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Immune and neuroendocrine correlates of temperament in infancy

  • Thomas G. O'Connor (a1), Kristin Scheible (a1), Ana Vallejo Sefair (a1), Michelle Gilchrist (a2), Emma Robertson Blackmore (a1), Marcia A. Winter (a3), Megan R. Gunnar (a4), Claire Wyman (a1), Jennifer Carnahan (a1), Jan A. Moynihan (a1) and Mary T. Caserta (a1)...


There is now a clear focus on incorporating, and integrating, multiple levels of analysis in developmental science. The current study adds to research in this area by including markers of the immune and neuroendocrine systems in a longitudinal study of temperament in infants. Observational and parent-reported ratings of infant temperament, serum markers of the innate immune system, and cortisol reactivity from repeated salivary collections were examined in a sample of 123 infants who were assessed at 6 months and again when they were, on average, 17 months old. Blood from venipuncture was collected for analyses of nine select innate immune cytokines; salivary cortisol collected prior to and 15 min and 30 min following a physical exam including blood draw was used as an index of neuroendocrine functioning. Analyses indicated fairly minimal significant associations between biological markers and temperament at 6 months. However, by 17 months of age, we found reliable and nonoverlapping associations between observed fearful temperament and biological markers of the immune and neuroendocrine systems. The findings provide some of the earliest evidence of robust biological correlates of fear behavior with the immune system, and identify possible immune and neuroendocrine mechanisms for understanding the origins of behavioral development.


Corresponding author

Address correspondence and reprint requests to: Thomas G. O'Connor, Wynne Center for Family Research, Department of Psychiatry, University of Rochester Medical Center, 300 Crittenden Boulevard, Rochester, NY 14642; E-mail:


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We thank Suzanne Coglitore, Carol Ferro, Mary Harper, Bridget O'Connor, Bridget Szczypinski, and the staff at the Clinical Research Center for their assistance with the study, and the mothers and babies who participated. The Thoughts, Emotions, and Mood in Pregnancy study was funded by National Institute of Health Grant MH073019; support was also provided by NIH Grants MH529173, K23MH080290, and K99HD070953. Additional support was provided through the Clinical Research Center from UL1 RR 024160 from the National Center for Research Resources, a component of the NIH, and the NIH Roadmap for Medical Research. Study contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or the NIH. All authors declare that there are no conflicts of interest.



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Ader, R. (1983). Developmental psychoneuroimmunology. Developmental Psychobiology, 16, 251267. doi:10.1002/dev.420160402
Ader, R., & Cohen, N. (1975). Behaviorally conditioned immunosuppression. Psychosomatic Medicine, 37, 333340.
Ahnert, L., Gunnar, M. R., Lamb, M. E., & Barthel, M. (2004). Transition to child care: Associations with infant-mother attachment, infant negative emotion, and cortisol elevations. Child Development, 75, 639650. doi:10.1111/j.1467-8624.2004.00698.x
Al-Ayadhi, L. Y., & Mostafa, G. A. (2012). Elevated serum levels of interleukin-17A in children with autism. Journal of Neuroinflammation, 9, 158. doi:10.1186/1742-2094-9-158
Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I. N., & Van de Water, J. (2011). Altered T cell responses in children with autism. Brain, Behavior, and Immunity, 25, 840849. doi:10.1016/j.bbi.2010.09.002
Avitsur, R., Stark, J. L., & Sheridan, J. F. (2001). Social stress induces glucocorticoid resistance in subordinate animals. Hormones and Behavior, 39, 247257. doi:10.1006/hbeh.2001.1653 S0018-506X(01)91653-8
Behar, E., Alcaine, O., Zuellig, A. R., & Borkovec, T. D. (2003). Screening for generalized anxiety disorder using the Penn State Worry Questionnaire: A receiver operating characteristic analysis. Journal of Behavior Therapy and Experimental Psychiatry, 34, 2543.
