Brain Structure and Function

, Volume 223, Issue 7, pp 3169–3181 | Cite as

Adolescent isolation rearing produces a prepulse inhibition deficit correlated with expression of the NMDA GluN1 subunit in the nucleus accumbens

  • Megan L. Fitzgerald
  • Virginia M. PickelEmail author
Original Article


Adolescence is a transition period during which social interaction is necessary for normal brain and behavior development. Severely abnormal social interactions during adolescence can increase the incidence of lifelong psychiatric disease. Decreased prepulse inhibition (PPI) is a quantifiable hallmark of some psychiatric illnesses in humans and can be elicited in rodents by isolation rearing throughout the adolescent transition period. PPI is a measure of sensorimotor gating in which the nucleus accumbens (Acb) is crucially involved. The Acb is comprised of core and shell subregions, which receive convergent dopaminergic and glutamatergic inputs. To gain insight into the neurobiological correlates of adolescent adversity, we conducted electron microscopic immunolabeling of dopamine D1 receptors (D1Rs) and the GluN1 subunit of glutamate NMDA receptors in the Acb of isolation-reared (IR) adult male rats. In all animals, GluN1 was primarily located in dendritic profiles, many of which also contained D1Rs. GluN1 was also observed in perisynaptic glia and axon terminals. In IR rats compared with group-reared controls, GluN1 density was selectively decreased in D1R-containing dendrites of the Acb core. Across all animals, dendritic GluN1 density correlated with average percent PPI, implicating endogenous expression of NMDA receptors of the Acb as a possible substrate of the PPI response. These results suggest that adolescent isolation dampens NMDA-mediated excitation in direct (D1R-containing) output neurons of the Acb, and that these changes influence the operational measure of PPI.


NMDA receptor D1 receptor Sensorimotor gating Social isolation Adolescence Electron microscopy 



The authors gratefully acknowledge the receipt of National Institute of Drug Abuse funding on Grants T32DA7274 to MLF and DA004600 to VMP, and National Institute of Mental Health funding on Grants T32MH15144 to MLF and MH40342 to VMP.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Human/animal rights

This article does not contain any studies with human participants performed by any of the authors. All procedures involving animals were carried out in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals, and were approved by the Institutional Animal Care and Use Committees (IACUC) at Weill-Cornell Medical College. Every effort was made to minimize the number of animals used and their suffering.


