Björklund A, Dunnett SB (2007) Dopamine neuron systems in the brain: an update. Trends Neurosci 30:194–202PubMedCrossRefGoogle Scholar
  9. Bortolato M, Devoto P, Roncada P et al (2011) Isolation rearing-induced reduction of brain 5α-reductase expression: relevance to dopaminergic impairments. Neuropharmacology 60:1301–1318PubMedCrossRefGoogle Scholar
  10. Brenes JC, Fornaguera J (2009) The effect of chronic fluoxetine on social isolation-induced changes on sucrose consumption, immobility behavior, and on serotonin and dopamine function in hippocampus and ventral striatum. Behav Brain Res 198:199–205PubMedCrossRefGoogle Scholar
  11. Calabrese B, Wilson MS, Halpain S (2006) Development and regulation of dendritic spine synapses. Physiology (Bethesda) 21:38–47CrossRefGoogle Scholar
  12. Cilia J, Reavill C, Hagan JJ et al (2001) Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats. Psychopharmacology 156:327–337PubMedCrossRefGoogle Scholar
  13. Cook SC, Wellman CL (2004) Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol 60:236–248PubMedCrossRefGoogle Scholar
  14. Dalley JW, Theobald DE, Pereira EA et al (2002) Specific abnormalities in serotonin release in the prefrontal cortex of isolation-reared rats measured during behavioural performance of a task assessing visuospatial attention and impulsivity. Psychopharmacology (Berl) 164:329–340CrossRefGoogle Scholar
  15. Day-Wilson KM, Jones DN, Southam E et al (2006) Medial prefrontal cortex volume loss in rats with isolation rearing-induced deficits in prepulse inhibition of acoustic startle. Neuroscience 141:1113–1121PubMedCrossRefGoogle Scholar
  16. Dazzi L, Serra M, Vacca G et al (2002) Depletion of cortical allopregnanolone potentiates stress-induced increase in cortical dopamine output. Brain Res 932:135–139PubMedCrossRefGoogle Scholar
  17. Dunlop BW, Nemeroff CB (2007) The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64:327–337PubMedCrossRefGoogle Scholar
  18. Eiland L, Ramroop J, Hill MN et al. (2011) Chronic juvenile stress produces corticolimbic dendritic architectural remodeling and modulates emotional behavior in male and female rats. Psychoneuroendocrinology doi: 10.1016/j.psyneuen.2011.04.015
  19. Fabricius K, Steiniger-Brach B, Helboe L et al (2011) Socially isolated rats exhibit changes in dopamine homeostasis pertinent to schizophrenia. Int J Dev Neurosci 29:347–350PubMedCrossRefGoogle Scholar
  20. Fiala JC, Spacek J, Harris KM (2002) Dendritic spine pathology: cause or consequence of neurological disorders? Brain Res Rev 39:29–54PubMedCrossRefGoogle Scholar
  21. Floresco SB (2007) Dopaminergic regulation of limbic-striatal interplay. J Psychiatry Neurosci 32:400–411PubMedGoogle Scholar
  22. Floresco SB, Tse MT (2007) Dopaminergic regulation of inhibitory and excitatory transmission in the basolateral amygdala-prefrontal cortical pathway. J Neurosci 27:2045–2057PubMedCrossRefGoogle Scholar
  23. Fone KC, Porkess MV (2008) Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev 32:1087–1102PubMedCrossRefGoogle Scholar
  24. Geyer MA, Wilkinson LS, Humby T et al (1993) Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia. Biol Psychiatry 34:361–372PubMedCrossRefGoogle Scholar
  25. Goto Y, Grace AA (2008) Limbic and cortical information processing in the nucleus accumbens. Trends Neurosci 31:552–558PubMedCrossRefGoogle Scholar
  26. Groenewegen HJ, Wright CI, Beijer AV et al (1999) Convergence and segregation of ventral striatal inputs and outputs. Ann N Y Acad Sci 877:49–63PubMedCrossRefGoogle Scholar
