Lifelong indices of maladaptive behavior or illness often stem from early physiological aberrations during periods of dynamic development. This is especially true when dysfunction is attributable to early life adversity (ELA), when the environment itself is unsuitable to support development of healthy behavior. Exposure to ELA is strongly associated with atypical sensitivity and responsivity to potential threats—a characteristic that could be adaptive in situations where early adversity prepares individuals for lifelong danger, but which often manifests in difficulties with emotion regulation and social relationships. By synthesizing findings from animal research, this review will consider threat sensitivity through the lenses of associated corticolimbic brain circuitry and immune mechanisms, both of which are immature early in life to maximize adaptation for protection against environmental challenges to an individual’s well-being. The forces that drive differential development of corticolimbic circuits include caretaking stimuli, physiological and psychological stressors, and sex, which influences developmental trajectories. These same forces direct developmental processes of the immune system, which bidirectionally communicates with sensory systems and emotion regulation circuits within the brain. Inflammatory signals offer a further force influencing the timing and nature of corticolimbic plasticity, while also regulating sensitivity to future threats from the environment (i.e., injury or pathogens). The early development of these systems programs threat sensitivity through juvenility and adolescence, carving paths for probable function throughout adulthood. To strategize prevention or management of maladaptive threat sensitivity in ELA-exposed populations, it is necessary to fully understand these early points of divergence.
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Bath KG, Manzano-Nieves G, Goodwill H. Early life stress accelerates behavioral and neural maturation of the hippocampus in male mice. Hormones Behav. 2016;82:64–71.
Pollak SD, Tolley-Schell SA. Selective attention to facial emotion in physically abused children. J Abnorm Psychol. 2003;112:323–38.
Edmiston EK, Blackford JU. Childhood maltreatment and response to novel face stimuli presented during functional magnetic resonance imaging in adults. Psychiatry Res. 2013;212:36–42.
Pollak SD, Cicchetti D, Hornung K, Reed A. Recognizing emotion in faces: developmental effects of child abuse and neglect. Dev Psychol. 2000;36:679–88.
Sandre A, Ethridge P, Kim I, Weinberg A. Childhood maltreatment is associated with increased neural response to ambiguous threatening facial expressions in adulthood: evidence from the late positive potential. Cogn Affect Behav Neurosci. 2018;18:143–54.
Gerhard DM, Meyer HC, Lee FS. An adolescent sensitive period for threat responding: impacts of stress and sex. Biol Psychiatry. 2021;89:651–8.
Nusslock R, Miller GE. Early-life adversity and physical and emotional health across the lifespan: a neuroimmune network hypothesis. Biol Psychiatry. 2016;80:23–32.
Kessler RC, Angermeyer M, Anthony JC, De Graaf R, Demyttenaere K, Gasquet I, et al. Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization’s World Mental Health Survey Initiative. World Psychiatry. 2007;6:168–76.
Gee DG, Humphreys KL, Flannery J, Goff B, Telzer EH, Shapiro M, et al. A developmental shift from positive to negative connectivity in human amygdala-prefrontal circuitry. J Neurosci. 2013;33:4584–93.
Zhang Y, Padmanabhan A, Gross JJ, Menon V. Development of human emotion circuits investigated using a big-data analytic approach: stability, reliability, and robustness. J Neurosci. 2019;39:7155–72.
Pollak SD, Sinha P. Effects of early experience on children’s recognition of facial displays of emotion. Dev Psychol. 2002;38:784–91.
Guadagno A, Belliveau C, Mechawar N, Walker CD. Effects of early life stress on the developing basolateral amygdala-prefrontal cortex circuit: the emerging role of local inhibition and perineuronal nets. Front Hum Neurosci. 2021;15:669120.
Brenhouse HC, Danese A, Grassi-Oliveira R. Neuroimmune impacts of early-life stress on development and psychopathology. Curr Top Behav Neurosci. 2018;43:423–47.
Danese A, Stephanie JL. Psychoneuroimmunology of early-life stress: the hidden wounds of childhood trauma? Neuropsychopharmacology. 2017;42:99–114.
