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Social withdrawal, neophobia, and stereotyped behavior in developing rats exposed to neonatal asphyxia

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Abstract

Perinatal asphyxia is a concern for public health and may promote subtle neuropsychiatric disorders. Anoxic insults to neonatal rats cause long-lasting neurobehavioral deficits. In the present study, we focussed on changes in emotional behaviors as a consequence of neonatal asphyxia in Wistar rats. Newborn pups (24 h after birth) underwent a single 30-min exposure to a 100% N2 atmosphere (or air). The offspring was tested for a) locomotor and exploratory activity with or without a d-amphetamine challenge (0, 1, or 2 mg/kg) on postnatal day (pnd) 15; b) social interactions and novelty seeking during adolescence; c) levels of the brain-derived neurotrophic factor (BDNF). In the open-field test (pnd 15), N2-exposed pups injected with the high (2 mg/kg) amphetamine dose exhibited reduced levels of locomotor hyperactivity, and a more marked involvement in stereotyped behaviors. Individual differences emerged in the locomotor response to the novelty-seeking test: two subgroups of rats (separated on the basis of the median value) showed either arousal/attraction or avoidance/inhibition in response to free-choice novelty. The N2-exposed group showed a more marked novelty-induced avoidance and inhibition. Time devoted to allogrooming and play-soliciting behaviors was reduced, whereas object exploration was increased. Levels of BDNF were reduced in the striatum of N2-exposed rats, suggesting poorer synaptic performance of dopamine pathways. In conclusion, these findings suggest an increased risk of developing social withdrawal, neophobia and behavioral stereotypies (common symptoms found in schizophrenia and autism) as a consequence of neonatal asphyxia in preterm humans.

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References

  • Adriani W, Sargolini F, Coccurello R, Oliverio A, Mele A (2000) Role of dopaminergic system in reactivity to spatial and non-spatial changes. Psychopharmacology 150:67–76

    Google Scholar 

  • Almli CR, Levy TJ, Han BH, Shah AR, Gidday JM, Holtzman DM (2000) BDNF protects against spatial memory deficits following neonatal hypoxia-ischemia. Exp Neurol 166:99–114

    Google Scholar 

  • Andersen SL, Thompson AT, Rutstein M, Hostetter JC, Teicher MH (2000) Dopamine receptor pruning in prefrontal cortex during the periadolescent period in rats. Synapse 37:167–169

    Article  CAS  PubMed  Google Scholar 

  • Balduini W, De Angelis V, Mazzoni E, Cimino M (2000) Long-lasting behavioral alterations following a hypoxic/ischemic brain injury in neonatal rats. Brain Res 859:318–325

    Article  CAS  PubMed  Google Scholar 

  • Bardo MT, Donohew RL, Harrington NG (1996) Psychobiology of novelty seeking and drug seeking behavior. Behav Brain Res 77:23–43

    CAS  PubMed  Google Scholar 

  • Bjelke B, Andersson K, Ogren SO, Bolme P (1991) Asphyctic lesion induce proliferation of tyrosine hydroxylase-immunoreactive nerve cell bodies in the rat substantia nigra and functional changes in dopamine neurotransmission. Brain Res 543:1–9

    CAS  PubMed  Google Scholar 

  • Boksa P, Krishnamurthy A, Brooks W (1995) Effects of a period of asphyxia during birth on spatial learning in the rat. Pediatr Res 37:489–496

    CAS  PubMed  Google Scholar 

  • Brixey SN, Gallagher BJ 3rd, McFalls JA Jr, Parmelee LF (1993) Gestational and neonatal factors in the etiology of schizophrenia. J Clin Psychol 49:447–456

    CAS  PubMed  Google Scholar 

  • Campbell BA, Randall PJ (1977) Paradoxical effects of amphetamine in pre-weanling and post-weanling rats. Science 195:888–891

    CAS  PubMed  Google Scholar 

  • Campbell BA, Lytle LD, Fibiger HC (1969) Ontogeny of adrenergic arousal and cholinergic inhibitory mechanisms in the rat. Science 166:635–637

    CAS  PubMed  Google Scholar 

  • Chen Y, Engidawork E, Loidl F, Dell’Anna E, Goiny M, Lubec G, Andersson K, Herrera-Marschitz M (1997a) Short- and long-term effects of perinatal asphyxia on monoamine, amino acid and glycolysis product levels measured in the basal ganglia of the rat. Dev Brain Res 104:19–30

    CAS  PubMed  Google Scholar 

  • Chen Y, Hillefors-Berglund M, Herrera-Marschitz M, Bjelke B, Gross J, Andersson K, von Euler G (1997b) Perinatal asphyxia induces long-term change in D1, D2 and D3 receptor binding in the rat brain. Exp Neurol 146:74–80

    Article  CAS  PubMed  Google Scholar 

  • Cheng Y, Gidday JM, Yan Q, Shah AR, Holtzmann DM (1997) Marked age-dependent neuroprotection by brain-derived neurotrophic factor against neonatal hypoxic/ischemic brain injury. Ann Neurol 41:521–529