  27. Han X, Wang W, Shao F et al (2011) Isolation rearing alters social behaviors and monoamine neurotransmission in the medial prefrontal cortex and nucleus accumbens of adult rats. Brain Res 1385:175–181PubMedCrossRefGoogle Scholar
  28. Heidbreder CA, Weiss IC, Domeney AM et al (2000) Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome. Neuroscience 100:749–768PubMedCrossRefGoogle Scholar
  29. Heinz A, Schlagenhauf F (2010) Dopaminergic dysfunction in schizophrenia: salience attribution revisited. Schizophr Bull 36:472–485PubMedCrossRefGoogle Scholar
  30. Horvitz JC (2000) Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience 96:651–656PubMedCrossRefGoogle Scholar
  31. Johnson ML, Day AE, Ho CC et al (2010) Androgen decreases dopamine neurone survival in rat midbrain. J Neuroendocrinol 22:238–247PubMedCrossRefGoogle Scholar
  32. Kapur S, Mann JJ (1992) Role of the dopaminergic system in depression. Biol Psychiatry 32:1–17PubMedCrossRefGoogle Scholar
  33. Katunar MR, Saez T, Brusco A et al (2009) Immunocytochemical expression of dopamine-related transcription factors Pitx3 and Nurr1 in prenatally stressed adult rats. J Neurosci Res 87:1014–1022PubMedCrossRefGoogle Scholar
  34. Katunar MR, Saez T, Brusco A et al (2010) Ontogenetic expression of dopamine-related transcription factors and tyrosine hydroxylase in prenatally stressed rats. Neurotox Res 18:69–81PubMedCrossRefGoogle Scholar
  35. Kaufmann WE, Moser HW (2000) Dendritic anomalies in disorders associated with mental retardation. Cereb Cortex 10:981–991PubMedCrossRefGoogle Scholar
  36. Kelley AE, Domesick VB, Nauta WJ (1982) The amygdalostriatal projection in the rat: an anatomical study by anterograde and retrograde tracing methods. Neuroscience 7:615–630PubMedCrossRefGoogle Scholar
  37. Koike H, Ibi D, Mizoguchi H et al (2009) Behavioral abnormality and pharmacologic response in social isolation-reared mice. Behav Brain Res 202:114–121PubMedCrossRefGoogle Scholar
  38. Komendantov AO, Ascoli GA (2009) Dendritic excitability and neuronal morphology as determinants of synaptic efficacy. J Neurophysiol 101:1847–1866PubMedCrossRefGoogle Scholar
  39. Kröner S, Rosenkranz JA, Grace AA (2005) Dopamine modulates excitability of basolateral amygdala neurons in vitro. J Neurophysiol 93:1598–1610PubMedCrossRefGoogle Scholar
  40. Lammel S, Hetzel A, Häckel O et al (2008) Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57:760–773PubMedCrossRefGoogle Scholar
  41. Lapiz MD, Fulford A, Muchimapura S et al (2003) Influence of postweaning social isolation in the rat on brain development, conditioned behavior, and neurotransmission. Neurosci Behav Physiol 33:13–29PubMedCrossRefGoogle Scholar
  42. Laviolette SR (2007) Dopamine modulation of emotional processing in cortical and subcortical neural circuits: evidence for a final common pathway in schizophrenia? Schizophr Bull 33:971–981PubMedCrossRefGoogle Scholar
  43. Laviolette SR, Lipski WJ, Grace AA (2005) A subpopulation of neurons in the medial prefrontal cortex encodes emotional learning with burst and frequency codes through a dopamine D4 receptor-dependent basolateral amygdala input. J Neurosci 25:6066–6075PubMedCrossRefGoogle Scholar
  44. Lee LJ (2009) Neonatal fluoxetine exposure affects the neuronal structure in the somatosensory cortex and somatosensory-related behaviors in adolescent rats. Neurotox Res 15:212–223PubMedCrossRefGoogle Scholar