Opendak M, Gould E, Sullivan R. Early life adversity during the infant sensitive period for attachment: Programming of behavioral neurobiology of threat processing and social behavior. Dev Cogn Neurosci. 2017;25:145–59.
Heim C, Nemeroff CB. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry. 2001;49:1023–39.
Gunn BG, Baram TZ. Stress and seizures: space, time and hippocampal circuits. Trends Neurosci. 2017;40:667–79.
Clancy B, Finlay BL, Darlington RB, Anand KJ. Extrapolating brain development from experimental species to humans. Neurotoxicology. 2007;28:931–7.
Hennessy MB, Schiml PA, Berberich K, Beasley NL, Deak T. Early attachment disruption, inflammation, and vulnerability for depression in rodent and primate models. Front Behav Neurosci. 2018;12:314.
Clancy B, Darlington RB, Finlay BL. Translating developmental time across mammalian species. Neuroscience. 2001;105:7–17.
Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 2013;0:1–16.
Meyer HC, Sangha S, Radley JJ, LaLumiere RT, Baratta MV. Environmental certainty influences the neural systems regulating responses to threat and stress. Neurosci Biobehav Rev. 2021;131:1037–55.
Nelson CA III, Gabard-Durnam LJ. Early adversity and critical periods: neurodevelopmental consequences of violating the expectable environment. Trends Neurosci. 2020;43:133–43.
McLaughlin KA, Sheridan MA, Nelson CA. Neglect as a violation of species-expectant experience: neurodevelopmental consequences. Biol Psychiatry. 2017;82:462–71.
Greenough WT, Black JE, Wallace CS. Experience and brain development. Child Dev. 1987;58:539–59.
Bick J, Nelson CA. Early adverse experiences and the developing brain. Neuropsychopharmacology. 2016;41:177–96.
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.
Raineki C, Moriceau S, Sullivan RM. Developing a neurobehavioral animal model of infant attachment to an abusive caregiver. Biol Psychiatry. 2010;67:1137–45.
Moriceau S, Shionoya K, Jakubs K, Sullivan RM. Early-life stress disrupts attachment learning: the role of amygdala corticosterone, locus ceruleus corticotropin releasing hormone, and olfactory bulb norepinephrine. J Neurosci. 2009;29:15745–55.
Gallo M, Shleifer DG, Godoy LD, Ofray D, Olaniyan A, Campbell T, et al. Limited bedding and nesting induces maternal behavior resembling both hypervigilance and abuse. Front Behav Neurosci. 2019;13:167.
Roth TL, Sullivan RM. Memory of early maltreatment: neonatal behavioral and neural correlates of maternal maltreatment within the context of classical conditioning. Biol Psychiatry. 2005;57:823–31.
Levine S. Maternal and environmental influences on the adrenocortical response to stress in weanling rats. Science. 1967;156:258–60.
Suchecki D. Maternal regulation of the infant’s hypothalamic-pituitary-adrenal axis stress response: Seymour ‘Gig’ Levine’s legacy to neuroendocrinology. J Neuroendocrinol. 2018;30:e12610.
Karabel M, Tan S, Tatli MM, Yilmaz AE, Tonbul A, Karadag A. Separation anxiety disorder increases among neonatal intensive care unit graduates. J Matern-Fetal Neonatal Med. 2012;25:783–8.
Cohen P, Velez CN, Brook J, Smith J. Mechanisms of the relation between perinatal problems, early childhood illness, and psychopathology in late childhood and adolescence. Child Dev. 1989;60:701–9.
McLaughlin KA, Sheridan MA, Lambert HK. Childhood adversity and neural development: deprivation and threat as distinct dimensions of early experience. Neurosci Biobehav Rev. 2014;47:578–91.
MacRae M, Kenkel WM, Kentner AC. Social rejection following neonatal inflammation is mediated by olfactory scent cues. Brain Behav Immun. 2015;49:43–48.
McLaughlin KA, Sheridan MA, Humphreys KL, Belsky J, Ellis BJ. The value of dimensional models of early experience: thinking clearly about concepts and categories. Perspect Psychol Sci. 2021;16:1463–472.
