Abstract
Rationale
Early-life stress (ELS) can increase anxiety, reduce prosocial behaviors, and impair brain regions that facilitate emotional and social development. This knowledge greatly stems from assessing disrupted mother–child relationships, while studies investigating the long-term effects of father-child relationships on behavioral development in children are scarce. However, available evidence suggests that fathers may uniquely influence a child’s behavioral development in a sex-specific manner. Rodent models examining mother–offspring interaction demonstrate relationships among ELS, neuroinflammatory mediators, and behavioral development; yet, the role paternal care may play in neuroimmune functioning remains unreported.
Objectives
Using the biparental California mouse (Peromyscus californicus), we examined to what extent paternal deprivation impairs social and anxiety-like behaviors, augments peripheral corticosterone (CORT) response, and alters central proinflammatory cytokine production following an acute stressor in adulthood.
Methods
Biparentally reared and paternally deprived (permanent removal of the sire 24 h post-birth) adult mice were assessed for sociability, preference for social novelty, social vigilance, and social avoidance behaviors, followed by novelty-suppressed feeding (NSF) testing for general anxiety-like behavior. Following an acute stressor, circulating CORT concentrations and region-specific proinflammatory cytokine concentrations were determined via radioimmunoassay and Luminex multianalyte analysis, respectively.
Results
In response to a novel same-sex conspecific, social vigilance behavior was associated with reduced sociability and increased avoidance in paternally deprived mice—an effect not observed in biparentally reared counterparts. Yet, in response to a familiar same-sex conspecific, social vigilance persisted but only in paternally deprived females. The latency to consume during NSF testing was not significantly altered by paternal deprivation. In response to an acute physical stressor, lower circulating CORT concentrations were observed in paternally deprived females. Compared to control-reared males, paternal deprivation increased hypothalamic interleukin-1β, but decreased hippocampal IL-6 protein concentration.
Conclusion
Greater social vigilance behavior was demonstrated in paternally deprived mice while they avoided social interaction with a novel same-sex conspecific; however, in response to a familiar same-sex conspecific, paternal deprivation increased social vigilance behavior but only in females. It is possible that different neurobiological mechanisms underlie these observed behavioral outcomes as sex-specific central proinflammatory cytokine and stress responsivity were observed in paternally deprived offspring.
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Data Availability
The authors are prepared to provide raw data from this publication, if ethically appropriate, to other investigators upon request.
References
Agarwal P, Palin N, Walker SL, Glasper ER (2020) Sex-dependent effects of paternal deprivation and chronic variable stress on novel object recognition in adult California mice (Peromyscus californicus). Horm Behav 117:104610. https://doi.org/10.1016/j.yhbeh.2019.104610
Ahern TH (2009) The impact of early life family structure on adult social attachment, alloparental behavior, and the neuropeptide systems regulating affiliative behaviors in the monogamous prairie vole (Microtus ochrogaster). Front Behav Neurosci 3:1–19. https://doi.org/10.3389/neuro.08.017.2009
Bales KL, Saltzman W (2016) Fathering in rodents: neurobiological substrates and consequences for offspring. Horm Behav 77:249–259. https://doi.org/10.1016/j.yhbeh.2015.05.021