  45. Lin YC, Koleske AJ (2010) Mechanisms of synapse and dendrite maintenance and their disruption in psychiatric and neurodegenerative disorders. Annu Rev Neurosci 33:349–378PubMedCrossRefGoogle Scholar
  46. Liston C, Miller MM, Goldwater DS et al (2006) Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci 26:7870–7874PubMedCrossRefGoogle Scholar
  47. Lukkes JL, Watt MJ, Lowry CA et al (2009) Consequences of post-weaning social isolation on anxiety behavior and related neural circuits in rodents. Front Behav Neurosci 3:18PubMedCrossRefGoogle Scholar
  48. Mainen ZF, Sejnowski TJ (1996) Influence of dendritic structure on firing pattern in model neocortical neurons. Nature 382:363–366PubMedCrossRefGoogle Scholar
  49. Martínez-Téllez RI, Hernández-Torres E, Gamboa C et al (2009) Prenatal stress alters spine density and dendritic length of nucleus accumbens and hippocampus neurons in rat offspring. Synapse 63:794–804PubMedCrossRefGoogle Scholar
  50. McDonald AJ (1991) Organization of amygdaloid projections to the prefrontal cortex and associated striatum in the rat. Neuroscience 44:1–14PubMedCrossRefGoogle Scholar
  51. Meyer U, Feldon J (2009) Prenatal exposure to infection: a primary mechanism for abnormal dopaminergic development in schizophrenia. Psychopharmacology (Berl) 206:587–602CrossRefGoogle Scholar
  52. Miura H, Qiao H, Ohta T (2002) Influence of aging and social isolation on changes in brain monoamine turnover and biosynthesis of rats elicited by novelty stress. Synapse 46:116–124PubMedCrossRefGoogle Scholar
  53. Nair-Roberts RG, Chatelain-Badie SD, Benson E et al (2008) Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat. Neuroscience 152:1024–1031PubMedCrossRefGoogle Scholar
  54. Nestler EJ, Carlezon WA Jr (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59:1151–1159PubMedCrossRefGoogle Scholar
  55. Niwa M, Kamiya A, Murai R et al (2010) Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron 65:480–489PubMedCrossRefGoogle Scholar
  56. Pascual R, Zamora-León SP, Valero-Cabré A (2006) Effects of postweaning social isolation and re-socialization on the expression of vasoactive intestinal peptide (VIP) and dendritic development in the medial prefrontal cortex of the rat. Acta Neurobiol Exp (Wars) 66:7–14Google Scholar
  57. Pascual R, Zamora-León P, Catalán-Ahumada M et al (2007) Early social isolation decreases the expression of calbindin D-28 k and dendritic branching in the medial prefrontal cortex of the rat. Int J Neurosci 117:465–476PubMedCrossRefGoogle Scholar
  58. Paus T, Keshavan M, Giedd JN (2008) Why do many psychiatric disorders emerge during adolescence? Nat Rev Neurosci 9:947–957PubMedGoogle Scholar
  59. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, New YorkGoogle Scholar
  60. Penzes P, Cahill ME, Jones KA et al (2011) Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 14:285–293PubMedCrossRefGoogle Scholar
  61. Perez-Cruz C, Simon M, Czéh B et al (2009) Hemispheric differences in basilar dendrites and spines of pyramidal neurons in the rat prelimbic cortex: activity- and stress-induced changes. Eur J Neurosci 29:738–747PubMedCrossRefGoogle Scholar
  62. Phillips AG, Ahn S, Howland JG (2003) Amygdalar control of the mesocorticolimbic dopamine system: parallel pathways to motivated behavior. Neurosci Biobehav Rev 27:543–554PubMedCrossRefGoogle Scholar
  63. Radley JJ, Sisti HM, Hao J et al (2004) Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience 125:1–6PubMedCrossRefGoogle Scholar