Nelson BD, Hodges A, Hajcak G, Shankman SA. Anxiety sensitivity and the anticipation of predictable and unpredictable threat: evidence from the startle response and event-related potentials. J Anxiety Disord. 2015;33:62–71.
Meyer HC, Sangha S, Radley JJ, LaLumiere RT, Baratta MV. Environmental certainty influences the neural systems regulating responses to threat and stress. Neurosci Biobehav Rev. 2021;131:1037–55.
Weems CF, Zakem AH, Costa NM, Cannon MF, Watts SE. Physiological response and childhood anxiety: association with symptoms of anxiety disorders and cognitive bias. J Clin Child Adolesc Psychol. 2005;34:712–23.
Granger DA, Weisz JR, Kauneckis D. Neuroendocrine reactivity, internalizing behavior problems, and control-related cognitions in clinic-referred children and adolescents. J Abnorm Psychol. 1994;103:267–76.
Shanks N, Lightman SL. The maternal-neonatal neuro-immune interface: are there long-term implications for inflammatory or stress-related disease? J Clin Investig. 2001;108:1567–73.
Danese A, Caspi A, Williams B, Ambler A, Sugden K, Mika J, et al. Biological embedding of stress through inflammation processes in childhood. Mol Psychiatry. 2011;16:244–6.
Viveros MP, Llorente R, Lopez-Gallardo M, Suarez J, Bermudez-Silva F, De la Fuente M, et al. Sex-dependent alterations in response to maternal deprivation in rats. Psychoneuroendocrinology. 2009;34:S217–26.
Avitsur R, Sheridan JF. Neonatal stress modulates sickness behavior. Brain Behav Immun. 2009;23:977–85.
Ganguly P, Brenhouse HC. Broken or maladaptive? Altered trajectories in neuroinflammation and behavior after early life adversity. Dev Cogn Neurosci. 2015;11:18–30.
Dutcher EG, Pama EAC, Lynall ME, Khan S, Clatworthy MR, Robbins TW, et al. Early-life stress and inflammation: a systematic review of a key experimental approach in rodents. Brain Neurosci Adv. 2020;4:2398212820978049.
Hartung HP, Heininger K, Schafer B, Fierz W, Toyka KV. Immune mechanisms in inflammatory polyneuropathy. Ann N Y Acad Sci. 1988;540:122–61.
Inagaki TK, Muscatell KA, Irwin MR, Cole SW, Eisenberger NI. Inflammation selectively enhances amygdala activity to socially threatening images. NeuroImage. 2012;59:3222–6.
Slopen N, Kubzansky LD, McLaughlin KA, Koenen KC. Childhood adversity and inflammatory processes in youth: a prospective study. Psychoneuroendocrinology. 2013;38:188–200.
Miller GE, Chen E. The biological residue of childhood poverty. Child Dev Perspect. 2013;7:67–73.
Engel ML, Coe CL, Reid BM, Donzella B, Gunnar MR. Selective inflammatory propensities in adopted adolescents institutionalized as infants. Psychoneuroendocrinology. 2021;124:105065.
Chiang JJ, Bower JE, Irwin MR, Taylor SE, Fuligni AJ. Adiposity moderates links from early adversity and depressive symptoms to inflammatory reactivity to acute stress during late adolescence. Brain Behav Immun. 2017;66:146–55.
Ehrlich KB, Ross KM, Chen E, Miller GE. Testing the biological embedding hypothesis: Is early life adversity associated with a later proinflammatory phenotype? Dev Psychopathol. 2016;28:1273–83.
Peña CJ, Kronman HG, Walker DM, Cates HM, Bagot RC, Purushothaman I, et al. Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science. 2017;356:1185–8.
Rudolph KD, Flynn M. Childhood adversity and youth depression: influence of gender and pubertal status. Dev Psychopathol. 2007;19:497–521.
Gassen J, White JD, Peterman JL, Mengelkoch S, Proffitt Leyva RP, Prokosch ML, et al. Sex differences in the impact of childhood socioeconomic status on immune function. Sci Rep. 2021;11:9827.
