Archival Report| Volume 72, ISSUE 2, P150-156, July 15, 2012

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Reducing Behavioral Inhibition to Novelty via Systematic Neonatal Novelty Exposure: The Influence of Maternal Hypothalamic-Pituitary-Adrenal Regulation


      Behavioral inhibition (BI) to novelty is thought to be a stable temperament type that appears early in life and is a major risk factor for anxiety disorders. In the rat, habituation of such inhibition can be facilitated via neonatal novelty exposure (NNE), thus reducing BI to novelty. Here, we tested the hypothesis that this early intervention effect is modulated by the context of maternal self-stress regulation.


      The NNE was carried out during postnatal days 1–21, in which one half of each litter was exposed to a relatively novel nonhome environment for 3-min daily while the remaining one half stayed in the home cage. After weaning, BI to novelty was assessed in an open field with a measure of disinhibition defined as a greater increase in exploration across two brief trials. Maternal context was characterized by trait measures of hypothalamic-pituitary-adrenal (HPA) axis reactivity, including basal and stress-evoked corticosterone (CORT) responses.


      Family-to-family variations in the NNE effect were associated with variations in maternal HPA function—a low-basal CORT and high-evoked CORT response profile constituting the context for a novelty-induced facilitation of disinhibition (i.e., a greater increase in exploratory activity over repeated trials) and an opposite HPA profile constituting the context for a novelty-induced reduction of disinhibition.


      This result is consistent with the hypothesis that maternal self-stress regulation modulates the effect of early life intervention on BI to novelty and suggests that effective interventions should include strategies to help mothers improve their self-stress regulation.

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        • Fox N.A.
        • Henderson H.A.
        • Marshall P.J.
        • Nichols K.E.
        • Ghera M.M.
        Behavioral inhibition: Linking biology and behavior within a developmental framework.
        Ann Rev Psychol. 2005; 56: 235-262
        • Kagan J.
        • Snidman N.
        • Kahn V.
        • Towsley S.
        The preservation of two infant temperaments into adolescence.
        Monogr Soc Res Child Dev. 2007; 72: 1-75
        • Biederman J.
        • Rosenbaum J.F.
        • Bolduc-Murphy E.A.
        • Faraone S.V.
        • Chaloff J.
        • Hirshfeld D.R.
        • et al.
        A 3-year follow-up of children with and without behavioral inhibition.
        J Am Acad Child Adolesc Psychiatry. 1993; 32: 814-821
        • Schwartz C.E.
        • Snidman N.
        • Kagan J.
        Adolescent social anxiety as an outcome of inhibited temperament in childhood.
        J Am Acad Child Adolesc Psychiatry. 1999; 38: 1008-1015
        • Degnan K.A.
        • Fox N.A.
        Behavioral inhibition and anxiety disorders: Multiple levels of resilience process.
        Dev Psychopathol. 2007; 19: 729-746
        • Degnan K.A.
        • Almas A.N.
        • Fox N.A.
        Temperament and the environment in the etiology of childhood anxiety.
        J Child Psychol Psychiatry. 2010; 51: 497-517
        • Perez-Edgar K.
        • Fox N.A.
        Temperament and anxiety disorders.
        Child Adolesc Psychiatric Clin N Am. 2005; 14: 681-706
        • Kagan J.
        • Reznick J.S.
        • Snidman N.
        The physiology and psychology of behavioral inhibition in children.
        Child Dev. 1987; 58: 1459-1473
        • Kagan J.
        • Reznick J.S.
        • Snidman N.
        Biological bases of childhood shyness.
        Science. 1988; 240: 167-171
        • Gunnar M.
        Psychoendocrine studies of temperament and stress in early childhood: Expanding current models.
        in: Bates J.E. Temperament: Individual Differences at the Interface of Biology and Behavior. American Psychological Association, Washington, DC1994: 175-198
        • Kalin N.H.
        • Shelton S.E.
        • Rickman M.
        • Davidson R.J.
        Individual differences in freezing and cortisol in infant and mother rhesus monkeys.
        Behav Neurosci. 1998; 112: 1-4
        • Kalin N.H.
        • Larson C.
        • Shelton S.E.
        • Davidson R.J.
        Asymmetric frontal brain activity, cortisol, and behavior associated with fearful temperament in rhesus monkeys.
        Behav Neurosci. 1998; 112: 286-292
        • Cavigelli S.A.
        • McClintock M.K.
