Primary social relationships influence the development of the hypothalamic–pituitary-adrenal axis in the rat
Abstract
In the developing rodent, there is a period from about days 4 to 14 when the adrenal response to stress is either minimal or non-existent. This has been designated as the stress hyporesponsive period (SHRP). Numerous experiments have demonstrated that maternal factors are critical for the regulation of the pup's hypothalamic--pituitary--adrenal (HPA) axis and the maintenance of the SHRP. Following 24 h of maternal deprivation, the neonatal rat shows elevated basal levels of corticosterone (CORT) and exhibits a robust CORT and ACTH response to mild stress. Further, c-fos mRNA in the paraventricular nucleus (PVN) is enhanced following stress in deprived pups. At least three aspects of maternal behavior play a role in the regulation of the HPA axis during development. Tactile stimulation appears capable of inhibiting most of the brain-related changes that occur following maternal deprivation. Feeding is essential for maintaining the adrenal-unresponsive and reduces the sensitivity of the adrenal to ACTH. Passive contact suppresses the response to stress. In the adult, corticotropin-releasing hormone (CRH) is the major neuropeptide that controls pituitary ACTH secretion. In the maternally deprived pup, CRH gene transcription is downregulated and arginine vasopressin (AVP) appears to assume the major regulatory hormone that modulates ACTH. These data all indicate that maternal factors are responsible for actively inhibiting the endocrine responses to stress postnatally. Thus, duri…
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Social buffering of the infant is a dynamic process that wanes as individuals across species mature and become independent.
“Social buffering of the infant is a dynamic process that wanes as individuals across species mature and become independent (Gee et al., 2014, Levine, 2001, McCormack et al., 2009, Sanchez, 2006, Stanton and Levine, 1990, Suchecki et al., 1995, van Oers et al., 1998) (Fig. 1).”
From Early life adversity during the infant sensitive period for attachment: Programming of behavioral neurobiology of threat processing and social behavior (2017) · cites this paper as Levine, 2001
Cites
Physiological functions of glucocorticoids in stress and their relation to pharmacological actions
MUNCK, A., GUYRE, P. M., & HOLBROOK, N. J. (1984) · Endocrine Reviews · doi:10.1210/edrv-5-1-25 · Cited by 3,083 · see citing works
Regulation of ACTH Secretion: Variations on a Theme of B
DALLMAN, M. F., AKANA, S. F., CASCIO, C. S., DARLINGTON, D. N., JACOBSON, L., & LEVIN, N. (1987) · Proceedings of the 1986 Laurentian Hormone Conference · doi:10.1016/b978-0-12-571143-2.50010-1 · Cited by 655 · see citing works
RIVIER, C. L., & Vale, W. (1983) · Endocrinology · doi:10.1210/endo-113-3-939 · Cited by 409 · see citing works
Kovacs, K., & Sawchenko, P. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-01-00262.1996 · Cited by 310 · see citing works
Ontogeny of the Stress Response in the Rat: Role of the Pituitary and the Hypothalamus*
Walker, C., Perrin, M. H., Vale, W., & RIVIER, C. L. (1986) · Endocrinology · doi:10.1210/endo-118-4-1445 · Cited by 309 · see citing works
Dobbing, J. (1984) · Early Human Development · doi:10.1016/0378-3782(84)90130-0 · Cited by 307 · see citing works
Levine, S. D., Huchton, D. M., Wiener, S. G., & Rosenfeld, P. (1991) · Developmental Psychobiology · doi:10.1002/dev.420240803 · Cited by 304 · see citing works
Self-citationvan Oers, H. J. J., de Kloet, E. R., Whelan, T., & Levine, S. D. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-23-10171.1998 · Cited by 284 · see citing works
Self-citationSuchecki, D., Rosenfeld, P., & Levine, S. (1993) · Developmental Brain Research · doi:10.1016/0165-3806(93)90022-3 · Cited by 276 · see citing works
Suckling behavior and intake control in the developing rat pup.