Bambico FR, Lacoste B, Hattan PR, Gobbi G (2015) Father absence in the monogamous California mouse impairs social behavior and modifies dopamine and glutamate synapses in the medial prefrontal cortex. Cereb Cortex 25:1163–1175. https://doi.org/10.1093/cercor/bht310
Beery AK, Christensen JD, Lee NS, Blandino KL (2018) Specificity in sociality: mice and prairie voles exhibit different patterns of peer affiliation. Front Behav Neurosci. https://doi.org/10.3389/fnbeh.2018.00050
Beery AK, Shambaugh KL (2021) Comparative assessment of familiarity/novelty preferences in rodents. Front Behav Neurosci 15. https://doi.org/10.3389/fnbeh.2021.648830
Boulanger LM (2009) Immune proteins in brain development and synaptic plasticity. Neuron 64:93–109. https://doi.org/10.1016/J.NEURON.2009.09.001
Brydges NM, Reddaway J (2020) Neuroimmunological effects of early life experiences. Brain Neurosci Adv 4:239821282095370. https://doi.org/10.1177/2398212820953706
Cabrera NJ, Volling BL, Barr R (2018) Fathers are parents, too! Widening the lens on parenting for children’s development. Child Dev Perspect 12:152–157. https://doi.org/10.1111/cdep.12275
Carlton CN, Garcia KM, Sullivan-Toole H et al (2021) From childhood maltreatment to adult inflammation: Evidence for the mediational status of social anxiety and low positive affect. Brain Behav Immun Health 18:100366. https://doi.org/10.1016/J.BBIH.2021.100366
Carpenter LL, Gawuga CE, Tyrka AR et al (2010) Association between plasma IL-6 response to acute stress and early-life adversity in healthy adults. Neuropsychopharmacology. https://doi.org/10.1038/npp.2010.159
Chen NTM, Clarke PJF (2017) Gaze-based assessments of vigilance and avoidance in social anxiety: a review. Curr Psychiatry Rep 19(9):1–9. https://doi.org/10.1007/S11920-017-0808-4
Coelho R, Viola TW, Walss-Bass C et al (2014) Childhood maltreatment and inflammatory markers: asystematic review. Acta Psychiatr Scand 129:180–192. https://doi.org/10.1111/ACPS.12217
de Schultz T, Bock J, Braun K (2020) Paternal deprivation and female biparental family rearing induce dendritic and synaptic changes in Octodon degus: I. Medial prefrontal cortex. Front Synaptic Neurosci 12. https://doi.org/10.3389/fnsyn.2020.00038
Drude S, Geißler A, Olfe J et al (2011) Side effects of control treatment can conceal experimental data when studying stress responses to injection and psychological stress in mice. Lab Anim 40(4):119–128. https://doi.org/10.1038/laban0411-119
Dudley D (1974) Paternal behavior in the California mouse, Peromyscus californicus. Behav Biol 11:247–252. https://doi.org/10.1016/S0091-6773(74)90433-7
Dunn AJ (2006) Cytokine activation of the HPA axis. Ann N Y Acad Sci 917:608–617. https://doi.org/10.1111/j.1749-6632.2000.tb05426.x
Duque-Wilckens N, Torres LY, Yokoyama S et al (2020) Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance. Proc Natl Acad Sci USA 117:26406–26413. https://doi.org/10.1073/PNAS.2011890117/SUPPL_FILE/PNAS.2011890117.SM01.MP4
Fitzsimons E, Villadsen A (2019) Father departure and children’s mental health: how does timing matter? Soc Sci Med 222:349–358. https://doi.org/10.1016/J.SOCSCIMED.2018.11.008
Fries E, Hesse J, Hellhammer J, Hellhammer DH (2005) A new view on hypocortisolism. Psychoneuroendocrinology 30:1010–1016. https://doi.org/10.1016/j.psyneuen.2005.04.006
Gillera SEA, Marinello WP, Nelson MA et al (2022) Individual and combined effects of paternal deprivation and developmental exposure to Firemaster 550 on socio-emotional behavior in prairie voles. Toxics 10. https://doi.org/10.3390/TOXICS10050268