    Google Scholar 

  • Connor B, Dragunow M (1998) The role of neuronal growth factors in neurodegenerative disorders of the human brain. Brain Res Rev 27:1–39

    Article  CAS  PubMed  Google Scholar 

  • Dell’Anna ME, Calzolari S, Molinari M, Iuvone L, Calimici R (1991) Neonatal anoxia induces transitory hyperactivity, permanent spatial memory deficits and CA1 cell density reduction in developing rats. Behav Brain Res 45:125–134

    CAS  PubMed  Google Scholar 

  • Dluzen DE, Gao X, Story GM, Anderson LI, Kucera J, Walro JM (2001) Evaluation of nigrostriatal dopaminergic function in adult +/+ and +/− BDNF mutant mice. Exp Neurol 170:121–128

    Article  CAS  PubMed  Google Scholar 

  • Dluzen DE, Anderson LI, McDermott JL, Kucera J, Walro JM (2002) Striatal dopamine output is compromised within +/− BDNF mice. Synapse 43:112–117

    Article  CAS  PubMed  Google Scholar 

  • El-Khodor BF, Boksa P (1997) Long-term reciprocal changes in dopamine levels in prefrontal cortex versus nucleus accumbens in rats born by Caesarean section compared to vaginal birth. Exp Neurol 145:118–129

    Article  CAS  PubMed  Google Scholar 

  • El-Khodor BF, Boksa P (1998) Birth insult increases amphetamine-induced behavioral responses in the adult rat. Neuroscience 87:893–904

    Article  CAS  PubMed  Google Scholar 

  • Goggi J, Pullar IA, Carney SL, Bradford HF (2002) Modulation of neuro-transmitter release induced by brain-derived neurotrophic factor in rat brain striatal slices in vitro. Brain Res 941:34–42

    Article  CAS  PubMed  Google Scholar 

  • Gunther-Genta F, Bovet P, Hohlfeld P (1994) Obstetric complications and schizophrenia. A case-control study. Br J Psychiatry 164:165–170

    CAS  PubMed  Google Scholar 

  • Hershkowitz M, Grimm VE, Speiser Z (1983) The effects of postnatal anoxia on behavior and on the muscarinic and beta-adrenergic receptors in the hippocampus of the developing rat. Brain Res 283:147–55

    CAS  PubMed  Google Scholar 

  • Hill A (1991) Current concepts of hypoxic-ischemic cerebral injury in the term newborn. Pediatr Neurol 7:317–325

    Article  CAS  PubMed  Google Scholar 

  • Hooks MS, Juncos JL, Justice JB, Meiergerd SM, Povlock SL, Schenck JO, Kalivas PW (1994) Individual locomotor response to novelty predicts selective alterations in dopamine D1 and D2 receptors and mRNAs. J Neurosci 14:6144–6152

    CAS  PubMed  Google Scholar 

  • Ikeda T, Mishima K, Yoshikawa T, Iwasaki K, Fujiwara M, Xia YX, Ikenoue T (2001) Selective and long-term learning impairment following neonatal hypoxic-ischemic brain insult in rats. Behav Brain Res 118:17–25

    Article  CAS  PubMed  Google Scholar 

  • Iuvone L, Geloso MC, Dell’Anna E (1996) Changes in open field behavior, spatial memory, and hippocampal parvalbumin immunoreactivity following enrichment in rats exposed to neonatal anoxia. Exp Neurol 139:25–33

    Article  CAS  PubMed  Google Scholar 

  • Laviola G, Adriani W (1998) Evaluation of unconditioned novelty seeking and d-amphetamine conditioned motivation in mice. Pharmacol Biochem Behav 59:1011–1020

    CAS  PubMed  Google Scholar 

  • Laviola G, Renna G, Bignami G, Cuomo V (1988) The ontogenetic and pharmacological disassociation of various components of locomotor activity and habituation in the rat. Int J Dev Neurosci 6:431–438

    Article  CAS  PubMed  Google Scholar 

  • Laviola G, Wood RD, Kuhn C, Francis R, Spear LP (1995) Cocaine sensitization in periadolescent and adult rats. J Pharmacol Exp Ther 275:345–357

    CAS  PubMed  Google Scholar 

  • Laviola G, Macri’ S, Morley-Fletcher S, Adriani W (2003) Risk-taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence. Neurosci Biobehav Rev 27:19–31

    Article  PubMed  Google Scholar 

  • Lipska BK, Khaing ZZ, Weickert CS, Weinberger DR (2001) BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs. Eur J Neurosci14:135–144

    Google Scholar 

  • Misslin R, Ropartz P (1981a) Effects of metamphetamine on novelty-seeking behavior by mice. Psychopharmacology 75:39–43

    CAS  PubMed  Google Scholar 

  • Misslin R, Ropartz P (1981b) Responses in mice to a novel object. Behavior 78:169–177

    Google Scholar 

  • Molteni R, Lipska BK, Weinberger DR, Racagni G, Riva MA (2001) Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia. Mol Psychiatry 6:285–292