Bergman, K., Sarkar, P., Glover, V., & O'Connor, T. G. (2008). Quality of child-parent attachment moderates the impact of antenatal stress on child fearfulness. Journal of Child Psychology and Psychiatry, 49, 10891098. doi:10.1111/j.1469-7610.2008.01987.x
Bergman, K., Sarkar, P., Glover, V., & O'Connor, T. G. (2010). Maternal prenatal cortisol and infant cognitive development: Moderation by infant-mother attachment. Biological Psychiatry, 67, 10261032. doi:10.1016/j.biopsych.2010.01.002
Bergman, K., Sarkar, P., O'Connor, T. G., Modi, N., & Glover, V. (2007). Maternal stress during pregnancy predicts cognitive ability and fearfulness in infancy. Journal of the American Academy of Child & Adolescent Psychiatry, 46, 14541463. doi:10.1097/chi.0b013e31814a62f6 00004583-200711000-00007
Brooks, A. K., Janda, T. M., Lawson, M. A., Rytych, J. L., Smith, R. A., Ocampo-Solis, C., & McCusker, R. H. (2017). Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases. Brain Behavior and Immunity, 62, 219229. doi:10.1016/j.bbi.2017.02.010
Brooks, A. K., Lawson, M. A., Smith, R. A., Janda, T. M., Kelley, K. W., & McCusker, R. H. (2016). Interactions between inflammatory mediators and corticosteroids regulate transcription of genes within the Kynurenine Pathway in the mouse hippocampus. Journal of Neuroinflammation, 13, 98. doi:10.1186/s12974-016-0563-1
Buss, K. A., Davidson, R. J., Kalin, N. H., & Goldsmith, H. H. (2004). Context-specific freezing and associated physiological reactivity as a dysregulated fear response. Developmental Psychology, 40, 583594. doi:10.1037/0012-1649.40.4.583
Chapman, B. P., Khan, A., Harper, M., Stockman, D., Fiscella, K., Walton, J., … Moynihan, J. (2009). Gender, race/ethnicity, personality, and interleukin-6 in urban primary care patients. Brain, Behavior, and Immunity, 23, 636642. doi:10.1016/j.bbi.2008.12.009
Cicchetti, D., & Blender, J. A. (2006). A multiple-levels-of-analysis perspective on resilience: Implications for the developing brain, neural plasticity, and preventive interventions. Annals of the New York Academy of Sciences, 1094, 248258. doi:10.1196/annals.1376.029
Clifford, S., Lemery-Chalfant, K., & Goldsmith, H. H. (2015). The unique and shared genetic and environmental contributions to fear, anger, and sadness in childhood. Child Development, 86, 15381556. doi:10.1111/cdev.12394
Coe, C. L. (1996). Developmental psychoneuroimmunology revisited. Brain, Behavior, and Immunity, 10, 185187.
Colder, C. R., Mott, J. A., & Berman, A. S. (2002). The interactive effects of infant activity level and fear on growth trajectories of early childhood behavior problems. Development and Psychopathology, 14, 123.
Cunningham, C. L., Martinez-Cerdeno, V., & Noctor, S. C. (2013). Microglia regulate the number of neural precursor cells in the developing cerebral cortex. Journal of Neuroscience, 33, 42164233. doi:10.1523/Jneurosci.3441-12.2013
Davis, E. P., Glynn, L. M., Schetter, C. D., Hobel, C., Chicz-Demet, A., & Sandman, C. A. (2007). Prenatal exposure to maternal depression and cortisol influences infant temperament. Journal of the American Academy of Child & Adolescent Psychiatry, 46, 737746. doi:10.1097/chi.0b013e318047b775 S0890-8567(09)62153-5
Enlow, M. B., White, M. T., Hails, K., Cabrera, I., & Wright, R. J. (2016). The Infant Behavior Questionnaire—Revised: Factor structure in a culturally and sociodemographically diverse sample in the United States. Infant Behavior and Development, 43, 2435.
Finegood, E. D., Wyman, C., O'Connor, T. G., Blair, C. B., & Family Life Project Investigators. (2017). Salivary cortisol and cognitive development in infants from low-income communities. Stress, 20, 112121. doi:10.1080/10253890.2017.1286325
Fortunato, C. K., Dribin, A. E., Granger, D. A., & Buss, K. A. (2008). Salivary alpha-amylase and cortisol in toddlers: Differential relations to affective behavior. Developmental Psychobiology, 50, 807818. doi:10.1002/dev.20326
Fox, N. A., Henderson, H. A., Rubin, K. H., Calkins, S. D., & Schmidt, L. A. (2001). Continuity and discontinuity of behavioral inhibition and exuberance: Psychophysiological and behavioral influences across the first four years of life. Child Development, 72, 121.