  1. Bakshi V, Geyer M (1999) Ontogeny of isolation rearing-induced deficits in sensorimotor gating in rats. Physiol Behav 67(3):385–392PubMedCrossRefGoogle Scholar
  2. Berendse H, Galis-de Graaf Y, Groenewegen H (1992) Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J Comp Neurol 316(3):314–347PubMedCrossRefGoogle Scholar
  3. Braff D, Geyer M, Swerdlow N (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology 156(2–3):234–258PubMedCrossRefGoogle Scholar
  4. Broersen LM, Feldon J, Weiner I (1999) Dissociative effects of apomorphine infusions into the medial prefrontal cortex of rats on latent inhibition, prepulse inhibition and amphetamine-induced locomotion. Neuroscience 94(1):39–46PubMedCrossRefGoogle Scholar
  5. Brog J, Salyapongse A, Deutch A, Zahm D (1993) The patterns of afferent innervation of the core and shell in the “accumbens” part of the rat ventral striatum: Immunohistochemical detection of retrogradely transported fluoro-gold. J Comp Neurol 338:255–278PubMedCrossRefGoogle Scholar
  6. Casey BJ, Jones RM (2010) Neurobiology of the adolescent brain and behavior. J Am Acad Child Adolesc Psychiatry 49(12):1189–1285. PubMedPubMedCentralCrossRefGoogle Scholar
  7. Chavez C, Gogos A, Jones ME, van den Buuse M (2009) Psychotropic drug-induced locomotor hyperactivity and prepulse inhibition regulation in male and female aromatase knockout (ArKO) mice: role of dopamine D1 and D2 receptors and dopamine transporters. Psychopharmacology 206(2):267–279. PubMedCrossRefGoogle Scholar
  8. D’Ascenzo M, Fellin T, Terunuma M, Revilla-Sanchez R, Meaney DF, Auberson YP, Moss SJ, Haydon PG (2007) mGluR5 stimulates gliotransmission in the nucleus accumbens. Proc Natl Acad Sci USA 104(6):1995–2000. PubMedCrossRefGoogle Scholar
  9. Day-Wilson KM, Jones DNC, Southam E, Cilia J, Totterdell S (2006) Medial prefrontal cortex volume loss in rats with isolation rearing-induced deficits in prepulse inhibition of acoustic startle. Neuroscience 141(3):1113–1121. PubMedCrossRefGoogle Scholar
  10. Duguid I, Sjostrom PJ (2006) Novel presynaptic mechanisms for coincidence detection in synaptic plasticity. Curr Opin Neurobiol 16(3):312–322. PubMedCrossRefGoogle Scholar
  11. Dunah AW, Standaert DG (2001) Dopamine D1 receptor-dependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane. J Neurosci 21(15):5546–5558PubMedCrossRefPubMedCentralGoogle Scholar
  12. Fiorentini C, Gardoni F, Spano P, Di Luca M, Missale C (2003) Regulation of dopamine D1 receptor trafficking and desensitization by oligomerization with glutamate N-methyl-d-aspartate receptors. J Biol Chem 278(22):20196–20202PubMedCrossRefGoogle Scholar
  13. Fitzgerald ML, Mackie K, Pickel VM (2013) The impact of adolescent social isolation on dopamine D2 and cannabinoid CB1 receptors in the adult rat prefrontal cortex. Neuroscience 235:40–50. PubMedPubMedCentralCrossRefGoogle Scholar
  14. 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(6):1087–1102. PubMedCrossRefGoogle Scholar
  15. Froemke R, Li C, Dan Y (2003) A form of presynaptic coincidence detection. Neuron 39(4):579–581PubMedCrossRefGoogle Scholar
  16. Gerfen CR, Herkenham M, Thibault J (1987) The neostriatal mosaic: II. Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems. J Neurosci 7(12):3915–3934PubMedCrossRefGoogle Scholar
  17. Glass MJ, Lane DA, Colago EE, Chan J, Schlussman SD, Zhou Y, Kreek MJ, Pickel VM (2008) Chronic administration of morphine is associated with a decrease in surface AMPA GluR1 receptor subunit in dopamine D1 receptor expressing neurons in the shell and non-D1 receptor expressing neurons in the core of the rat nucleus accumbens. Exp Neurol 210(2):750–761. PubMedPubMedCentralCrossRefGoogle Scholar
