Editorial: Moments in Time—The Neonatal Rat Hypothalamo-Pituitary-Adrenal Axis
Abstract
The functional activity of the hypothalamo-pituitary- adrenal (HPA) axis of neonatal rats exposed to stressors has provided an intriguing source of study to endocrinologists for decades. The studies can be divided into three phases, each of which depended to an extent on new methodology and modified the interpretation of what was going on in control of the neonatal HPA axis. Between 1950 and the 1970s, when determination of the activity in the HPA axis depended on bioassays for ACTH and fairly insensitive assays for corticosterone, the neonatal HPA axis was thought to undergo a stress nonresponsive period (SNRP) between days 3–14 of life (1, 2). Although, at the end of gestation and during the first day of life, fetal and very young neonatal rats were shown to respond to stress with increased corticosterone, this responsivity vanished in subsequent days, not to return until after 2 weeks postpartum. Based on the lack of plasma and adrenal corticosterone responses to many different stressors after day 1 of life, the results suggested that the axis was absolutely unresponsive, and that, if there was any response to stress at all, it was very slow compared with that of adults (3). In retrospect, this period of study pointed strongly to both insensitivity of the adrenal gland to stimulation by ACTH, and to the lack of amplification of corticosterone levels in plasma because of very low levels of the corticosteroid binding protein, transcortin (4). Subsequently, study of the adrenal capacity to synthesize and secrete glucocorticoids in response to ACTH has shown that in sheep, the fetal adrenal undergoes a period of unresponsiveness like that of the neonatal rat adrenal (5). The precise mechanism(s) of this damped adrenal responsivity to ACTH is still unknown, although in fetal sheep it appears to involve immaturity at the membrane receptor system (5). In infant rats, although insensitive to ACTH, there is a relatively high level of constitutive corticosterone secretion (6) that provides basal levels of nonrhythmic corticosterone in plasma allowing maturation, without excess, of developing corticosteroid-responsive systems. Although the mechanism of adrenal insensitivity to ACTH in neonatal rats is not solved, a very tight, positive correlation between the corticosterone response to ACTH and the peripheral-type benzodiazepine receptor has been demonstrated, suggesting that this cholesterol transporter may be a key to the stress-hyporesponsive adrenal (7). The periods of hyporesponsiveness appear to be highly protective for the organisms. Because elevated fetal corticosteroids appear to trigger parturition in sheep (5), and elevated corticosteroids result in harmful developmental advances in neonatal rats (8), banking of adrenal fires is a physiologically meaningful protective mechanism. In the 1980s and 1990s, cracks appeared in the monolithic notion of a fetal or neonatal period of HPA unresponsiveness, and during this time, the phenomenon acquired the sobriquet of the “stress-hyporesponsive period” (SHRP) (9). During this period, there was a report that the capacity of CRF to respond to adrenalectomy or stress was highly limited ontogenetically, and that this could explain the SHRP (10). However, there was also evidence that this might not be the case. Adrenalectomy was shown to produce increases in ACTH that were of both normal amplitude and time-course, compared with adults (11); the characteristics of the adult HPA axis of corticosteroid feedback sensitivity (12) and facilitated responsivity to repeated stressors (13) were shown to be similar in neonates during the SHRP. A stunning example of full responsivity of ACTH secretion to stress during the SHRP of rats was provided by showing remarkably normal responses to injected endotoxin throughout this period (14). Responsivity in the usual neural components of the HPA axis during the SHRP was far less certain. Although stimuli provoked evidence for increased neural activity in the hypothalamic paraventricular nuclei (PVN) (15), most reported that many of the stimuli shown to provoke elevated ACTH secretion in neonatal rats did not stimulate normal increases in CRF gene transcription as they do in adult rats. The paper by Dent and Levine (16) in this issue of Endocrinology now clarifies this problem and suggests strongly that not only do neonatal rats work in their own time domain, but, as in any good paper, also suggests that there are other mysteries about the rich neonatal HPA axis left to be plumbed. After the relatively minor stimulus of ip injection of isotonic saline, Dent and Levine (16) show that significant responses occur in expression of both heteronuclear RNA (hnRNA) and messenger RNA (mRNA) for CRF in the PVN, as well as in plasma ACTH and corticosterone in rat pups exposed at 6, 12, or 18 days of life. At all ages, the authors show significant responses in all variables in pups that heteronuclear RNA (hnRNA) remained with their mothers until the
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At birth, rat pups have a functional HPA axis that soon becomes hypo-responsive and not activated by most painful stimuli, a period termed the stress hypo-responsive period (SHRP).