Danese A, Moffitt TE, Harrington H, Milne BJ, Polanczyk G, Pariante CM, et al. Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. Arch Pediatr Adolesc Med. 2009;163:1135–43.
Fagundes CP, Way B. Early-life stress and adult inflammation. Curr Directions Psychological Sci. 2014;23:277–83.
Hennessy MB, Paik KD, Caraway JD, Schiml PA, Deak T. Proinflammatory activity and the sensitization of depressive-like behavior during maternal separation. Behav Neurosci. 2011;125:426–33.
Grassi-Oliveira R, Honeycutt JA, Holland FH, Ganguly P, Brenhouse HC. Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: impacts of sex, experience, and cytokines. Psychoneuroendocrinology. 2016;71:19–30.
Park HJ, Kim SA, Kang WS, Kim JW. Early-life stress modulates gut microbiota and peripheral and central inflammation in a sex-dependent manner. Int J Mol Sci. 2021;22:1899.
File SE, Zangrossi H Jr., Sanders FL, Mabbutt PS. Raised corticosterone in the rat after exposure to the elevated plus-maze. Psychopharmacology. 1994;113:543–6.
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.
Brenhouse HC, Bath KG. Bundling the haystack to find the needle: challenges and opportunities in modeling risk and resilience following early life stress. Front Neuroendocrinol. 2019;54:100768.
Chen Y, Baram TZ. Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology. 2016;41:197–206.
McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH, Dhabhar FS, et al. The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res Brain Res Rev. 1997;23:79–133.
Mondelli V, Vernon AC. From early adversities to immune activation in psychiatric disorders: the role of the sympathetic nervous system. Clin Exp Immunol. 2019;197:319–28.
Rinaman L, Banihashemi L, Koehnle TJ. Early life experience shapes the functional organization of stress-responsive visceral circuits. Physiol Behav. 2011;104:632–40.
Card JP, Levitt P, Gluhovsky M, Rinaman L. Early experience modifies the postnatal assembly of autonomic emotional motor circuits in rats. J Neurosci. 2005;25:9102–11.
Rinaman L, Levitt P, Card JP. Progressive postnatal assembly of limbic-autonomic circuits revealed by central transneuronal transport of pseudorabies virus. J Neurosci. 2000;20:2731–41.
Gensollen T, Iyer SS, Kasper DL, Blumberg RS. How colonization by microbiota in early life shapes the immune system. Science. 2016;352:539–44.
Brenhouse HC, Schwarz JM. Immunoadolescence: neuroimmune development and adolescent behavior. Neurosci Biobehav Rev. 2016;70:288–99.
Bilbo SD, Schwarz JM. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci. 2009;3:14.
Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, et al. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun. 2018;9:1228.
Lim TK, Ruthazer ES. Microglial trogocytosis and the complement system regulate axonal pruning in vivo. Elife. 2021;10:e62167.
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.
Cheadle L, Rivera SA, Phelps JS, Ennis KA, Stevens B, Burkly LC, et al. Sensory experience engages microglia to shape neural connectivity through a non-phagocytic mechanism. Neuron. 2020;108:451–68.e459.
Crapser JD, Arreola MA, Tsourmas KI, Green KN. Microglia as hackers of the matrix: sculpting synapses and the extracellular space. Cell Mol Immunol. 2021;18:2472–88.
Frost JL, Schafer DP. Microglia: architects of the developing nervous system. Trends Cell Biol. 2016;26:587–97.
Gildawie KR, Honeycutt JA, Brenhouse HC. Region-specific effects of maternal separation on perineuronal net and parvalbumin-expressing interneuron formation in male and female rats. Neuroscience. 2019;428:23–37.
Gray E, Thomas TL, Betmouni S, Scolding N, Love S. Elevated matrix metalloproteinase-9 and degradation of perineuronal nets in cerebrocortical multiple sclerosis plaques. J Neuropathol Exp Neurol. 2008;67:888–99.
Hensch TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 2005;6:877–88.
Takesian AE, Hensch TK. Balancing plasticity/stability across brain development. Prog Brain Res. 2013;207:3–34.