Glasper ER, Hyer MM, Hunter TJ (2018) Enduring effects of paternal deprivation in California mice (Peromyscus californicus): behavioral dysfunction and sex-dependent alterations in hippocampal new cell survival. Front Behav Neurosci 12:20. https://doi.org/10.3389/fnbeh.2018.00020
Gorka AX, Hanson JL, Radtke SR, Hariri AR (2014) Reduced hippocampal and medial prefrontal gray matter mediate the association between reported childhood maltreatment and trait anxiety in adulthood and predict sensitivity to future life stress. Biol Mood Anxiety Disord 4:1–10. https://doi.org/10.1186/2045-5380-4-12/FIGURES/6
Goshen I, Yirmiya R (2009) Interleukin-1 (IL-1): A central regulator of stress responses. Front Neuroendocrinol 30:30–45. https://doi.org/10.1016/J.YFRNE.2008.10.001
Grippo AJ, Scotti MAL (2013) Stress and neuroinflammation. Inflamm Psychiatry 28:20–32. https://doi.org/10.1159/000343965
Gubernick DJ, Alberts JR (1987) The biparental care system of the California mouse, Peromyscus californicus. J Comp Psychol 101:169–177. https://doi.org/10.1037/0735-7036.101.2.169
Harris BN, Saltzman W, de Jong TR, Milnes MR (2012) Hypothalamic-pituitary-adrenal (HPA) axis function in the California mouse (Peromyscus californicus): changes in baseline activity, reactivity, and fecal excretion of glucocorticoids across the diurnal cycle. Gen Comp Endocrinol 179:436. https://doi.org/10.1016/J.YGCEN.2012.08.026
Helmeke C, Seidel K, Poeggel G et al (2009) Paternal deprivation during infancy results in dendrite- and time-specific changes of dendritic development and spine formation in the orbitofrontal cortex of the biparental rodent Octodon degus. Neuroscience 163:790–798. https://doi.org/10.1016/j.neuroscience.2009.07.008
Himanshu D, Sarkar D, Nutan, (2020) A review of behavioral tests to evaluate different types of anxiety and anti-anxiety effects. Clin Psychopharmacol Neurosci 18:341. https://doi.org/10.9758/CPN.2020.18.3.341
Hodes GE, Pfau ML, Leboeuf M et al (2014) Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA 111:16136–16141. https://doi.org/10.1073/PNAS.1415191111/-/DCSUPPLEMENTAL
Jia R, Tai F, An S et al (2009) Effects of neonatal paternal deprivation or early deprivation on anxiety and social behaviors of the adults in mandarin voles. Behav Processes 82:271–278. https://doi.org/10.1016/j.beproc.2009.07.006
Kaidanovich-Beilin O, Lipina T, Vukobradovic I et al (2011) Assessment of social interaction behaviors. J Vis Exp 0:6–10. https://doi.org/10.3791/2473
Kentrop J, Kalamari A, Danesi CH et al (2020) Pro-social preference in an automated operant two-choice reward task under different housing conditions: exploratory studies on pro-social decision making. Dev Cogn Neurosci 45:100827
Kessler RC, McLaughlin KA, Green JG et al (2010) Childhood adversities and adult psychopathology in the WHO world mental health surveys. Br J Psychiatry. https://doi.org/10.1192/bjp.bp.110.080499
Khairova RA, MacHado-Vieira R, Du J, Manji HK (2009) A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol 12:561–578. https://doi.org/10.1017/S1461145709009924
Li M, D’Arcy C, Meng X (2016) Maltreatment in childhood substantially increases the risk of adult depression and anxiety in prospective cohort studies: systematic review, meta-analysis, and proportional attributable fractions. Psychol Med 46:717–730. https://doi.org/10.1017/S0033291715002743
Lumertz FS, Kestering-Ferreira E, Orso R et al (2022) Effects of early life stress on brain cytokines: a systematic review and meta-analysis of rodent studies. Neurosci Biobehav Rev 139:104746. https://doi.org/10.1016/J.NEUBIOREV.2022.104746
Luo PX, Zakharenkov HC, Torres LY et al (2022) Oxytocin receptor behavioral effects and cell types in the bed nucleus of the stria terminalis. Horm Behav 143:105203. https://doi.org/10.1016/J.YHBEH.2022.105203
Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445. https://doi.org/10.1038/nrn2639
Madison FN, Palin N, Whitaker A, Glasper ER (2022) Sex-specific effects of neonatal paternal deprivation on microglial cell density in adult California mouse (Peromyscus californicus) dentate gyrus. Brain Behav Immun 106:1–10. https://doi.org/10.1016/J.BBI.2022.07.161
Majcher-Maślanka I, Solarz A, Chocyk A (2019) Maternal separation disturbs postnatal development of the medial prefrontal cortex and affects the number of neurons and glial cells in adolescent rats. Neuroscience 423:131–147. https://doi.org/10.1016/J.NEUROSCIENCE.2019.10.033
Malik S, Spencer SJ (2019) Early life stress and metabolism. Curr Opin Behav Sci 28:25–30. https://doi.org/10.1016/J.COBEHA.2019.01.016
Marco EM, Llorente R, López-Gallardo M et al (2015) The maternal deprivation animal model revisited. Neurosci Biobehav Rev 51:151–163. https://doi.org/10.1016/J.NEUBIOREV.2015.01.015
McHenry J, Carrier N, Hull E, Kabbaj M (2014) Sex differences in anxiety and depression: role of testosterone. Front Neuroendocrinol 35:42–57. https://doi.org/10.1016/J.YFRNE.2013.09.001
McKim DB, Weber MD, Niraula A et al (2018) Microglial recruitment of IL-1β producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry 23:1421. https://doi.org/10.1038/MP.2017.64
Michopoulos V, Powers A, Gillespie CF et al (2017) Inflammation in fear-and anxiety-based disorders: PTSD, GAD, and beyond. Neuropsychopharmacol 42:254–270. https://doi.org/10.1038/NPP.2016.146
Mitchell SJ, See HM, Tarkow AKH et al (2007) Conducting Studies with Fathers: Challenges and Opportunities. Appl Dev Sci 11:239–244. https://doi.org/10.1080/10888690701762159
Moy SS, Nadler JJ, Perez A et al (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 3:287–302. https://doi.org/10.1111/j.1601-1848.2004.00076.x
Packard AEB, Egan AE, Ulrich-Lai YM (2016) HPA axis-interaction with behavioral systems. Compr Physiol 6:1897. https://doi.org/10.1002/CPHY.C150042
Pawlby S, Hay D, Sharp D et al (2011) Antenatal depression and offspring psychopathology: the influence of childhood maltreatment. Br J Psychiatry 199:106–112. https://doi.org/10.1192/BJP.BP.110.087734
Rogers FD, Bales KL (2020) Revisiting paternal absence: female alloparental replacement of fathers recovers partner preference formation in female, but not male prairie voles (Microtus ochrogaster). Dev Psychobiol 62:573–590. https://doi.org/10.1002/dev.21943
Rogers FD, Freeman SM, Anderson M et al (2021) Compositional variation in early-life parenting structures alters oxytocin and vasopressin 1a receptor development in prairie voles (Microtus ochrogaster). J Neuroendocrinol 33. https://doi.org/10.1111/JNE.13001
Ruiz-Ortiz R, Braza P, Carreras R, Muñoz JM (2017) Differential effects of mother’s and father’s parenting on prosocial and antisocial behavior: child sex moderating. J Child Fam Stud 26:2182–2190. https://doi.org/10.1007/s10826-017-0726-4
Samuels BA, Hen R (2011) Novelty-suppressed feeding in the mouse. Neuromethods 63:107–121. https://doi.org/10.1007/978-1-61779-313-4_7
Schoppe-Sullivan SJ, Fagan J (2020) The Evolution of Fathering Research in the 21st Century: Persistent Challenges, New Directions. J Marriage Fam 82:175–197. https://doi.org/10.1111/jomf.12645
Silverman MN, Pearce BD, Biron CA, Miller AH (2005) Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 18:41–78. https://doi.org/10.1089/vim.2005.18.41
Sotnikov S, Wittmann A, Bunck M et al (2014) Blunted HPA axis reactivity reveals glucocorticoid system dysbalance in a mouse model of high anxiety-related behavior. Psychoneuroendocrinology 48:41–51. https://doi.org/10.1016/J.PSYNEUEN.2014.06.006