“For example, at birth, rat pups have a functional HPA axis, although it soon becomes hypo-responsive and not activated by most painful stimuli, a period of life termed the stress hypo-responsive period (SHRP) (Dallman, 2000, Stanton and Levine, 1985).”
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 Dallman, 2000
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Cites
Plotsky, P. M., & Meaney, M. J. (1993) · Molecular Brain Research · doi:10.1016/0169-328x(93)90189-v · Cited by 1,638 · see citing works
Sapolsky, R. M., & Meaney, M. J. (1986) · Brain Research Reviews · doi:10.1016/0165-0173(86)90010-x · Cited by 991 · see citing works
Plasma concentrations of total and free corticosterone during development in the rat.
Henning, S. (1978) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1978.235.5.e451 · Cited by 414 · 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
van 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
Maturation and Activation of Hypothalamic-Pituitary Adrenal Function in Fetal Sheep*
Challis, J. R. G., & Brooks, A. N. (1989) · Endocrine Reviews · doi:10.1210/edrv-10-2-182 · Cited by 260 · see citing works
Walker, C., Scribner, K. A., Cascio, C. S., & Dallman, M. F. (1991) · Endocrinology · doi:10.1210/endo-128-3-1385 · Cited by 255 · see citing works
Rots, N. Y., de Jong, J., Workel, J. O., Levine, S. D., Cools, A. R., & de Kloet, E. R. (1996) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.1996.04843.x · Cited by 179 · 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
Effects of Maternal Deprivation on the ACTH Stress Response in the Infant Rat
Suchecki, D., Mozaffarian, D., Gross, G., Rosenfeld, P., & Levine, S. D. (2008) · Neuroendocrinology · doi:10.1159/000126361 · Cited by 141 · see citing works
Grino, M., Young, W. S., & Burgunder, J. ‐. (1989) · Endocrinology · doi:10.1210/endo-124-1-60 · Cited by 122 · 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
The Pituitary—Adrenal System and the Developing Brain
Levine, S. (1970) · Progress in brain research · doi:10.1016/s0079-6123(08)61521-6 · Cited by 102 · see citing works
Maturation of Adrenal Stress Responsiveness in the Rat
Schoenfeld, N. M., LEATHEM, J. H., & Rabii, J. (2008) · Neuroendocrinology · doi:10.1159/000123058 · Cited by 97 · see citing works
Pituitary-adrenal response to bacterial endotoxin in developing rats
Witek‐Janusek, L. (1988) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1988.255.4.e525 · Cited by 97 · see citing works
Eghbal-Ahmadi, M., Avishai‐Eliner, S., Hatalski, C. G., & Baram, T. Z. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-10-03982.1999 · Cited by 92 · see citing works
Sato, T., Sato, M., Shinsako, J., & Dallman, M. F. (1975) · Endocrinology · doi:10.1210/endo-97-2-265 · Cited by 80 · see citing works
Walker, C., Akana, S. F., Cascio, C. S., & Dallman, M. F. (1990) · Endocrinology · doi:10.1210/endo-127-2-832 · Cited by 79 · see citing works
de 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
Pituitary ACTH and Compensatory Adrenal Hypertrophy in Stress-Non-responsive Infant Rats
Schapiro, S. (1962) · Endocrinology · doi:10.1210/endo-71-6-986 · Cited by 65 · see citing works
Zilz, A., Li, H., Castello, R., Papadopoulos, V., & Widmaier, E. P. (1999) · Endocrinology · doi:10.1210/endo.140.2.6475 · Cited by 58 · see citing works
The ontogeny of the neuroendocrine response to endotoxin
Dent, G. W., Smith, M. A., & Levine, S. (1999) · Developmental Brain Research · doi:10.1016/s0165-3806(99)00091-7 · Cited by 55 · see citing works
Steroidogenesis in isolated adrenocortical cells during development in rats
Arai, M., & Widmaier, E. P. (1993) · Molecular and Cellular Endocrinology · doi:10.1016/0303-7207(93)90079-y · Cited by 47 · see citing works
Walker, C. D., & Dallman, M. F. (1993) · Endocrinology · doi:10.1210/endo.132.3.8382596 · Cited by 46 · see citing works
MILKOVIĆ, S., & Milković, K. (1969) · Elsevier eBooks · doi:10.1016/b978-0-08-012023-2.50006-3 · Cited by 14 · see citing works
