In humans, early-life adversity is associated with impairments in learning and memory that may emerge later in life. In rodent models, early-life adversity directly impacts hippocampal neuron structure and connectivity with progressive deficits in long-term potentiation and spatial memory function. Previous work has demonstrated that augmented release and actions of the stress-activated neuropeptide, CRH, contribute to the deleterious effects of early-life adversity on hippocampal dendritic arborization, synapse number and memory-function. Early-life adversity increases hippocampal CRH expression, and blocking hippocampal CRH receptor type-1 (CRHR1) immediately following early-life adversity prevented the consequent memory and LTP defects. Here, we tested if blocking CRHR1 in young adults ameliorates early-life adversity-provoked memory deficits later in life. A weeklong course of a CRHR1 antagonist in 2-month-old male rats prevented early-life adversity-induced deficits in object recognition memory that emerged by 12 months of age. Surprisingly, whereas the intervention did not mitigate early-life adversity-induced spatial memory losses at 4 and 8 months, it restored hippocampus-dependent location memory in 12-month-old rats that experienced early-life adversity. Neither early-life adversity nor CRHR1 blockade in the adult influenced anxiety- or depression-related behaviors. Altogether, these findings suggest that cognitive deficits attributable to adversity during early-life-sensitive periods are at least partially amenable to interventions later in life.
Subscribe to Journal
Get full journal access for 1 year
only $43.69 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Prince M, Wimo A, Guerchet M, Gemma-Claire Ali M, Wu Y-T, Prina M, et al. World Alzheimer Report 2015. The global impact of dementia an analysis of prevalence, incidence, cost and trends. London: Alzheimer’s Disease International; 2015.
Prince M, Guerchet M, Prina M. Policy brief for heads of government: the global impact of dementia. London: Alzheimer's Disease International; 2013. p. 2013–50.
Klengel T, Binder EB. Epigenetics of stress-related psychiatric disorders and gene × environment interactions. Neuron. 2015;86:1343–57.
Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–9.
Brown AS, Susser ES, Lin SP, Neugebauer R, Gorman JM. Increased risk of affective disorders in males after second trimester prenatal exposure to the Dutch hunger winter of 1944-45. Br J Psychiatry. 1995;166:601–6.
Eriksson M, Räikkönen K, Eriksson JG. Early life stress and later health outcomes-findings from the Helsinki Birth Cohort Study. Am J Hum Biol. 2014;26:111–6.
Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10:434–45.
Chen Y, Baram TZ. Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology. 2016;41:197–206.
Novick AM, Levandowski ML, Laumann LE, Philip NS, Price LH, Tyrka AR. The effects of early life stress on reward processing. J Psychiatr Res. 2018;101:80–103.
Raymond C, Marin M-F, Majeur D, Lupien S. Early child adversity and psychopathology in adulthood: HPA axis and cognitive dysregulations as potential mechanisms. Prog Neuropsychopharmacol Biol Psychiatry. 2018;85:152–60.
Avishai-Eliner S. Stressed-out, or in (utero)? Trends Neurosci. 2002;25:518–24.
Kaplan GA, Turrell G, Lynch JW, Everson SA, Helkala E-LL, Salonen JT. Childhood socioeconomic position and cognitive function in adulthood. Int J Epidemiol. 2001;30:256–63.
Nelson CA, Zeanah CH, Fox NA, Marshall PJ, Smyke AT, Guthrie D. Cognitive recovery in socially deprived young children: the Bucharest Early Intervention Project. Science. 2007;318:1937–40.
Short AK, Baram TZ. Adverse early-life experiences and neurologic disease: age-old questions and novel answers. Nat Rev Neurol. 2019;2019:657–69.
Brunson KL, Kramár E, Lin B, Chen Y, Colgin LL, Yanagihara TK, et al. Mechanisms of late-onset cognitive decline after early-life stress. J Neurosci. 2005;25:9328–38.
Maras PM, Baram TZ. Sculpting the hippocampus from within: stress, spines, and CRH. Trends Neurosci. 2012;35:315–24.
Bath KG, Manzano-Nieves G, Goodwill H. Early life stress accelerates behavioral and neural maturation of the hippocampus in male mice. Horm Behav. 2016;82:64–71.