        Fear of novelty in infant rats predicts adult corticosterone dynamics and an early death.
        Proc Natl Acad Sci U S A. 2003; 100: 16131-16136
        • Cavigelli S.A.
        • Stine M.M.
        • Kovacsics C.
        • Jefferson A.
        • Diep M.N.
        • Barrett C.E.
        Behavioral inhibition and glucocorticoid dynamics in a rodent model.
        Physiol Behav. 2007; 92: 897-905
        • Denenberg V.H.
        Critical periods, stimulus input, and emotional reactivity: A theory of infantile stimulation.
        Psychol Rev. 1964; 71: 335-351
        • Denenberg V.H.
        Open field behavior in the rat: What does it mean?.
        Ann N Y Acad Sci. 1969; 159: 852-859
        • Denenberg V.
        • Garbanati J.
        • Sherman G.
        • Yutzey D.
        • Kaplan R.
        Infantile stimulation induces brain lateralization in rats.
        Science. 1978; 201: 1150-1152
        • Russell P.
        Infantile stimulation in rodents: A consideration of possible mechanisms.
        Psychol Bull. 1971; 75: 192-202
        • Daly M.
        Early stimulation of rodents: A critical review of present interpretations.
        Br J Psychol. 1973; 64: 435-460
        • Tang A.C.
        Neonatal exposure to novel environment enhances hippocampal-dependent memory function during infancy and adulthood.
        Learn Mem. 2001; 8: 257-264
        • Reeb-Sutherland B.C.
        • Tang A.C.
        Dissociation between neonatal novelty-induced preferential maternal care and enhancement in cognitive, social, and emotional functions.
        Behav Brain Res. 2011; 224: 318-325
        • Tang A.C.
        • Akers K.G.
        • Reeb B.C.
        • Romeo R.D.
        • McEwen B.S.
        Programming social, cognitive, and neuroendocrine development by early exposure to novelty.
        Proc Natl Acad Sci U S A. 2006; 103: 15716-15721
        • Smotherman W.P.
        Mother-infant interaction and the modulation of pituitary-adrenal activity in rat pups after early stimulation.
        Dev Psychobiol. 1983; 16: 169-176
        • Denenberg V.H.
        • Brumaghim J.T.
        • Haltmeyer G.C.
        • Zarrow M.X.
        Increased adrenocortical activity in the neonatal rat following handling.
        Endocrinology. 1967; 81: 1047-1052
        • Catalani A.
        • Alemà G.S.
        • Cinque C.
        • Zuena A.R.
        • Casolini P.
        Maternal corticosterone effects on hypothalamus-pituitary-adrenal axis regulation and behavior of the offspring in rodents.
        Neurosci Biobehav Rev. 2011; 35: 1502-1517
        • Macrì S.
        • Zoratto F.
        • Laviola G.
        Early-stress regulates resilience, vulnerability and experimental validity in laboratory rodents through mother-offspring hormonal transfer.
        Neurosci Biobehav Rev. 2011; 35: 1534-1543
        • Tang A.C.
        • Reeb B.C.
        • Romeo R.D.
        • McEwen B.S.
        Modification of social memory, hypothalamic-pituitary-adrenal axis, and brain asymmetry by neonatal novelty exposure.
        J Neurosci. 2003; 23: 8254-8260
        • Tang A.C.
        • Reeb-Sutherland B.C.
        • Yang Z.
        • Romeo R.D.
        • McEwen B.S.
        Neonatal novelty-induced persistent enhancement in offspring spatial memory and the modulatory role of maternal self-stress regulation.
        J Neurosci. 2011; 31: 5348-5352
        • Tang A.C.
        • Nakazawa M.
        • Reeb B.C.
        Neonatal novelty exposure affects sex difference in open field disinhibition.
        Neuroreport. 2003; 14: 1553-1556
        • Lyons D.M.
        • Parker K.J.
        • Schatzberg A.F.
        Animal models of early life stress: Implications for understanding resilience.
        Dev Psychobiol. 2010; 52: 402-410
        • Fox N.A.
        • Henderson H.A.
        • Rubin K.H.
        • Calkins S.D.
        • Schmidt L.A.
        Continuity and discontinuity of behavioral inhibition and exuberance: Psychophysiological and behavioral influences across the first four years of life.
        Child Dev. 2001; 72: 1-21
        • McCall R.B.
        • Van Ijzendoorn M.H.
        • Juffer F.