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Landers, M. S., & Sullivan, R. M. (2012) · Developmental Neuroscience · doi:10.1159/000336732 · Cited by 180 · see citing works
Long-Term Alterations in Neuroimmune Responses after Neonatal Exposure to Lipopolysaccharide
Lomax, L. B., Mouihate, A., Ellis, S. L., & Pittman, Q. J. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1077-04.2004 · Cited by 142 · see citing works
Avishai‐Eliner, S., Gilles, E. E., Eghbal‐Ahmadi, M., Bar‐El, Y., & Baram, T. Z. (2001) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.2001.00698.x · Cited by 139 · see citing works
Rincón‐Cortés, M., & Sullivan, R. M. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00033 · Cited by 138 · see citing works
Programming social, cognitive, and neuroendocrine development by early exposure to novelty
Tang, A. C., Akers, K. G., Reeb, B. C., Romeo, R. D., & McEwen, B. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607374103 · Cited by 127 · see citing works
Amygdala hyper-connectivity in a mouse model of unpredictable early life stress
Johnson, F. K., Delpech, J.-C., Thompson, G. J., Wei, L., Jin, H., Hermán, P., Hyder, F., & Kaffman, A. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0092-z · Cited by 115 · see citing works
Transitions in sensitive period attachment learning in infancy: The role of corticosterone
Sullivan, R. M., & Holman, P. J. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.11.010 · Cited by 117 · 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
Brunson, K. L., Avishai-Eliner, S., Hatalski, C. G., & Baram, T. Z. (2001) · Molecular Psychiatry · doi:10.1038/sj.mp.4000942 · Cited by 112 · see citing works
On the causes of early life experience effects: Evaluating the role of mom
Tang, A. C., Reeb‐Sutherland, B. C., Romeo, R. D., & McEwen, B. S. (2013) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.11.002 · Cited by 108 · see citing works
The central corticotropin releasing factor system during development and adulthood
Korosi, A., & Baram, T. Z. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.11.066 · Cited by 102 · see citing works
Tang, A. C. (2001) · Learning & Memory · doi:10.1101/lm.43101 · Cited by 101 · see citing works
McClelland, S., Kőrösi, A., Cope, J. L., Ivy, A. S., & Baram, T. Z. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.02.008 · Cited by 96 · 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
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Callaghan, B. L., Meyer, H. C., Opendak, M. M., Tieghem, M. V., Harmon, C., Li, A., Lee, F. S., Sullivan, R. M., & Tottenham, N. (2019) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-050718-095727 · Cited by 81 · see citing works
Tang, A. C., Reeb, B. C., Romeo, R. D., & McEwen, B. S. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-23-08254.2003 · Cited by 78 · see citing works
Defining age limits of the sensitive period for attachment learning in rat pups
Upton, K. J., & Sullivan, R. M. (2010) · Developmental Psychobiology · doi:10.1002/dev.20448 · Cited by 71 · see citing works
Aïn, S. A., Perry, R. E., Nuñez, B. S., Kayser, K. E., Hochman, C., Brehman, E., LaComb, M., Wilson, D. A., & Sullivan, R. M. (2016) · Social Neuroscience · doi:10.1080/17470919.2016.1159605 · Cited by 63 · see citing works
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The neurobiology of safety and threat learning in infancy
Dębiec, J., & Sullivan, R. M. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.10.015 · Cited by 45 · see citing works
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Ježová, D., Škultétyová, I., Makatsori, A., Moncek, F., & Dunčko, R. (2002) · Stress · doi:10.1080/1025389021000010512 · Cited by 33 · see citing works
Vázquez, D. M., Eskandari, R., Phelka, A., & López, J. F. (2002) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300126 · Cited by 30 · see citing works
Williams, S. K., & Johns, J. M. (2013) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.07.004 · Cited by 26 · see citing works
Shishkina, G. T., Kalinina, T. S., Bulygina, V. V., Lanshakov, D. A., Babluk, E. V., & Дыгало, Н. Н. (2015) · PLoS ONE · doi:10.1371/journal.pone.0143978 · Cited by 24 · see citing works