Schulmann A, Bolton JL, Curran MM, Regev L, Kamei N, Singh-Taylor A, et al. Blocking NRSF function rescues spatial memory impaired by early-life adversity and reveals unexpected underlying transcriptional programs. SSRN Electron J. 2019. Nov. https://doi.org/10.2139/ssrn.3284454.
Singh-Taylor A, Korosi A, Molet J, Gunn BG, Baram TZ. Synaptic rewiring of stress-sensitive neurons by early-life experience: A mechanism for resilience? Neurobiol Stress. 2015;1:109–15.
Bale TL. Epigenetic and transgenerational reprogramming of brain development. Nat Rev Neurosci. 2015;16:332–44.
Hodel AS, Hunt RH, Cowell RA, Van Den Heuvel SE, Gunnar MR, Thomas KM, et al. Duration of early adversity and structural brain development in post-institutionalized adolescents. Neuroimage. 2015;105:112–9.
Teicher MH, Samson JA, Anderson CM, Ohashi K. The effects of childhood maltreatment on brain structure, function and connectivity. Nat Rev Neurosci. 2016;17:652–66.
Hatfield T, Wing DA, Buss C, Head K, Muftuler LT, Davis E. 71: Magnetic resonance imaging (MRI) shows long term changes in brain structure in preterm infants exposed to chorioamnionitis. Am J Obstet Gynecol. 2011;204:S41.
Ivy AS, Rex CS, Chen Y, Dubé C, Maras PM, Grigoriadis DE, et al. Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J Neurosci. 2010;30:13005–15.
Molet J, Maras PM, Kinney-Lang E, Harris NG, Rashid F, Ivy AS, et al. MRI uncovers disrupted hippocampal microstructure that underlies memory impairments after early-life adversity. Hippocampus. 2016;26:1618–32.
Wang XD, Su YA, Wagner KV, Avrabos C, Scharf SH, Hartmann J, et al. Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. Nat Neurosci. 2013;16:706–13.
Wang X-D, Chen Y, Wolf M, Wagner KV, Liebl C, Scharf SH, et al. Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling. Neurobiol Dis. 2011;42:300–10.
Curran MM, Sandman CA, Poggi Davis E, Glynn LM, Baram TZ. Abnormal dendritic maturation of developing cortical neurons exposed to corticotropin releasing hormone (CRH): insights into effects of prenatal adversity? PLoS ONE. 2017;12:e0180311.
Magarinõs AM, McEwen BS. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Comparison of stressors. Neuroscience. 1995;69:83–8.
Joëls M, Baram TZ. The neuro-symphony of stress. Nat Rev Neurosci. 2009;10:459–66.
Chen Y, Kramár EA, Chen LY, Babayan AH, Andres AL, Gall CM, et al. Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling. Mol Psychiatry. 2013;18:485–96.
Zhou Q, Homma KJ, Poo M. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron. 2004;44:749–57.
Segal M. Dendritic spines and long-term plasticity. Nat Rev Neurosci. 2005;6:277–84.
Alfarez DN, De Simoni A, Velzing EH, Bracey E, Joëls M, Edwards FA, et al. Corticosterone reduces dendritic complexity in developing hippocampal CA1 neurons. Hippocampus. 2009;19:828–36.
Yan X-X, Toth Z, Schultz L, Ribak CE, Baram TZ. Corticotropin-releasing hormone (CRH)-containing neurons in the immature rat hippocampal formation: Light and electron microscopic features and colocalization with glutamate decarboxylase and parvalbumin. Hippocampus. 1998;8:231–43.
Chen Y, Bender RA, Frotscher M, Baram TZ. Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J Neurosci. 2001;21:7171–81.
Chen Y, Bender RA, Brunson KL, Pomper JK, Grigoriadis DE, Wurst W, et al. Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus. Proc Natl Acad Sci. 2004;101:15782–7.
Hooper A, Maguire J. Characterization of a novel subtype of hippocampal interneurons that express corticotropin-releasing hormone. Hippocampus. 2016;26:41–53.
Hooper A, Fuller PM, Maguire J. Hippocampal corticotropin-releasing hormone neurons support recognition memory and modulate hippocampal excitability. PLoS ONE. 2018;13:e0191363.
