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

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Abstract

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.

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References

  • Bakshi V, Geyer M (1999) Ontogeny of isolation rearing-induced deficits in sensorimotor gating in rats. Physiol Behav 67(3):385–392

    Article  CAS  PubMed  Google Scholar 

  • 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):314–347

    Article  CAS  PubMed  Google Scholar 

  • 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):234–258

    Article  CAS  PubMed  Google Scholar 

  • 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):39–46

    Article  CAS  PubMed  Google Scholar 

  • 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 338:255–278

    Article  CAS  PubMed  Google Scholar 

  • Casey BJ, Jones RM (2010) Neurobiology of the adolescent brain and behavior. J Am Acad Child Adolesc Psychiatry 49(12):1189–1285. https://doi.org/10.1016/j.jaac.2010.08.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. https://doi.org/10.1007/s00213-009-1604-6

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1073/pnas.0609408104

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1016/j.neuroscience.2006.04.048

    Article  CAS  PubMed  Google Scholar 

  • Duguid I, Sjostrom PJ (2006) Novel presynaptic mechanisms for coincidence detection in synaptic plasticity. Curr Opin Neurobiol 16(3):312–322. https://doi.org/10.1016/j.conb.2006.05.008

    Article  CAS  PubMed  Google Scholar 

  • Dunah AW, Standaert DG (2001) Dopamine D1 receptor-dependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane. J Neurosci 21(15):5546–5558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):20196–20202

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1016/j.neuroscience.2013.01.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. https://doi.org/10.1016/j.neubiorev.2008.03.003

    Article  CAS  PubMed  Google Scholar 

  • Froemke R, Li C, Dan Y (2003) A form of presynaptic coincidence detection. Neuron 39(4):579–581

    Article  CAS  PubMed  Google Scholar 

  • 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):3915–3934

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1016/j.expneurol.2008.01.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):169–181

    Article  CAS  PubMed  Google Scholar 

  • 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):4839–4848

    Article  CAS  PubMed  Google Scholar 

  • Groenewegen HJ, Wright CI, Beijer AV, Voorn P (1999) Convergence and segregation of ventral striatal inputs and outputs. Ann N Y Acad Sci 877:49–63

    Article  CAS  PubMed  Google Scholar 

  • 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):442–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):965–977

    Article  CAS  Google Scholar 

  • Insel TR (2014) The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. Am J Psychiatry 171(4):395–397. https://doi.org/10.1176/appi.ajp.2014.14020138

    Article  PubMed  Google Scholar 

  • Kirouac GJ (2015) Placing the paraventricular nucleus of the thalamus within the brain circuits that control behavior. Neurosci Biobehav Rev 56:315–329. https://doi.org/10.1016/j.neubiorev.2015.08.005

    Article  PubMed  Google Scholar 

  • 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. https://doi.org/10.1002/cne.902890210

    Article  CAS  PubMed  Google Scholar 

  • 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):8861–8865

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1007/978-1-61779-328-8_3

    Chapter  Google Scholar 

  • 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. https://doi.org/10.1523/JNEUROSCI.1167-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. https://doi.org/10.1002/(SICI)1096-9861(19960715)371:1<116::AID-CNE7>3.0.CO;2-6

    Article  CAS  PubMed  Google Scholar 

  • 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):3622–3639

    Article  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  • 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. https://doi.org/10.1111/psyp.12679

    Article  PubMed  Google Scholar 

  • 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):233–240

    Article  CAS  PubMed  Google Scholar 

  • Ramocki MB, Zoghbi HY (2008) Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455(7215):912–918. https://doi.org/10.1038/nature07457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):131–138

    Article  CAS  PubMed  Google Scholar 

  • 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):213–217

    Article  CAS  PubMed  Google Scholar 

  • Salgado S, Kaplitt MG (2015) The nucleus accumbens: a comprehensive review. Stereotact Funct Neurosurg 93(2):75–93. https://doi.org/10.1159/000368279

    Article  PubMed  Google Scholar 

  • 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. https://doi.org/10.1016/j.neuroscience.2008.12.019

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1016/j.bandc.2009.06.008 pii]

    Article  PubMed  Google Scholar 

  • 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. https://doi.org/10.1002/cne.903200202

    Article  CAS  PubMed  Google Scholar 

  • 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 290:213–242

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1016/j.bandc.2009.07.003

    Article  PubMed  Google Scholar 

  • Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24(4):417–463

    Article  CAS  PubMed  Google Scholar 

  • 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):414–420

    Article  CAS  PubMed  Google Scholar 

  • 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):185–204

    Article  CAS  PubMed  Google Scholar 

  • 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):194–215

    Article  CAS  PubMed  Google Scholar 

  • 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):1325–1335

    Article  PubMed  Google Scholar 

  • Wan FJ, Swerdlow NR (1993) Intra-accumbens infusion of quinpirole impairs sensorimotor gating of acoustic startle in rats. Psychopharmacology 113(1):103–109

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1038/npp.1994.8

    Article  CAS  PubMed  Google Scholar 

  • 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):176–183

    Article  CAS  PubMed  Google Scholar 

  • 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):383–403

    Article  CAS  PubMed  Google Scholar 

  • 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):85–105

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA

    Megan L. Fitzgerald & Virginia M. Pickel

  2. New York State Psychiatric Institute, Columbia University, New York, NY, 10032, USA

    Megan L. Fitzgerald

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  1. Megan L. Fitzgerald
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  2. Virginia M. Pickel
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Correspondence to Virginia M. Pickel.

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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.

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Fitzgerald, M.L., Pickel, V.M. Adolescent isolation rearing produces a prepulse inhibition deficit correlated with expression of the NMDA GluN1 subunit in the nucleus accumbens. Brain Struct Funct 223, 3169–3181 (2018). https://doi.org/10.1007/s00429-018-1673-6

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