        • Groark C.J.
        • Groza V.K.
        Children without permanent parents: Research, practice, and policy.
        Monographs of the Society for Research in Child Development. Wiley, Boston2011
        • Macrì S.
        • Würbel H.
        Developmental plasticity of HPA and fear responses in rats: A critical review of the maternal mediation hypothesis.
        Horm Behav. 2006; 50: 667-680
        • Cameron N.M.
        • Shahrokh D.
        • Del Corpo A.
        • Dhir S.K.
        • Szyf M.
        • Champagne F.A.
        • et al.
        Epigenetic programming of phenotypic variations in reproductive strategies in the rat through maternal care.
        J Neuroendocrinol. 2008; 20: 795-801
        • Meaney M.J.
        Epigenetics and the biological definition of gene x environment interactions.
        Child Dev. 2010; 81: 41-79
        • Zhang T.Y.
        • Meaney M.J.
        Epigenetics and the environmental regulation of the genome and its function.
        Annu Reve Psychol. 2010; 61: 439-466
        • Bagot R.C.
        • Meaney M.J.
        Epigenetics and the biological basis of gene x environment interactions.
        J Am Acad Child Adolesc Psychiatry. 2010; 49: 752-771
        • Tang A.C.
        • Yang Z.
        • Reeb-Sutherland B.C.
        • Romeo R.D.
        • McEwen B.S.
        Maternal modulation of novelty effects on physical development.
        Proc Natl Acad Sci U S A. 2012; 109: 2120-2125
        • Reeb-Sutherland B.C.
        • Tang A.C.
        Functional specificity in the modulation of novelty exposure effects by reliability of maternal care.
        Behav Br Res. 2012; 226: 345-350
        • Levine S.
        Plasma-free corticosteroid response to electric shock in rats stimulated in infancy.
        Science. 1962; 135: 795-796
        • Sapolsky R.
        Stress in the wild.
        Sci Am. 1990; 262: 116-123
        • Sapolsky R.M.
        Endocrinology al fresco: Psychoneuroendocrinology of wild baboons.
        Recent Prog Horm Res. 1991; 48: 437-467
        • Rose R.M.
        • Jenkins C.D.
        • Hurst M.
        • Livingston L.
        • Hall R.P.
        Endocrine activity in air traffic controllers at work.
        Psychoneuroendocrinology. 1982; 7: 101-111
        • Rose R.M.
        • Jenkins C.D.
        • Hurst M.
        • Herd J.A.
        • Hall R.P.
        Endocrine activity in air traffic controllers at work.
        Psychoneuroendocrinology. 1982; 7: 113-123
        • Rose R.M.
        • Jenkins C.D.
        • Hurst M.
        • Kreger B.E.
        • Barrett J.
        • Hall R.P.
        Endocrine activity in air traffic controllers at work.
        Psychoneuroendocrinology. 1982; 7: 125-134
        • Marquez C.
        • Nadal R.
        • Armario A.
        Responsiveness of the hypothalamic-pituitary-adrenal axis to different novel environments is a consistent individual trait in adult male outbred rats.
        Psychoneuroendocrinology. 2005; 30: 179-187
        • Tang A.C.
        • Jiang H.
        • Yang Z.
        • Zhang Y.
        • Romeo R.D.
        • McEwen B.S.
        Converging influence of neonatal novelty experience and maternal self-stress regulation on the plasticity of offspring acoustic startle response latency.
        Behav Brain Res. 2011; 221: 253-260
        • Walsh R.N.
        • Cummins R.A.
        The open-field test: A critical review.
        Psychol Bull. 1976; 83: 482-502
        • Whimbey A.E.
        • Denenberg V.H.
        Two independent behavioral dimensions in open-field performance.
        J Comp Physiol Psychol. 1967; 63: 500-504
        • Bokhorst C.L.
        • Bakermans-Kranenburg M.J.
        • Fearon R.M.P.
        • van Ijzendoorn M.H.
        • Fonagy P.
        • Schuengel C.
        The importance of shared environment in mother-infant attachment security: A behavioral genetic study.
        Child Dev. 2003; 74: 1769-1782
        • Kalin N.H.
        • Shelton S.E.
        Defensive behaviors in infant rhesus monkeys: Environmental cues and neurochemical regulation.
        Science. 1989; 243: 1718-1721
        • Kalin N.H.
        • Shelton S.E.
        • Takahashi L.K.