  18. Gracy KN, Pickel VM (1996) Ultrastructural immunocytochemical localization of the N-methyl-d-aspartate receptor and tyrosine hydroxylase in the shell of the rat nucleus accumbens. Brain Res 739(1–2):169–181PubMedCrossRefGoogle Scholar
  19. Gracy K, Svingos A, Pickel V (1997) Dual ultrastructural localization of mu-opioid receptors and NMDA- type glutamate receptors in the shell of the rat nucleus accumbens. J Neurosci 17(12):4839–4848PubMedCrossRefGoogle Scholar
  20. Groenewegen HJ, Wright CI, Beijer AV, Voorn P (1999) Convergence and segregation of ventral striatal inputs and outputs. Ann N Y Acad Sci 877:49–63PubMedCrossRefGoogle Scholar
  21. Hara Y, Pickel V (2005) Overlapping intracellular and differential synaptic distributions of dopamine D1 and glutamate N-methyl-d-aspartate receptors in rat nucleus accumbens. J Comp Neurol 492(4):442–455PubMedPubMedCentralCrossRefGoogle Scholar
  22. Hara Y, Pickel (2009) Preferential relocation of the N-methyl-d-aspartate receptor NR1 subunit in nucleus accumbens neurons that contain dopamine D1 receptors in rats showing an apomorphine-induced sensorimotor gating deficit. Neuroscience 154(3):965–977CrossRefGoogle Scholar
  23. Insel TR (2014) The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. Am J Psychiatry 171(4):395–397. PubMedCrossRefGoogle Scholar
  24. Kirouac GJ (2015) Placing the paraventricular nucleus of the thalamus within the brain circuits that control behavior. Neurosci Biobehav Rev 56:315–329. PubMedCrossRefGoogle Scholar
  25. Leranth C, Frotscher M (1989) Organization of the septal region in the rat brain: cholinergic-GABAergic interconnections and the termination of hippocampo-septal fibers. J Comp Neurol 289(2):304–314. PubMedCrossRefGoogle Scholar
  26. Levey A, Hersch S, Rye D, Sunahara R, Niznik H, Kitt C, Price D, Maggio R, Brann M, Ciliax B (1993) Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc Natl Acad Sci USA 90(19):8861–8865PubMedCrossRefGoogle Scholar
  27. Milner TA, Waters EM, Robinson DC, Pierce JP (2011) Degenerating processes identified by electron microscopic immunocytochemical methods. In: Giovanni Manfredi HK (ed) Neurodegeneration: methods and protocols, vol 793. Methods in molecular biology, 1st edn. Humana Press, New York, pp 23–59. CrossRefGoogle Scholar
  28. Morel L, Higashimori H, Tolman M, Yang Y (2014) VGluT1 + neuronal glutamatergic signaling regulates postnatal developmental maturation of cortical protoplasmic astroglia. J Neurosci 34(33):10950–10962. PubMedPubMedCentralCrossRefGoogle Scholar
  29. Nirenberg MJ, Chan J, Liu Y, Edwards RH, Pickel VM (1996) Ultrastructural localization of the vesicular monoamine transporter-2 in midbrain dopaminergic neurons: potential sites for somatodendritic storage and release of dopamine. J Neurosci 16 (13):4135–4145.<116::AID-CNE7>3.0.CO;2-6PubMedCrossRefGoogle Scholar
  30. O’Donnell P, Grace AA (1995) Synaptic interactions among excitatory afferents to nucleus accumbens neurons: hippocampal gating of prefrontal cortical input. J Neurosci 15(5 Pt 1):3622–3639PubMedCrossRefGoogle Scholar
  31. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
  32. Pineles SL, Blumenthal TD, Curreri AJ, Nillni YI, Putnam KM, Resick PA, Rasmusson AM, Orr SP (2016) Prepulse inhibition deficits in women with PTSD. Psychophysiology 53(9):1377–1385. PubMedCrossRefGoogle Scholar
  33. Powell SB, Geyer MA, Preece MA, Pitcher LK, Reynolds GP, Swerdlow NR (2003) Dopamine depletion of the nucleus accumbens reverses isolation-induced deficits in prepulse inhibition in rats. Neuroscience 119(1):233–240PubMedCrossRefGoogle Scholar
  34. Ramocki MB, Zoghbi HY (2008) Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455(7215):912–918. PubMedPubMedCentralCrossRefGoogle Scholar
  35. Reijmers LG, Vanderheyden PM, Peeters BW (1995) Changes in prepulse inhibition after local administration of NMDA receptor ligands in the core region of the rat nucleus accumbens. Eur J Pharmacol 272(2–3):131–138PubMedCrossRefGoogle Scholar