  64. Radley JJ, Rocher AB, Rodriguez A et al (2008) Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J Comp Neurol 507:1141–1150PubMedCrossRefGoogle Scholar
  65. Reynolds GP (1983) Increased concentrations and lateral asymmetry of amygdala dopamine in schizophrenia. Nature 305:527–529PubMedCrossRefGoogle Scholar
  66. Romeo RD, McEwen BS (2006) Stress and the adolescent brain. Ann N Y Acad Sci 1094:202–214PubMedCrossRefGoogle Scholar
  67. Roncada P, Bortolato M, Frau R et al (2009) Gating deficits in isolation-reared rats are correlated with alterations in protein expression in nucleus accumbens. J Neurochem 108:611–620PubMedCrossRefGoogle Scholar
  68. Roozendaal B, McEwen BS, Chattarji S (2009) Stress, memory and the amygdala. Nat Rev Neurosci 10:423–433PubMedCrossRefGoogle Scholar
  69. Rosenkranz JA, Grace AA (2002) Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo. J Neurosci 22:324–337PubMedGoogle Scholar
  70. Rougé-Pont F, Mayo W, Marinelli M et al (2002) The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens. Eur J Neurosci 16:169–173PubMedCrossRefGoogle Scholar
  71. Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–152PubMedCrossRefGoogle Scholar
  72. Serra M, Sanna E, Mostallino MC et al (2007) Social isolation stress and neuroactive steroids. Eur Neuropsychopharmacol 17:1–11PubMedCrossRefGoogle Scholar
  73. Shansky RM, Morrison JH (2009) Stress-induced dendritic remodeling in the medial prefrontal cortex: effects of circuit, hormones and rest. Brain Res 1293:108–113PubMedCrossRefGoogle Scholar
  74. Shansky RM, Hamo C, Hof PR et al (2009) Stress-induced dendritic remodeling in the prefrontal cortex is circuit specific. Cereb Cortex 19:2479–2484PubMedCrossRefGoogle Scholar
  75. Silva-Gómez AB, Rojas D, Juárez I et al (2003) Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats. Brain Res 983:128–136PubMedCrossRefGoogle Scholar
  76. Vucetic Z, Totoki K, Schoch H et al (2010) Early life protein restriction alters dopamine circuitry. Neuroscience 168:359–370PubMedCrossRefGoogle Scholar
  77. Vyas A, Mitra R, Shankaranarayana Rao BS et al (2002) Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22:6810–6818PubMedGoogle Scholar
  78. Wise RA (1982) Neuroleptics and operant behavior: the anhedonia hypothesis. Behav Brain Sci 5:39–87CrossRefGoogle Scholar
  79. Yadid G, Overstreet DH, Zangen A (2001) Limbic dopaminergic adaptation to a stressful stimulus in a rat model of depression. Brain Res 896:43–47PubMedCrossRefGoogle Scholar
  80. Young KA, Gobrogge KL, Wang Z (2011) The role of mesocorticolimbic dopamine in regulating interactions between drugs of abuse and social behavior. Neurosci Biobehav Rev 35:498–515PubMedCrossRefGoogle Scholar
  81. Zhang TY, Chrétien P, Meaney MJ et al (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 25:1493–1502PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Yu-Chun Wang
    • 1
  • Ue-Cheung Ho
    • 1
  • Meng-Ching Ko
    • 2
  • Chun-Chieh Liao
    • 2
  • Li-Jen Lee
    • 1
    • 2
    • 3
    • 4
  1. 1.School of MedicineNational Taiwan UniversityTaipeiTaiwan
  2. 2.Graduate Institute of Anatomy and Cell Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  3. 3.Graduate Institute of Brain and Mind SciencesNational Taiwan UniversityTaipeiTaiwan
  4. 4.Neurobiology and Cognitive Science CenterNational Taiwan UniversityTaipeiTaiwan

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