        Defensive behaviors in infant rhesus monkeys: Ontogeny and context-dependent selective expression.
        Child Dev. 1991; 62: 1175-1183
        • Lyons D.M.
        • Macrì S.
        Resilience and adaptive aspects of stress in neurobehavioral development.
        Neurosci Biobehav Rev. 2011; 35: 1451
        • Stern J.M.
        Offspring-induced nurturance: Animal-human parallels.
        Dev Psychobiol. 1998; 31: 19-37
        • Barnett S.A.
        • Burn J.
        Early stimulation and maternal behaviour.
        Nature. 1967; 213: 150-152
        • Lee M.H.S.
        • Williams D.I.
        Changes in licking behavior of rat mother following handling of young.
        Anim Behav. 1974; 22: 679-681
        • Levine S.
        The potential influence of infantile stimulation on emotional disorders.
        in: Levi L. Society, Stress and Disease. Oxford University Press, London1975: 411-415
        • Smotherman W.P.
        • Bell R.W.
        Maternal mediation of early experience.
        in: Bell R.W. Smotherman W.P. Maternal Influences and Early Behavior. Spectrum, New York1980: 201-210
        • Liu D.
        • Diorio J.
        • Tannenbaum B.
        • Caldji C.
        • Francis D.
        • Freedman A.
        • et al.
        Maternal care, hippocampal glucocorticoid receptor gene expression and hypothalamic-pituitary-adrenal responses to stress.
        Science. 1997; 277: 1659-1662
        • Denenberg V.H.
        Commentary: Is maternal stimulation the mediator of the handling effect in infancy?.
        Dev Psychobiol. 1999; 34: 1-3
        • Pryce C.R.
        • Feldon J.
        Long-term neurobehavioral impact of the postnatal environment in rats: Manipulations, effects, and mediating mechanisms.
        Neurosci Biobehav Rev. 2003; 27: 57-71
        • Ragan C.M.
        • Loken E.
        • Stifter C.A.
        • Cavigelli S.A.
        Within-litter variance in early pup-mother interactions and adult offspring responses to novelty.
        Dev Psychobiol. 2012; 54: 199-206
        • Parker K.J.
        • Buckmaster C.L.
        • Sundlass K.
        • Schatzberg A.F.
        • Lyons D.M.
        Maternal mediation, stress inoculation, and the development of neuroendocrine stress resistance in primates.
        Proc Natl Acad Sci U S A. 2006; 103: 3000-3005
        • Stanton M.E.
        • Wallstrom J.
        • Levine S.
        Maternal contact inhibits pituitary-adrenal stress responses in preweanling rats.
        Dev Psychobiol. 1987; 20: 131-145
        • Moriceau S.
        • Sullivan R.M.
        Maternal presence serves as a switch between learning fear and attraction in infancy.
        Nat Neurosci. 2006; 9: 1004-1006
        • Akers K.G.
        • Yang Z.
        • DelVecchio D.P.
        • Reeb B.C.
        • Romeo R.D.
        • McEwen B.S.
        • et al.
        Social competitiveness and plasticity of neuroendocrine function in old age: Influence of neonatal novelty exposure and maternal care reliability.
        PLoS ONE. 2008; 7: e2840
        • Benetti F.
        • Andrade de Araujo P.
        • Sanvitto G.L.
        • Lucion A.B.
        Effects of neonatal novelty exposure on sexual behavior, fear, and stress-response in adult rats.
        Dev Psychobiol. 2007; 49: 258-264
        • Essex M.J.
        • Klein M.H.
        • Cho E.
        • Kalin N.H.
        Maternal stress beginning in infancy may sensitize children to later stress exposure: Effects on cortisol and behavior.
        Biol Psychiatry. 2002; 52: 776-784
        • Lupien S.J.
        • Parent S.
        • Evans A.C.
        • Tremblay R.E.
        • Zelazo P.D.
        • Corbo V.
        • et al.
        Larger amygdala but no change in hippocampal volume in 10-year-old children exposed to maternal depressive symptomatology since birth.
        Proc Natl Acad Sci U S A. 2011; 108: 14324-14329
        • Thelen E.
        • Smith L.B.
        A Dynamic Systems Approach to the Development of Cognition and Action.
        MIT Press, Cambridge, MA1994
        • Boyce W.T.
        • Ellis B.J.
        Biological sensitivity to context: I.
        Dev Neuropsychol. 2005; 17: 271-301
        • Mischel W.
        From personality and assessment (1968) to personality science.