    Article  CAS  PubMed  Google Scholar 

  • Piazza PV, Maccari S, Deminiere JM, Le Moal M, Mormede P, Simon H (1991) Corticosterone levels determine individual vulnerability to amphetamine self-administration. Proc Natl Acad Sci USA 88:2088–2092

    CAS  PubMed  Google Scholar 

  • Plotsky PM, Bradley CC, Anand KJS (2000) Behavioral and neuro-endocrine consequences of neonatal stress. In: Anand KJS, McGrath PJ, Stevens BJ (eds) Pain in neonates. Elsevier, Amsterdam, pp 77–99

  • Robertson CMT, Finner NN (1993) Long-term follow-up of term neonates with perinatal asphyxia. Clin Perinatol 20:483–499

    CAS  PubMed  Google Scholar 

  • Romijin HJ, Hofman MA, Gramsbergen A (1991) At what age is the developing cerebral cortex of the rat comparable to the full-term newborn human baby? Early Hum Dev 26:61–67

    PubMed  Google Scholar 

  • Roohey T, Raju TN, Moustogiannis AN (1997) Animal models for the study of perinatal hypoxic-ischemic encephalopathy: a critical analysis. Early Hum Dev 47:115–146

    Article  CAS  PubMed  Google Scholar 

  • Sams-Dodd F (1999) Phencyclidine in the social interaction test: animal models of schizophrenia with face and predictive validity. Rev Neurosci 10:59–90

    CAS  PubMed  Google Scholar 

  • Scheepens A, Wassink G, Blanco CE (2003) The effect of a global birth asphyxia on the ontogeny of BDNF and NGF protein expression in the juvenile brain. Dev Brain Res 140:215–221

    Article  CAS  Google Scholar 

  • Shankaran S, Woldt E, Koepke T, Bedard MP, Nandyal R (1991) Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants. Early Hum Dev 25:135–148

    CAS  PubMed  Google Scholar 

  • Silverstein F, Johnston MV (1984) Effects of hypoxia-ischemia on monoamine metabolism in the immature brain. Ann Neurol 15:342–347

    CAS  PubMed  Google Scholar 

  • Spear LP, Brake SC (1983) Periadolescence: age-dependent behavior and psychopharmacological responsivity in rats. Dev Psychobiol 16:83–109

    CAS  PubMed  Google Scholar 

  • Speiser Z, Korczyn AD, Teplitzky I, Gitter S (1983) Hyperactivity in rats following postnatal anoxia. Behav Brain Res 7:379–382

    Article  CAS  PubMed  Google Scholar 

  • Speiser Z, Amitzi-Sonder J, Gitter S, Cohen S (1988) Behavioral differences in the developing rat following postnatal anoxia or postnatally injected AF-64A, a cholinergic neurotoxin. Behav Brain Res 30:89–94

    Article  CAS  PubMed  Google Scholar 

  • Stamford JA (1989) Development and ageing of the rat nigrostriatal dopamine system studied with fast cyclic voltammetry. J Neurochem 52:1582–1589

    CAS  PubMed  Google Scholar 

  • Staton DM, Solomon PR (1984) Microinjections of d-amphetamine into the nucleus accumbens and caudate-putamen differentially affects stereotypy and locomotion in the rat. Physiol Psychol 12:159–162

    CAS  Google Scholar 

  • Teicher MH, Andersen SL, Hostetter JC (1995) Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens. Devl Brain Res 89:167–172

    Article  CAS  Google Scholar 

  • Tirelli E, Laviola G, Adriani W (2003) Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in laboratory rodents. Neurosci Biobehav Rev 27:163–178

    Article  PubMed  Google Scholar 

  • Volpe JJ (1987) Neurology of the newborn (vol 22). Saunders, Philadelphia

  • Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE (2003) Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 8:592–610

    Article  CAS  PubMed  Google Scholar 

  • Weinberger DR (1995) From neuropathology to neurodevelopment. Lancet 346:552–557

    CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by the Research Project on “Hypoxic-ischemic brain damage in the newborn” (0AN/F grant to E.A.), Ministry of Health, Italy, and by the Young Investigator Award “Behavioral handicap at developing ages” (CNRG00A0A8 grant to W.A.), Agenzia 2000, CNR, Italy. We wish to thank A. Valanzano for expert technical assistance and A. Venerosi for precious help in literature discussion.

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  1. Section of Behavioral Pathophysiology, Lab Fisiopatologia OS, Dipartimento Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanita’, viale Regina Elena 299, 00161, Roma, Italy

    G. Laviola, W. Adriani, M. Rea & E. Alleva

  2. Institute of Neurobiology and Molecular Medicine, CNR, Roma, Italy

    L. Aloe

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  1. G. Laviola
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  2. W. Adriani
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Correspondence to G. Laviola.

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Laviola, G., Adriani, W., Rea, M. et al. Social withdrawal, neophobia, and stereotyped behavior in developing rats exposed to neonatal asphyxia. Psychopharmacology 175, 196–205 (2004). https://doi.org/10.1007/s00213-004-1800-3

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  • DOI: https://doi.org/10.1007/s00213-004-1800-3

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