Friedman, E. M., Karlamangla, A. S., Almeida, D. M., & Seeman, T. E. (2012). Social strain and cortisol regulation in midlife in the US. Social Science & Medicine, 74, 607615. doi:10.1016/j.socscimed.2011.11.003
Fuertig, R., Azzinnari, D., Bergamini, G., Cathomas, F., Sigrist, H., Seifritz, E., … Pryce, C. R. (2016). Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase. Brain Behavior and Immunity, 54, 5972. doi:10.1016/j.bbi.2015.12.020
Gagne, J. R., Van Hulle, C. A., Aksan, N., Essex, M. J., & Goldsmith, H. H. (2011). Deriving childhood temperament measures from emotion-eliciting behavioral episodes: Scale construction and initial validation. Psychological Assessment, 23, 337353. doi:10.1037/a0021746
Gartstein, M. A., & Rothbart, M. K. (2003). Studying infant temperament via the Revised Infant Behavior Questionnaire. Infant Behavior and Development, 26, 6486.
Goldsmith, H. H., & Rothbart, M. K. (1999). The Laboratory Temperament Assessment Battery Locomotor (Version 3.1) description of procedures. Madison, WI: University of Wisconsin Press.
Granger, D. A., Blair, C., Willoughby, M., Kivlighan, K. T., Hibel, L. C., Fortunato, C. K., & Wiegand, L. E. (2007). Individual differences in salivary cortisol and alpha-amylase in mothers and their infants: Relation to tobacco smoke exposure. Developmental Psychobiology, 49, 692701. doi:10.1002/dev.20247
Gunnar, M. R., Brodersen, L., Nachmias, M., Buss, K., & Rigatuso, J. (1996). Stress reactivity and attachment security. Developmental Psychobiology, 29, 191204. doi:10.1002/(sici)1098-2302(199604)29:3<191::aid-dev1>;2-m
Gunnar, M. R., Larson, M. C., Hertsgaard, L., Harris, M. L., & Brodersen, L. (1992). The stressfulness of separation among nine-month-old infants: Effects of social context variables and infant temperament. Child Development, 63, 290303.
Gunnar, M. R., & Nelson, C. A. (1994). Event-related potentials in year-old infants: Relations with emotionality and cortisol. Child Development, 65, 8094.
Heim, C., Newport, D. J., Mletzko, T., Miller, A. H., & Nemeroff, C. B. (2008). The link between childhood trauma and depression: Insights from HPA axis studies in humans. Psychoneuroendocrinology, 33, 693710. doi:10.1016/j.psyneuen.2008.03.008
Howren, M. B., Lamkin, D. M., & Suls, J. (2009). Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis. Psychosomatic Medicine, 71, 171186. doi:10.1097/psy.0b013e3181907c1b
Huizink, A. C., de Medina, P. G., Mulder, E. J., Visser, G. H., & Buitelaar, J. K. (2002). Psychological measures of prenatal stress as predictors of infant temperament. Journal of the American Academy of Child & Adolescent Psychiatry, 41, 10781085.
Jones, S. P., Franco, N. F., Varney, B., Sundaram, G., Brown, D. A., de Bie, J., … Brew, B. J. (2015). Expression of the kynurenine pathway in human peripheral blood mononuclear cells: Implications for inflammatory and neurodegenerative disease. PLOS ONE, 10, e0131389. doi:10.1371/journal.pone.0131389
Kagan, J., Reznick, J. S., & Snidman, N. (1987). The physiology and psychology of behavioral inhibition in children. Child Development, 58, 14591473.
Kiel, E. J., & Kalomiris, A. E. (2016). Correlates and consequences of toddler cortisol reactivity to fear. Journal of Experimental Child Psychology, 142, 400413. doi:10.1016/j.jecp.2015.08.006
Kochanska, G., Coy, K. C., Tjebkes, T. L., & Husarek, S. J. (1998). Individual differences in emotionality in infancy. Child Development, 69, 375390.