        J Res Pers. 2009; 43: 282-290
        • Harlow H.F.
        • Zimmerman R.
        Affectional responses in the infant monkey.
        Science. 1959; 130: 421-432
        • Harlow H.F.
        • Dodsworth R.O.
        • Harlow M.K.
        Total social isolation in monkeys.
        Proc Natl Acad Sci U S A. 1965; 54: 90-97
        • Sanchez M.M.
        • Ladd C.O.
        • Plotsky P.M.
        Early adverse experience as a developmental risk factor for later psychopathology: Evidence from rodent and primate models.
        Dev Psychopathol. 2001; 13: 419-449
        • Stevens H.E.
        • Leckman J.F.
        • Coplan J.D.
        • Suomi S.J.
        Risk and resilience: Early manipulation of macaque social experience and persistent behavioral and neurophysiological outcomes.
        J Am Acad Child Adolesc Psychiatry. 2009; 48: 114-127
        • Bowlby J.
        Ethological light on psychoanalytical problems.
        in: Bateson P. The Development and Integration of Behaviour: Essays in Honour of Robert Hinde. Cambridge University Press, London1991: 301-313
        • Bowlby J.
        Attachment and Loss.
        Basic Books, New York1969
        • Ainsworth M.D.S.
        • Blehar M.C.
        • Waters E.
        • Wall S.
        Patterns of Attachment: A Psychological Study of the Strange Situation.
        Lawrence Erlbaum, Hillsdale, NJ1978
        • Champagne F.C.
        • Francis D.D.
        • Mar A.
        • Meaney M.J.
        Variations in maternal care in the rat as a mediating influence for the effects of environment on development.
        Physiol Behav. 2003; 79: 359-371
        • Glover V.
        • O'Connor T.G.
        • O'Donnell K.
        Prenatal stress and the programming of the HPA axis.
        Neurosci Biobehav Rev. 2010; 35: 17-22
        • Gunnar M.R.
        • Kryzer E.
        • Van Ryzin M.J.
        • Phillips D.A.
        The rise in cortisol in family day care: Associations with aspects of care quality, child behavior, and child sex.
        Child Dev. 2010; 81: 851-869
        • Stevenson-Hinde J.
        On the interplay between attachment, temperament, and maternal style.
        in: Grossman K.E. Grossman K. Waters E. The Power and Dynamics of Longitudinal Attachment Research. Guilford Press, New York2005: 198-222
        • Kagan J.
        • Snidman N.
        Infant predictors of inhibited and uninhibited profiles.
        Psych Sci. 1991; 2: 40-44
        • Calkins S.D.
        • Fox N.A.
        • Marshall T.R.
        Behavioral and physiological antecedants of inhibited and uninhibited behavior.
        Child Dev. 1996; 67: 523-540
        • Moehler E.
        • Kagan J.
        • Parzer P.
        • Brunner R.
        • Reck C.
        • Wiebel A.
        • et al.
        Childhood behavioral inhibition and maternal symptoms of depression.
        Psychopathology. 2007; 40: 446-452
        • Lupien S.J.
        • King S.
        • Meaney M.J.
        • McEwen B.S.
        Child's stress hormone levels correlate with mother's socioeconomic status and depressive state.
        Biol Psychiatry. 2000; 48: 976-980
        • Volbrecht M.M.
        • Goldsmith H.H.
        Early tempermental and family predictors of shyness and anxiety.
        Dev Psychol. 2010; 46: 1192-1205
        • Sumner M.M.
        • Bernard K.
        • Dozier M.
        Young children's full-day patterns of cortisol production on child care days.
        Arch Pediatr Adolesc Med. 2010; 164: 567-571
        • Hinde R.A.
        Some implications of evolutionary theory and comparative data for the study of human prosocial and aggressive behavior.
        in: Olweus D. Block J. Radke-Yarrow M. Development of Anti-Social and Prosocial Behaviour. Academic Press, Orlando, FL1986: 13-32
        • Kessler R.C.
        • Berglund P.
        • Demler O.
        • Jin R.
        • Merikangas K.R.
        • Walters E.E.
        Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 593-602
        • Greenberg P.E.
        • Sisitsky T.
        • Kessler R.C.
        • Finkelstein S.N.
        • Berndt E.R.
        • Davidson J.R.
        • et al.
        The economic burden of anxiety disorders in the 1990s.
        J Clin Psychiatry. 1999; 60: 427-435