Carlezon WA Jr., Kim W, Missig G, Finger BC, Landino SM, Alexander AJ, et al. Maternal and early postnatal immune activation produce sex-specific effects on autism-like behaviors and neuroimmune function in mice. Sci Rep. 2019;9:16928.
Orso R, Creutzberg KC, Kestering-Ferreira E, Wearick-Silva LE, Tractenberg SG, Grassi-Oliveira R. Maternal separation combined with limited bedding increases anxiety-like behavior and alters hypothalamic-pituitary-adrenal axis function of male BALB/cJ mice. Front Behav Neurosci. 2020;14:600766.
Custodio CS, Mello BSF, Filho A, de Carvalho Lima CN, Cordeiro RC, Miyajima F, et al. Neonatal immune challenge with lipopolysaccharide triggers long-lasting sex- and age-related behavioral and immune/neurotrophic alterations in mice: relevance to autism spectrum disorders. Mol Neurobiol. 2018;55:3775–88.
Williamson LL, Bilbo SD. Chemokines and the hippocampus: a new perspective on hippocampal plasticity and vulnerability. Brain Behav Immun. 2013;30:186–94.
Silver R, Curley JP. Mast cells on the mind: new insights and opportunities. Trends Neurosci. 2013;36:513–21.
Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev. 1997;77:1033–79.
Nautiyal KM, Ribeiro AC, Pfaff DW, Silver R. Brain mast cells link the immune system to anxiety-like behavior. Proc Natl Acad Sci USA. 2008;105:18053–7.
Joshi A, Page CE, Damante M, Dye CN, Haim A, Leuner B, et al. Sex differences in the effects of early life stress exposure on mast cells in the developing rat brain. Hormones Behav. 2019;113:76–84.
Gildawie KR, Orso R, Peterzell S, Thompson V, Brenhouse HC. Sex differences in prefrontal cortex microglia morphology: impact of a two-hit model of adversity throughout development. Neurosci Lett. 2020;738:135381.
Ganguly P, Honeycutt JA, Rowe JR, Demaestri C, Brenhouse HC. Effects of early life stress on cocaine conditioning and AMPA receptor composition are sex-specific and driven by TNF. Brain Behav Immun. 2019;78:41–51.
Réus GZ, Fernandes GC, de Moura AB, Silva RH, Darabas AC, de Souza TG, et al. Early life experience contributes to the developmental programming of depressive-like behaviour, neuroinflammation and oxidative stress. J Psychiatr Res. 2017;95:196–207.
Viola TW, Creutzberg KC, Zaparte A, Kestering-Ferreira É, Tractenberg SG, Centeno-Silva A, et al. Acute neuroinflammation elicited by TLR-3 systemic activation combined with early life stress induces working memory impairments in male adolescent mice. Behav Brain Res. 2019;376:112221.
Wieck A, Andersen SL, Brenhouse HC. Evidence for a neuroinflammatory mechanism in delayed effects of early life adversity in rats: relationship to cortical NMDA receptor expression. Brain Behav Immun. 2013;28:218–26.
González-Pardo H, Arias JL, Gómez-Lázaro E, López Taboada I, Conejo NM. Sex-specific effects of early life stress on brain mitochondrial function, monoamine levels and neuroinflammation. Brain Sci. 2020;10:447.
Castro-Zavala A, Martín-Sánchez A, Montalvo-Martínez L, Camacho-Morales A, Valverde O. Cocaine-seeking behaviour is differentially expressed in male and female mice exposed to maternal separation and is associated with alterations in AMPA receptors subunits in the medial prefrontal cortex. Prog Neuro-Psychopharmacol Biol Psychiatry. 2021;109:110262.
Callaghan BL, Richardson R. Early-life stress affects extinction during critical periods of development: an analysis of the effects of maternal separation on extinction in adolescent rats. Stress. 2012;15:671–9.
Zelena D, Mikics É, Balázsfi D, Varga J, Klausz B, Urbán E, et al. Enduring abolishment of remote but not recent expression of conditioned fear by the blockade of calcium-permeable AMPA receptors before extinction training. Psychopharmacology. 2016;233:2065–76.