HALL, W. G., & Rosenblatt, J. S. (1977) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0077420 · Cited by 245 · see citing works
Endocrine responses to mother‐infant separation in developing rats
Kuhn, C. M., Pauk, J. S., & Schanberg, S. M. (1990) · Developmental Psychobiology · doi:10.1002/dev.420230503 · Cited by 242 · see citing works
Multifactorial regulation of the hypothalamic-pituitary-adrenal axis during development
Rosenfeld, P., Suchecki, D., & Levine, S. D. (1992) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(05)80196-4 · Cited by 230 · see citing works
Self-citationBartanusz, V., Ježová, D., Bertini, L. T., Tilders, F. J. H., Aubry, J. M., & Kiss, J. Z. (1993) · Endocrinology · doi:10.1210/endo.132.2.8425502 · Cited by 222 · see citing works
Postweaning Development of Negative Feedback in the Pituitary-Adrenal System of the Rat
Goldman, L., Winget, C., Hollingshead, G. W., & Levine, S. D. (2008) · Neuroendocrinology · doi:10.1159/000122169 · Cited by 202 · see citing works
Self-citationRELATIONSHIP BETWEEN FOETAL CORTICOSTEROIDS, MATERNAL PROGESTERONE AND PARTURITION IN THE RAT
Martin, C. E., Cake, M. H., Hartmann, P. E., & Cook, I. F. (1977) · European Journal of Endocrinology · doi:10.1530/acta.0.0840167 · Cited by 181 · see citing works
Schanberg, S. M., Evoniuk, G., & Kuhn, C. M. (1984) · Experimental Biology and Medicine · doi:10.3181/00379727-175-41779 · Cited by 169 · see citing works
RIVIER, C., RIVIER, J., MORMEDE, P., & VALE, W. (1984) · Endocrinology · doi:10.1210/endo-115-3-882 · Cited by 154 · see citing works
Selective Depression of Serum Growth Hormone During Maternal Deprivation in Rat Pups
Kuhn, C. M., Butler, & Schanberg, S. M. (1978) · Science · doi:10.1126/science.684424 · Cited by 153 · see citing works
Maternal Deprivation and Stress Induce Immediate Early Genes in the Infant Rat Brain
Smith, M. A., Kim, S.-Y., van Oers, H. J. J., & Levine, S. D. (1997) · Endocrinology · doi:10.1210/endo.138.11.5529 · Cited by 151 · see citing works
Self-citationMaternal contact inhibits pituitary‐adrenal stress responses in preweanling rats
Stanton, M. E., Wallstrom, J., & Levine, S. D. (1987) · Developmental Psychobiology · doi:10.1002/dev.420200204 · Cited by 146 · see citing works
Self-citationVázquez, D. M., & Akil, H. (1993) · Pediatric Research · doi:10.1203/00006450-199311000-00017 · Cited by 144 · see citing works
Inhibition of infant glucocorticoid stress response: Specific role of maternal cues
Stanton, M. E., & Levine, S. (1990) · Developmental Psychobiology · doi:10.1002/dev.420230504 · Cited by 132 · see citing works
Self-citationGranule cell genesis in the hippocampus of rats treated neonatally with hydrocortisone
Bohn, M. C. (1980) · Neuroscience · doi:10.1016/0306-4522(80)90045-7 · Cited by 121 · see citing works
Dent, G. W., Smith, M. A., & Levine, S. D. (2000) · Endocrinology · doi:10.1210/endo.141.5.7455 · Cited by 117 · see citing works
Self-citationGlucocorticoid induced teratologies of the nervous system.
Bohn, M. (1984) · Cited by 103 · see citing works
Hidden Regulatory Processes in Early Social Relationships
Hofer, M. A. (1978) · Perspectives in ethology · doi:10.1007/978-1-4684-2901-5_7 · Cited by 98 · see citing works
Scaccianoce, S., Muscolo, L. A. A., Cigliana, G., Navarra, D., Nicolai, R., & Angelucci, L. (1991) · Endocrinology · doi:10.1210/endo-128-6-3138 · Cited by 97 · see citing works
SPEAR, L. P., Specht, S. M., Kirstein, C. L., & Kuhn, C. M. (1989) · Developmental Psychobiology · doi:10.1002/dev.420220407 · Cited by 91 · see citing works
Dent, G. W., Okimoto, D. K., Smith, M. A., & Levine, S. D. (2000) · Neuroendocrinology · doi:10.1159/000054554 · Cited by 82 · see citing works
Self-citationAdrenal and Plasma Corticosterone and Vitamin A in Rat Adrenal Glands During Postnatal Development
Levine, S., GLICK, D. M., & Nakane, P. K. (1967) · Endocrinology · doi:10.1210/endo-80-5-910 · Cited by 80 · see citing works
Self-citationde Goeij, D. C. E., Binnekade, R., & Tilders, F. J. H. (1992) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1992.263.2.e394 · Cited by 74 · see citing works
Maternal regulation of adrenocortical activity in the infant rat: Effects of feeding
Rosenfeld, P., Ekstrand, J. J., Olson, E., Suchecki, D., & Levine, S. D. (1993) · Developmental Psychobiology · doi:10.1002/dev.420260504 · Cited by 71 · see citing works