Gunn BG, Sanchez GA, Lynch G, Baram TZ, Chen Y. Hyper-diversity of CRH interneurons in mouse hippocampus. Brain Struct Funct. 2019;224:583–98.
Gunn BG, Cox CD, Chen Y, Frotscher M, Gall CM, Baram TZ, et al. The endogenous stress hormone CRH modulates excitatory transmission and network physiology in hippocampus. Cereb Cortex. 2017;27:4182–98.
Chen Y, Brunson KL, Müller MB, Cariaga W, Baram TZ. Immunocytochemical distribution of corticotropin-releasing hormone receptor type-1 (CRF(1))-like immunoreactivity in the mouse brain: light microscopy analysis using an antibody directed against the C-terminus. J Comp Neurol. 2000;420:305–23.
Aldenhoff JB, Gruol DL, Rivier J, Vale W, Siggins GR. Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons. Science. 1983;221:875–7.
Chen Y, Dube CM, Rice CJ, Baram TZ. Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone. J Neurosci. 2008;28:2903–11.
Chen Y, Rex CS, Rice CJ, Dubé CM, Gall CM, Lynch G, et al. Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling. Proc Natl Acad Sci USA. 2010;107:13123–8.
Andres AL, Regev L, Phi L, Seese RR, Chen Y, Gall CM, et al. NMDA receptor activation and calpain contribute to disruption of dendritic spines by the stress neuropeptide CRH. J Neurosci. 2013;33:16945–60.
Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci. 2002;3:453.
McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci. 1999;22:105–22.
Bailey CH, Kandel ER, Harris KM. Structural components of synaptic plasticity and memory consolidation. Cold Spring Harb Perspect Biol. 2015;7:a021758.
Naninck EF, Hoeijmakers L, Kakava-Georgiadou N, Meesters A, Lazic SE, Lucassen PJ, et al. Chronic early life stress alters developmental and adult neurogenesis and impairs cognitive function in mice. Hippocampus. 2015;25:309–28.
Rice CJ, Sandman CA, Lenjavi MR, Baram TZ. A novel mouse model for acute and long-lasting consequences of early life stress. Endocrinology. 2008;149:4892–900.
Walker C-D, Bath KG, Joels M, Korosi A, Larauche M, Lucassen PJ, et al. Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential. Stress. 2017;20:421–48.
Brunson KL, Eghbal-Ahmadi M, Bender R, Chen Y, Baram TZ. Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress. Proc Natl Acad Sci USA. 2001;98:8856–61.
Levis SC, Bentzley BS, Bolton JL, Molet J, Baram TZ, Mahler SV. On the origins of a selective vulnerability to opioid addiction. bioRxiv. 2019:716522.
Molet J, Maras PM, Avishai-Eliner S, Baram TZ. Naturalistic rodent models of chronic early-life stress. Dev Psychobiol. 2014;56:1675–88.
Gilles EE, Schultz L, Baram TZ. Abnormal corticosterone regulation in an immature rat model of continuous chronic stress. Pediatr Neurol. 1996;15:114–9.
Singh-Taylor A, Molet J, Jiang S, Korosi A, Bolton JL, Noam Y, et al. NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience. Mol Psychiatry. 2018;23:648–57.
Cryan JF, Valentino RJ, Lucki I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev. 2005;29:547–69.
Molet J, Heins K, Zhuo X, Mei YT, Regev L, Baram TZ, et al. Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome. Transl Psychiatry. 2016;6:e702–2.
Winters BD, Saksida LM, Bussey TJ. Object recognition memory: neurobiological mechanisms of encoding, consolidation and retrieval. Neurosci Biobehav Rev. 2008;32:1055–70.
Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H. Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts. Learn Mem. 2002;9:49–57.
Vogel-Ciernia A, Wood MA. Examining object location and object recognition memory in mice. Curr Protoc Neurosci. 2014;69:8.31.1–17.
Yajima H, Haijima A, Khairinisa MA, Shimokawa N, Amano I, Takatsuru Y. Early-life stress induces cognitive disorder in middle-aged mice. Neurobiol Aging. 2018;64:139–46.
Travaglia A, Bisaz R, Cruz E, Alberini CM. Developmental changes in plasticity, synaptic, glia and connectivity protein levels in rat dorsal hippocampus. Neurobiol Learn Mem. 2016;135:125–38.