Early-Life Experiences: Enduring Behavioral, Neurological, and Endocrinological Consequences
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Archer, T. (2010) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2010.00171.x · Cited by 22 · see citing works
Wiedenmayer, C. P., Magariños, A. M., McEwen, B. S., & Barr, G. A. (2004) · Hormones and Behavior · doi:10.1016/j.yhbeh.2004.09.001 · Cited by 22 · see citing works
Wang, W., Murphy, B., Dow, K. E., Andrew, R. D., & Fraser, D. D. (2004) · Pediatric Research · doi:10.1203/01.pdr.0000112105.33521.dc · Cited by 21 · see citing works
Carnell, S., Grillot, C. L., Ungredda, T., Ellis, S., Mehta, N., Holst, J. J., & Geliebter, A. (2017) · International Journal of Obesity · doi:10.1038/ijo.2017.307 · Cited by 20 · see citing works
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Nelson, E. A. S., Wong, Y., Yu, L., Fok, T. F., & Li, K. (2002) · Pediatric Research · doi:10.1203/00006450-200212000-00013 · Cited by 18 · see citing works
Reeb‐Sutherland, B. C., & Tang, A. C. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.06.010 · Cited by 12 · see citing works
Mabandla, M. V., Dobson, B., Johnson, S., Kellaway, L. A., Daniels, W. M. U., & Russell, V. A. (2007) · Metabolic Brain Disease · doi:10.1007/s11011-007-9049-2 · Cited by 12 · see citing works
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Bisaz, R., & Sullivan, R. M. (2012) · Behavioral Sciences · doi:10.3390/bs2020079 · Cited by 11 · see citing works
Tang, A. C., Jiang, H., Yang, Z., Zhang, Y., Romeo, R. D., & McEwen, B. S. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.03.009 · Cited by 10 · see citing works
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Barr, G. A., Opendak, M. M., Perry, R. E., Sarro, E. C., & Sullivan, R. M. (2023) · PLoS ONE · doi:10.1371/journal.pone.0290871 · Cited by 9 · see citing works
Буткевич, И. П., Михайленко, В. А., Bagaeva, T. R., Vershinina, E. A., Aloisi, A. M., & Otellin, V. A. (2013) · Mediators of Inflammation · doi:10.1155/2013/915189 · Cited by 8 · see citing works
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Romeo, R. D., Tang, A. C., & Sullivan, R. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-803592-4.00099-7 · Cited by 5 · see citing works
Буткевич, И. П., Михайленко, В. А., Makukhina, G. V., Bagaeva, T. R., & Stolyarova, Y. A. (2013) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-013-2110-8 · Cited by 3 · see citing works
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Stylianopoulou, F., & Stamatakis, A. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809324-5.21102-4 · Cited by 2 · see citing works
Programming effects of adversity on adolescent adaptive capacity
Laceulle, O. M. (2013) · University of Groningen research database (University of Groningen / Centre for Information Technology) · Cited by 1 · see citing works
Elison, J. T., & Sera, M. D. (2018) · Wiley eBooks · doi:10.1002/9781119461746.ch2 · Cited by 1 · see citing works
Maken, D. S. (2009) · OhioLink ETD Center (Ohio Library and Information Network)
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- Authors
- Dallman, M. F.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Dallman, Mary F.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2000-05-01
- Volume
- 141
- Issue
- 5
- Pages
- 1590-1592
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2041833534
- Cited by
- 48
- References
- 25
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 5 · 2012: 2
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- hypothalamic-pituitary-adrenal axis, neonatal rats, ACTH, corticosterone, corticosteroid-binding globulin, glucocorticoid receptor, translocator protein (TSPO), fetal adrenal development, glucocorticoid feedback, glucocorticoid synthesis, glucocorticoid secretion
- MeSH terms
- Adrenocorticotropic Hormone, Animals, Animals, Newborn, Corticotropin-Releasing Hormone, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Stress, Physiological, Rats
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