Tabbaa M, Lei K, Liu Y, Wang Z (2017) Paternal deprivation affects social behaviors and neurochemical systems in the offspring of socially monogamous prairie voles. Neuroscience 343:284–297. https://doi.org/10.1016/j.neuroscience.2016.12.011
Taymans SE, Devries AC, Devries MB et al (1997) The hypothalamic-pituitary-adrenal axis of prairie voles (Microtus ochrogaster): evidence for target tissue glucocorticoid resistance. Gen Comp Endocrinol 106:48–61. https://doi.org/10.1006/GCEN.1996.6849
Toth I, Neumann ID (2013) Animal models of social avoidance and social fear. Cell Tissue Res 354:107–118. https://doi.org/10.1007/s00441-013-1636-4
Veenema AH, Neumann ID (2009) Maternal separation enhances offensive play-fighting, basal corticosterone and hypothalamic vasopressin mRNA expression in juvenile male rats. Psychoneuroendocrinology 34:463–467. https://doi.org/10.1016/J.PSYNEUEN.2008.10.017
Wang L, Zhang W, Wu R et al (2014) Neuroendocrine responses to social isolation and paternal deprivation at different postnatal ages in mandarin voles. Dev Psychobiol 56:1214–1228. https://doi.org/10.1002/dev.21202
Williams A v, Duque-Wilckens N, Ramos-Maciel S et al (2020) Social approach and social vigilance are differentially regulated by oxytocin receptors in the nucleus accumbens. Neuropsychopharmacology 45(9):1423–1430. https://doi.org/10.1038/s41386-020-0657-4
Wright EC, Hostinar CE, Trainor BC (2020) Anxious to see you: neuroendocrine mechanisms of social vigilance and anxiety during adolescence. Eur J Neurosci 52:2516–2529. https://doi.org/10.1111/EJN.14628
Wu R, Song Z, Wang S et al (2014) Early paternal deprivation alters levels of hippocampal brain-derived neurotrophic factor and glucocorticoid receptor and serum corticosterone and adrenocorticotropin in a sex-specific way in socially monogamous mandarin voles. Neuroendocrinology 100:119–128. https://doi.org/10.1159/000366441
Yamakawa K, Matsunaga M, Isowa T et al (2009) Transient responses of inflammatory cytokines in acute stress. Biol Psychol 82:25–32. https://doi.org/10.1016/J.BIOPSYCHO.2009.05.001
Yohn CN, Leithead AB, Ford J et al (2018) Paternal care impacts oxytocin expression in California mouse offspring and basal testosterone in female, but not male pups. Front Behav Neurosci 12:181. https://doi.org/10.3389/FNBEH.2018.00181/BIBTEX
Zhong X, Ming Q, Dong D et al (2020) Childhood maltreatment experience influences neural response to psychosocial stress in adults: an fMRI study. Front Psychol 10. https://doi.org/10.3389/FPSYG.2019.02961/FULL
Acknowledgements
The authors thank Sabina Khantsis, Lidia Castillo, Priyanka Agarwal, Morgan Harris, Abigail Santoni, Hannah Lee, Alejandro E. Relling, Janet McCormick, and Lisa Hester for their behavioral and/or technical assistance and Zachary Weisenseel, Huazhen Chen, and Emily Oakley for feedback on data presentation.
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This work was supported by the University of Maryland Department of Psychology and College of Behavioral and Social Sciences, The Ohio State University Department of Neuroscience and College of Medicine, and in part by a NIH grant to ERG (R01NS125589) and NIH-funded summer internship support for RB (R25NS120282).
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Walker, S.L., Sud, N., Beyene, R. et al. Paternal deprivation induces vigilance-avoidant behavior and accompanies sex-specific alterations in stress reactivity and central proinflammatory cytokine response in California mice (Peromyscus californicus). Psychopharmacology 240, 2317–2334 (2023). https://doi.org/10.1007/s00213-023-06354-2
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DOI: https://doi.org/10.1007/s00213-023-06354-2