Landers, M. S., & Sullivan, R. M. (2012). The development and neurobiology of infant attachment and fear. Developmental Neuroscience, 34, 101114. doi:10.2012/000336732
Laurent, H. K., Harold, G. T., Leve, L., Shelton, K. H., & Van Goozen, S. H. (2016). Understanding the unfolding of stress regulation in infants. Development and Psychopathology, 28, 14311440. doi:10.1017/S0954579416000171
Lewis, M., Ramsay, D. S., & Sullivan, M. W. (2006). The relation of ANS and HPA activation to infant anger and sadness response to goal blockage. Developmental Psychobiology, 48, 397405. doi:10.1002/dev.20151
Loucks, E. B., Berkman, L. F., Gruenewald, T. L., & Seeman, T. E. (2006). Relation of social integration to inflammatory marker concentrations in men and women 70 to 79 years. American Journal of Cardiology, 97, 10101016. doi:10.1016/j.amjcard.2005.10.043
Lusby, C. M., Goodman, S. H., Yeung, E. W., Bell, M. A., & Stowe, Z. N. (2016). Infant EEG and temperament negative affectivity: Coherence of vulnerabilities to mothers’ perinatal depression. Development and Psychopathology, 28, 895911. doi:10.1017/S0954579416000614
Lynch, M., Manly, J. T., & Cicchetti, D. (2015). A multilevel prediction of physiological response to challenge: Interactions among child maltreatment, neighborhood crime, endothelial nitric oxide synthase gene (eNOS), and GABA(A) receptor subunit alpha-6 gene (GABRA6). Development and Psychopathology, 27, 14711487. doi:10.1017/S0954579415000887
Mastorakos, G., Chrousos, G. P., & Weber, J. S. (1993). Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. Journal of Clinical Endocrinology and Metabolism, 77, 16901694. doi:10.1210/jcem.77.6.8263159
Meyer, T. J., Miller, M. L., Metzger, R. L., & Borkovec, T. D. (1990). Development and validation of the Penn State Worry Questionnaire. Behavioral Research and Therapy, 28, 487495. doi:10.1990/0005-7967(90)90135-6
Miller, G. E., Gaudin, A., Zysk, E., & Chen, E. (2009). Parental support and cytokine activity in childhood asthma: The role of glucocorticoid sensitivity. Journal of Allergy and Clinical Immunology, 123, 824830. doi:10.1016/j.jaci.2008.12.019
Mills, N. T., Scott, J. G., Wray, N. R., Cohen-Woods, S., & Baune, B. T. (2013). Research review: The role of cytokines in depression in adolescents: A systematic review. Journal of Child Psychology and Psychiatry, 54, 816835.
Mills-Koonce, W. R., Wagner, N. J., Willoughby, M. T., Stifter, C., Blair, C., Granger, D. A., & Family Life Project Key Investigators. (2015). Greater fear reactivity and psychophysiological hyperactivity among infants with later conduct problems and callous-unemotional traits. Journal of Child Psychology and Psychiatry, 56, 147154. doi:10.1111/jcpp.12289
O'Connor, T. G., Moynihan, J. A., & Caserta, M. T. (2014). Annual Research Review: The neuroinflammation hypothesis for stress and psychopathology in children—Developmental psychoneuroimmunology. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 55, 615631. doi:10.1111/jcpp.12187
O'Connor, T. G., Moynihan, J. A., Wyman, P. A., Carnahan, J., Lofthus, G., Quataert, S. A., … Caserta, M. T. (2014). Depressive symptoms and immune response to meningococcal conjugate vaccine in early adolescence. Development and Psychopathology, 26, 15671576. doi:10.1017/S0954579414001242
O'Connor, T. G., Winter, M. A., Hunn, J., Carnahan, J., Pressman, E. K., Glover, V., … Caserta, M. T. (2013). Prenatal maternal anxiety predicts reduced adaptive immunity in infants. Brain, Behavior, and Immunity, 32, 2128. doi:10.1016/j.bbi.2013.02.002
O'Donnell, K. J., Glover, V., Lahti, J., Lahti, M., Edgar, R. D., Raikkonen, K., & O'Connor, T. G. (2017). Maternal prenatal anxiety and child COMT genotype predict working memory and symptoms of ADHD. PLOS ONE, 12, e0177506. doi:10.1371/journal.pone.0177506
Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., … Gross, C. T. (2011). Synaptic pruning by microglia is necessary for normal brain development. Science, 333, 14561458. doi:10.1126/science.1202529
Pruessner, J. C., Kirschbaum, C., Meinlschmid, G., & Hellhammer, D. H. (2003). Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology, 28, 916931. doi:10.2003/S0306453002001087
Raison, C. L., Dantzer, R., Kelley, K. W., Lawson, M. A., Woolwine, B. J., Vogt, G., … Miller, A. H. (2010). CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: Relationship to CNS immune responses and depression. Molecular Psychiatry, 15, 393403. doi:10.1038/mp.2009.116
Raison, C. L., & Miller, A. H. (2011). Is depression an inflammatory disorder? Current Psychiatry Reports, 13, 467475. doi:10.1007/s11920-011-0232-0
Rothbart, M. K. (1988). Temperament and the development of inhibited approach. Child Development, 59, 12411250.