Crain B, Cotman C, Taylor D, Lynch G. A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat. Brain Res. 1973;63:195–204.
Sandman CA, Curran MM, Davis EP, Glynn LM, Head K, Baram TZ. Cortical thinning and neuropsychiatric outcomes in children exposed to prenatal adversity: a role for placental CRH? Am J Psychiatry. 2018;175:471–9.
Chen Y, Molet J, Lauterborn JC, Trieu BH, Bolton JL, Patterson KP, et al. Converging, synergistic actions of multiple stress hormones mediate enduring memory impairments after acute simultaneous stresses. J Neurosci. 2016;36:11295–307.
McEwen BS, Cameron H, Chao HM, Gould E, Magarinos AM, Watanabe Y, et al. Adrenal steroids and plasticity of hippocampal neurons: toward an understanding of underlying cellular and molecular mechanisms. Cell Mol Neurobiol. 1993;13:457–82.
Hollrigel GS, Chen K, Baram TZ, Soltesz I. The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats. Neuroscience. 1998;84:71–9.
Chen Y, Brunson KL, Adelmann G, Bender RA, Frotscher M, Baram TZ. Hippocampal corticotropin releasing hormone: pre- and postsynaptic location and release by stress. Neuroscience. 2004;126:533–40.
Fenoglio KA, Brunson KL, Baram TZ. Hippocampal neuroplasticity induced by early-life stress: Functional and molecular aspects. Front Neuroendocrinol. 2006;27:180–92.
Brunson KL, Grigoriadis DE, Lorang MT, Baram TZ. Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain. Exp Neurol. 2002;176:75–86.
McClelland S, Brennan GP, Dubé C, Rajpara S, Iyer S, Richichi C, et al. The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. Elife. 2014;3:e01267.
Chen Y, Fenoglio KA, Dubé CM, Grigoriadis DE, Baram TZ. Cellular and molecular mechanisms of hippocampal activation by acute stress are age-dependent. Mol Psychiatry. 2006;11:992–1002.
Manzano Nieves G, Schilit Nitenson A, Lee H-I, Gallo M, Aguilar Z, Johnsen A, et al. Early life stress delays sexual maturation in female mice. Front Mol Neurosci. 2019;12:27.
Guadagno A, Wong TP, Walker C-D. Morphological and functional changes in the preweaning basolateral amygdala induced by early chronic stress associate with anxiety and fear behavior in adult male, but not female rats. Prog Neuro-Psychopharmacology Biol Psychiatry. 2018;81:25–37.
Bolton JL, Molet J, Regev L, Chen Y, Rismanchi N, Haddad E, et al. Anhedonia following early-life adversity involves aberrant interaction of reward and anxiety circuits and is reversed by partial silencing of amygdala corticotropin-releasing hormone gene. Biol Psychiatry. 2018;83:137–47.
Dalle Molle R, Portella AK, Goldani MZ, Kapczinski FP, Leistner-Segala S, Salum GA, et al. Associations between parenting behavior and anxiety in a rodent model and a clinical sample: relationship to peripheral BDNF levels. Transl Psychiatry. 2012;2:e195.
Wang X-D, Labermaier C, Holsboer F, Wurst W, Deussing JM, Müller MB, et al. Early-life stress-induced anxiety-related behavior in adult mice partially requires forebrain corticotropin-releasing hormone receptor 1. Eur J Neurosci. 2012;36:2360–7.
Raineki C, Cortés MR, Belnoue L, Sullivan RM. Effects of early-life abuse differ across development: infant social behavior deficits are followed by adolescent depressive-like behaviors mediated by the amygdala. J Neurosci. 2012;32:7758–65.
Bolton JL, Ruiz CM, Rismanchi N, Sanchez GA, Castillo E, Huang J, et al. Early-life adversity facilitates acquisition of cocaine self-administration and induces persistent anhedonia. Neurobiol Stress. 2018;8:57–67.
Funding and disclosure
The authors declare no competing interests. Work was supported by NIH grants NS28912, MH73136, and MH096889.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Short, A.K., Maras, P.M., Pham, A.L. et al. Blocking CRH receptors in adults mitigates age-related memory impairments provoked by early-life adversity. Neuropsychopharmacol. (2019) doi:10.1038/s41386-019-0562-x