Schwarz JM, Bilbo SD. Sex, glia, and development: interactions in health and disease. Hormones Behav. 2012;62:243–53.
Nelson LH, Warden S, Lenz KM. Sex differences in microglial phagocytosis in the neonatal hippocampus. Brain Behav Immun. 2017;64:11–22.
Nelson LH, Lenz KM. The immune system as a novel regulator of sex differences in brain and behavioral development. J Neurosci Res. 2017;95:447–61.
Chocyk A, Przyborowska A, Makuch W, Majcher-Maślanka I, Dudys D, Wędzony K. The effects of early-life adversity on fear memories in adolescent rats and their persistence into adulthood. Behav Brain Res. 2014;264:161–72.
Walker CD, 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.
Felger JC. Imaging the role of inflammation in mood and anxiety-related disorders. Curr Neuropharmacol. 2018;16:533–58.
Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, et al. Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry. 2003;54:906–14.
Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15:393–403.
Wong HR, Carcillo JA, Burckart G, Kaplan SS. Nitric oxide production in critically ill patients. Arch Dis Child. 1996;74:482–9.
Chikada N, Imaki T, Seki T, Harada S, Nakajima K, Yoshimoto T, et al. Distribution of c-fos mRNA in the brain following intracerebroventricular injection of nitric oxide (NO)-releasing compounds: possible role of NO in central cardiovascular regulation. J Neuroendocrinol. 2000;12:1112–23.
Tellez-Merlo G, Morales-Medina JC, Camacho-Ábrego I, Juárez-Díaz I, Aguilar-Alonso P, de la Cruz F, et al. Prenatal immune challenge induces behavioral deficits, neuronal remodeling, and increases brain nitric oxide and zinc levels in the male rat offspring. Neuroscience. 2019;406:594–605.
Sunico CR, Portillo F, González-Forero D, Moreno-López B. Nitric-oxide-directed synaptic remodeling in the adult mammal CNS. J Neurosci. 2005;25:1448–58.
Konsman JP, Veeneman J, Combe C, Poole S, Luheshi GN, Dantzer R. Central nervous action of interleukin-1 mediates activation of limbic structures and behavioural depression in response to peripheral administration of bacterial lipopolysaccharide. Eur J Neurosci. 2008;28:2499–510.
Tan YL, Yuan Y, Tian L. Microglial regional heterogeneity and its role in the brain. Mol Psychiatry. 2020;25:351–67.
Bolton JL, Short AK, Othy S, Kooiker CL, Shao M, Gunn BG, et al. Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses. Cell Rep. 2022;38:110600.
Chocyk A, Dudys D, Przyborowska A, Majcher I, Maćkowiak M, Wędzony K. Maternal separation affects the number, proliferation and apoptosis of glia cells in the substantia nigra and ventral tegmental area of juvenile rats. Neuroscience. 2011;173:1–18.
Northcutt AL, Hutchinson MR, Wang X, Baratta MV, Hiranita T, Cochran TA, et al. DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling. Mol Psychiatry. 2015;20:1525–37.
Wang X, Northcutt AL, Cochran TA, Zhang X, Fabisiak TJ, Haas ME, et al. Methamphetamine activates toll-like receptor 4 to induce central immune signaling within the ventral tegmental area and contributes to extracellular dopamine increase in the nucleus accumbens shell. ACS Chem Neurosci. 2019;10:3622–34.
Yang S, Tseng KY. Maturation of corticolimbic functional connectivity during sensitive periods of brain development. Curr Top Behav Neurosci. 2021; https://doi.org/10.1007/7854_2021_239. Online ahead of print.
Carr DB, Sesack SR. Hippocampal afferents to the rat prefrontal cortex: synaptic targets and relation to dopamine terminals. J Comp Neurol. 1996;369:1–15.
Gabbott P, Headlam A, Busby S. Morphological evidence that CA1 hippocampal afferents monosynaptically innervate PV-containing neurons and NADPH-diaphorase reactive cells in the medial prefrontal cortex (Areas 25/32) of the rat. Brain Res. 2002;946:314–22.