Rothbart, M. K., Derryberry, D., & Hershey, K. (2000). Stability of temperament in childhood: Laboratory infant assessment to parent report at seven years. In Molfese, V. J. & Molfese, D. L. (Eds.), Temperament and personality development across the lifespan (pp. 85119). Hillsdale, NJ: Erlbaum.
Sapolsky, R. M., Alberts, S. C., & Altmann, J. (1997). Hypercortisolism associated with social subordinance or social isolation among wild baboons. Archives of General Psychiatry, 54, 11371143.
Seeman, T., Epel, E., Gruenewald, T., Karlamangla, A., & McEwen, B. S. (2010). Socio-economic differentials in peripheral biology: Cumulative allostatic load. Annals of the New York Academy of Sciences, 1186, 223239. doi:10.1111/j.1749-6632.2009.05341.x
Seifer, R., Sameroff, A. J., Barrett, L. C., & Krafchuk, E. (1994). Infant temperament measured by multiple observations and mother report. Child Development, 65, 14781490.
Shenk, C. E., Griffin, A. M., & O'Donnell, K. J. (2015). Symptoms of major depressive disorder subsequent to child maltreatment: Examining change across multiple levels of analysis to identify transdiagnostic risk pathways. Development and Psychopathology, 27, 15031514. doi:10.1017/S0954579415000905
Slavich, G. M., & Irwin, M. R. (2014). From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. Psychological Bulletin, 140, 774815. doi:10.1037/a0035302
Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., … Barres, B. A. (2007). The classical complement cascade mediates CNS synapse elimination. Cell, 131, 11641178. doi:10.1016/j.cell.2007.10.036
Stifter, C. A., Willoughby, M. T., Towe-Goodman, N., & Family Life Project Key Investigators. (2008). Agree or agree to disagree? Assessing the convergence between parents and observers on infant temperament. Infant and Child Development, 17, 407426. doi:10.1002/icd.584
Sutin, A. R., Terracciano, A., Deiana, B., Naitza, S., Ferrucci, L., Uda, M., … Costa, P. T. Jr. (2010). High neuroticism and low conscientiousness are associated with interleukin-6. Psychological Medicine, 40, 14851493. doi:10.1017/S0033291709992029
Swedo, S. E. (2002). Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Molecular Psychiatry, 7(Suppl. 2), S24S25. doi:10.1038/
Talge, N. M., Donzella, B., & Gunnar, M. R. (2008). Fearful temperament and stress reactivity among preschool-aged children. Infant and Child Development, 17, 427445. doi:10.1002/icd.585
Tout, K., de Haan, M., Campbell, E. K., & Gunnar, M. R. (1998). Social behavior correlates of cortisol activity in child care: Gender differences and time-of-day effects. Child Development, 69, 12471262.
Vaughn, B. E., Bradley, C. F., Joffe, L. S., Seifer, R., & Barglow, P. (1987). Maternal characteristics measured prenatally are predictive of ratings of temperamental “difficulty” on the Carey Infant Questionnaire. Developmental Psychology, 23, 152161.
Waage, A., Slupphaug, G., & Shalaby, R. (1990). Glucocorticoids inhibit the production of IL6 from monocytes, endothelial cells and fibroblasts. European Journal of Immunology, 20, 24392443. doi:10.1002/eji.1830201112
Warren, S. L., Gunnar, M. R., Kagan, J., Anders, T. F., Simmens, S. J., Rones, M., … Sroufe, L. A. (2003). Maternal panic disorder: Infant temperament, neurophysiology, and parenting behaviors. Journal of the American Academy of Child & Adolescent Psychiatry, 42, 814825. doi:10.1097/01.CHI.0000046872.56865.02
Yirmiya, R., & Goshen, I. (2011). Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain, Behavior, and Immunity, 25, 181213. doi:10.1016/j.bbi.2010.10.015
Yirmiya, R., Pollak, Y., Morag, M., Reichenberg, A., Barak, O., Avitsur, R., … Pollmacher, T. (2000). Illness, cytokines, and depression. Annals of the New York Academy of Sciences, 917, 478487.
Zhu, C. B., Blakely, R. D., & Hewlett, W. A. (2006). The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology, 31, 21212131. doi:10.1038/sj.npp.1301029


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