Self-citationGrino, M., Burgunder, J. M., Eskay, R. L., & Eiden, L. E. (1989) · Endocrinology · doi:10.1210/endo-124-6-2686 · Cited by 60 · see citing works
Maternal factors regulate stress responsiveness in the neonatal rat
Cirulli, F., Gottlieb, S. L., Rosenfeld, P., & Levine, S. D. (1992) · Psychobiology · doi:10.3758/bf03327174 · Cited by 48 · see citing works
Self-citationDent, G. W. (2000) · Endocrinology · doi:10.1210/en.141.5.1593 · Cited by 37 · see citing works
Maternal modulation of infant glucocorticoid stress responses: Role of age and maternal deprivation
Stanton, M. E., & Levine, S. (1988) · Psychobiology · doi:10.3758/bf03327311 · Cited by 36 · see citing works
Self-citationEarly Stages in the Organization of Cardiovascular Control
Hofer, M. A. (1984) · Experimental Biology and Medicine · doi:10.3181/00379727-175-41780 · Cited by 32 · see citing works
Development of circadian periodicity in base and stress levels of corticosterone
Levin, R., & Levine, S. (1975) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1975.229.5.1397 · Cited by 30 · see citing works
Self-citationErskine, M. S., Geller, E., & Yuwiler, A. (2008) · Neuroendocrinology · doi:10.1159/000122922 · Cited by 28 · see citing works
Neonatal Androgen or Estrogen Treatment and the Adrenal Cortica Response to Stress in Adult Rats1
Levine, S., & MULLTNS, R. (1967) · Endocrinology · doi:10.1210/endo-80-6-1177 · Cited by 24 · see citing works
Self-citation
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Herman, J. P., Figueiredo, H., Mueller, N. K., Ulrich-Lai, Y., Ostrander, M. M., Choi, D. C., & Cullinan, W. E. (2003) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2003.07.001 · Cited by 1,586 · see citing works
depue, R. A., & morrone-strupinsky, J. V. (2005) · Behavioral and Brain Sciences · doi:10.1017/s0140525x05000063 · Cited by 958 · see citing works
Hostinar, C. E., Sullivan, R. M., & Gunnar, M. R. (2014) · Psychological Bulletin · doi:10.1037/a0032671 · Cited by 739 · see citing works
Daskalakis, N. P., Bagot, R. C., Parker, K. J., Vinkers, C. H., & de Kloet, E. R. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.06.008 · Cited by 579 · see citing works
Gee, D. G., Gabard-Durnam, L., Telzer, E. H., Humphreys, K. L., Goff, B., Shapiro, M., Flannery, J., Lumian, D. S., Fareri, D. S., Caldera, C., et al. (2014) · Psychological Science · doi:10.1177/0956797614550878 · Cited by 363 · see citing works
Developmental consequences of oxytocin
Carter, C. S. (2003) · Physiology & Behavior · doi:10.1016/s0031-9384(03)00151-3 · Cited by 367 · see citing works
Mismatch or cumulative stress: Toward an integrated hypothesis of programming effects
Nederhof, E., & Schmidt, M. V. (2012) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.12.008 · Cited by 363 · see citing works
Roceri, M., Cirulli, F., Pessina, C., Peretto, P., Racagni, G., & Riva, M. A. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2003.12.011 · Cited by 317 · see citing works
Early Developmental Processes and the Continuity of Risk for Underage Drinking and Problem Drinking
Zucker, R. A., Donovan, J. E., Masten, A. S., Mattson, M. E., & Moss, H. B. (2008) · Pediatrics · doi:10.1542/peds.2007-2243b · Cited by 276 · see citing works
Ahern, T. H. (2009) · Frontiers in Behavioral Neuroscience · doi:10.3389/neuro.08.017.2009 · Cited by 239 · see citing works
Lund, T. D., Hinds, L. R., & Handa, R. J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3777-05.2006 · Cited by 236 · see citing works
Moriceau, S., Shionoya, K., Jakubs, K., & Sullivan, R. M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4106-09.2009 · Cited by 214 · see citing works
Roth, T. L., & Sullivan, R. M. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.01.032 · Cited by 204 · see citing works
Kanitz, E., Tuchscherer, M., Puppe, B., Tuchscherer, A., & Stabenow, B. (2004) · Brain, Behavior, and Immunity · doi:10.1016/s0889-1591(03)00085-0 · Cited by 200 · see citing works
The molecular physiology of CRH neurons
Aguilera, G., & Liu, Y. (2012) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2011.08.002 · Cited by 198 · see citing works
Bernard, K., Dozier, M., Bick, J., & Gordon, M. K. (2015) · Development and Psychopathology · doi:10.1017/s095457941400073x · Cited by 189 · see citing works
Infant bonding and attachment to the caregiver: insights from basic and clinical science