  36. Rouillon C, Abraini J, David H (2008) Prefrontal cortex and basolateral amygdala modulation of dopamine-mediated locomotion in the nucleus accumbens core. Exp Neurol 212(1):213–217PubMedCrossRefGoogle Scholar
  37. Salgado S, Kaplitt MG (2015) The nucleus accumbens: a comprehensive review. Stereotact Funct Neurosurg 93(2):75–93. PubMedCrossRefGoogle Scholar
  38. Schubert MI, Porkess MV, Dashdorj N, Fone KC, Auer DP (2009) Effects of social isolation rearing on the limbic brain: a combined behavioral and magnetic resonance imaging volumetry study in rats. Neuroscience 159(1):21–30. PubMedCrossRefGoogle Scholar
  39. Sebastian C, Viding E, Williams KD, Blakemore SJ (2010) Social brain development and the affective consequences of ostracism in adolescence. Brain Cogn 72(1):134–145. pii]PubMedCrossRefGoogle Scholar
  40. Sesack SR, Pickel VM (1992) Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol 320(2):145–160. PubMedCrossRefGoogle Scholar
  41. Sesack S, Deutch A, Roth R, Bunney B (1989) Topographic organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J Comp Neurol 290:213–242PubMedCrossRefGoogle Scholar
  42. Somerville LH, Jones RM, Casey BJ (2010) A time of change: behavioral and neural correlates of adolescent sensitivity to appetitive and aversive environmental cues. Brain Cogn 72(1):124–133. PubMedCrossRefGoogle Scholar
  43. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24(4):417–463PubMedCrossRefGoogle Scholar
  44. Swerdlow N, Braff D, Masten V, Geyer M (1990) Schizophrenic-like sensorimotor gating abnormalities in rats following dopamine infusion into the nucleus accumbens. Psychopharmacology 101(3):414–420PubMedCrossRefGoogle Scholar
  45. Swerdlow N, Braff D, Geyer M (2000) Animal models of deficient sensorimotor gating: what we know, what we think we know, and what we hope to know soon. Behav Pharmacol 11(3–4):185–204PubMedCrossRefGoogle Scholar
  46. Swerdlow NR, Geyer MA, Braff DL (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology 156(2–3):194–215PubMedCrossRefGoogle Scholar
  47. Swerdlow N, Light G, Cadenhead K, Sprock J, Hsieh M, Braff D (2006) Startle gating deficits in a large cohort of patients with schizophrenia: relationship to medications, symptoms, neurocognition, and level of function. Arch Gen Psychiatry 63(12):1325–1335PubMedCrossRefGoogle Scholar
  48. Wan FJ, Swerdlow NR (1993) Intra-accumbens infusion of quinpirole impairs sensorimotor gating of acoustic startle in rats. Psychopharmacology 113(1):103–109PubMedCrossRefGoogle Scholar
  49. Wilkinson LS, Killcross SS, Humby T, Hall FS, Geyer MA, Robbins TW (1994) Social isolation in the rat produces developmentally specific deficits in prepulse inhibition of the acoustic startle response without disrupting latent inhibition. Neuropsychopharmacology 10(1):61–72. PubMedCrossRefGoogle Scholar
  50. Wood D, Buse J, Wellman C, Rebec G (2005) Differential environmental exposure alters NMDA but not AMPA receptor subunit expression in nucleus accumbens core and shell. Brain Res 1042(2):176–183PubMedCrossRefGoogle Scholar
  51. Wright CI, Groenewegen HJ (1995) Patterns of convergence and segregation in the medial nucleus accumbens of the rat: relationships of prefrontal cortical, midline thalamic, and basal amygdaloid afferents. J Comp Neurol 361(3):383–403PubMedCrossRefGoogle Scholar
  52. Zahm D (2000) An integrative neuroanatomical perspective on some subcortical substrates of adaptive responding with emphasis on the nucleus accumbens. Neurosci Biobehav Rev 24(1):85–105PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Brain and Mind Research InstituteWeill Cornell MedicineNew YorkUSA
  2. 2.New York State Psychiatric InstituteColumbia UniversityNew YorkUSA

Personalised recommendations