Sullivan, R., Perry, R., Sloan, A., Kleinhaus, K., & Burtchen, N. (2011) · Clinics in Perinatology · doi:10.1016/j.clp.2011.08.011 · Cited by 181 · see citing works
Impact of early adversity on glucocorticoid regulation and later mental disorders
Strüber, N., Strüber, D., & Roth, G. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.10.015 · Cited by 173 · see citing works
Bock, J., Gruss, M., Becker, S., & Braun, K. (2005) · Cerebral Cortex · doi:10.1093/cercor/bhh181 · Cited by 175 · see citing works
Bales, K. L., & Carter, C. S. (2003) · Behavioral Neuroscience · doi:10.1037/0735-7044.117.4.854 · Cited by 155 · see citing works
Hostinar, C. E., & Gunnar, M. R. (2013) · Journal of Clinical Child & Adolescent Psychology · doi:10.1080/15374416.2013.804387 · Cited by 153 · see citing works
Gareau, M. G., Jury, J., Yang, P. C., MacQueen, G., & Perdue, M. H. (2006) · Pediatric Research · doi:10.1203/01.pdr.0000190577.62426.45 · Cited by 139 · see citing works
Rodent model of infant attachment learning and stress
Moriceau, S., Roth, T. L., & Sullivan, R. M. (2010) · Developmental Psychobiology · doi:10.1002/dev.20482 · Cited by 119 · see citing works
Callaghan, B. L., Sullivan, R. M., Howell, B., & Tottenham, N. (2014) · Developmental Psychobiology · doi:10.1002/dev.21260 · Cited by 115 · see citing works
Developmental rodent models of fear and anxiety: from neurobiology to pharmacology
Ganella, D. E., & Kim, J. H. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12643 · Cited by 107 · see citing works
Opendak, M., Gould, E., & Sullivan, R. (2017) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2017.02.002 · Cited by 94 · see citing works
Sze, Y., & Brunton, P. J. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14615 · Cited by 85 · see citing works
Shionoya, K., Moriceau, S., Bradstock, P., & Sullivan, R. M. (2007) · Hormones and Behavior · doi:10.1016/j.yhbeh.2007.06.004 · Cited by 85 · see citing works
Developmental effects of oxytocin on stress response: Single versus repeated exposure
KRAMER, K., CUSHING, B., & CARTER, C. (2003) · Physiology & Behavior · doi:10.1016/s0031-9384(03)00175-6 · Cited by 79 · see citing works
Sinclair, D., Webster, M. J., Wong, J., & Weickert, C. S. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.28 · Cited by 66 · see citing works
Raber, J., Arzy, S., Bertolus, J. B., Depue, B., Haas, H. E., Hofmann, S. G., Kangas, M., Kensinger, E., Lowry, C. A., Marusak, H. A., et al. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.03.015 · Cited by 62 · see citing works
“This period of life is characterized by reduced corticosterone and ACTH release in response to mild stress and is referred to as the stress hyporesponsive period (SHRP) (Levine, 2001).”
Dent, G., Choi, D. C., Herman, J. P., & Levine, S. (2007) · Brain Research · doi:10.1016/j.brainres.2006.04.082 · Cited by 44 · see citing works
Self-citationRazzoli, M., Andreoli, M., Maraia, G., Di Francesco, C., & Arban, R. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.07.022 · Cited by 20 · see citing works
- Authors
- Levine, S.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Levine, Seymour
- Venue
- Physiology & Behavior
- Publisher
- Elsevier BV
- Published
- 2001-06
- Volume
- 73
- Issue
- 3
- Pages
- 255-260
- ISSN
- 0031-9384 (ISSN-L)
- OpenAlex
- W2099042039
- Cited by
- 428
- References
- 40
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 4 · 2023: 7 · 2022: 6 · 2021: 13 · 2020: 15 · 2019: 20 · 2018: 16 · 2017: 20 · 2016: 17 · 2015: 16 · 2014: 30 · 2013: 23 · 2012: 24
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Physiology & Behavior (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute for Health and Care Research
- National Institutes of Health (5p01hd002881-23, 5r37mh045006-11)
- U.S. Public Health Service
- National Institute of Mental Health (MH 45006, MH-19936)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 02881)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- hypothalamic-pituitary-adrenal axis, stress hyporesponsive period, maternal deprivation, maternal behavior, corticosterone, ACTH, corticotropin-releasing factor, vasopressin, paraventricular nucleus, c-fos, tactile stimulation, neonatal development, stress response
- MeSH terms
- Animals, Hormones, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Social Environment, Stress, Psychological, Rats
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