Sotres-Bayon F, Sierra-Mercado D, Pardilla-Delgado E, Quirk GJ. Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron. 2012;76:804–12.
Maren S, Phan KL, Liberzon I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci. 2013;14:417–28.
Cenquizca LA, Swanson LW. Spatial organization of direct hippocampal field CA1 axonal projections to the rest of the cerebral cortex. Brain Res Rev. 2007;56:1–26.
Zimmermann KS, Richardson R, Baker KD. Maturational changes in prefrontal and amygdala circuits in adolescence: implications for understanding fear inhibition during a vulnerable period of development. Brain Sci. 2019;9:65.
Sullivan RM. Developing a sense of safety: the neurobiology of neonatal attachment. Ann N Y Acad Sci. 2003;1008:122–31.
Thompson JV, Sullivan RM, Wilson DA. Developmental emergence of fear learning corresponds with changes in amygdala synaptic plasticity. Brain Res. 2008;1200:58–65.
Kim JH, Richardson R. A developmental dissociation in reinstatement of an extinguished fear response in rats. Neurobiol Learn Mem. 2007;88:48–57.
Callaghan BL, Richardson R. The effect of adverse rearing environments on persistent memories in young rats: removing the brakes on infant fear memories. Transl Psychiatry. 2012;2:e138.
Callaghan BL, Tottenham N. The stress acceleration hypothesis: effects of early-life adversity on emotion circuits and behavior. Curr Opin Behav Sci. 2016;7:76–81.
Johnson CM, Loucks FA, Peckler H, Thomas AW, Janak PH, Wilbrecht L. Long-range orbitofrontal and amygdala axons show divergent patterns of maturation in the frontal cortex across adolescence. Developmental Cogn Neurosci. 2016;18:113–20.
Honeycutt JA, Demaestri C, Peterzell S, Silveri MM, Cai X, Kulkarni P, et al. Altered corticolimbic connectivity reveals sex-specific adolescent outcomes in a rat model of early life adversity. Elife. 2020;9:e52651.
Morin EL, Howell BR, Feczko E, Earl E, Pincus M, Reding K, et al. Developmental outcomes of early adverse care on amygdala functional connectivity in nonhuman primates. Dev Psychopathol. 2020;32:1579–96.
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.
Manzano Nieves G, Bravo M, Baskoylu S, Bath KG. Early life adversity decreases pre-adolescent fear expression by accelerating amygdala PV cell development. Elife. 2020;9:e55263.
Gee DG, Gabard-Durnam LJ, Flannery J, Goff B, Humphreys KL, Telzer EH, et al. Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation. Proc Natl Acad Sci USA. 2013;110:15638–43.
Colich NL, Rosen ML, Williams ES, McLaughlin KA. Biological aging in childhood and adolescence following experiences of threat and deprivation: a systematic review and meta-analysis. Psychological Bull. 2020;146:721–64.
Avishai-Eliner S, Brunson KL, Sandman CA, Baram TZ. Stressed-out, or in (utero)? Trends Neurosci. 2002;25:518–24.
Fenoglio KA, Brunson KL, Baram TZ. Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects. Front Neuroendocrinol. 2006;27:180–92.
Herringa RJ, Birn RM, Ruttle PL, Burghy CA, Stodola DE, Davidson RJ, et al. Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence. Proc Natl Acad Sci USA. 2013;110:19119–24.
Silvers JA, Lumian DS, Gabard-Durnam L, Gee DG, Goff B, Fareri DS, et al. Previous institutionalization is followed by broader amygdala-hippocampal-PFC network connectivity during aversive learning in human development. J Neurosci. 2016;36:6420–30.
Doherty TS, Forster A, Roth TL. Global and gene-specific DNA methylation alterations in the adolescent amygdala and hippocampus in an animal model of caregiver maltreatment. Behav Brain Res. 2016;298:55–61.
Roth TL, Matt S, Chen K, Blaze J. Bdnf DNA methylation modifications in the hippocampus and amygdala of male and female rats exposed to different caregiving environments outside the homecage. Dev Psychobiol. 2014;56:1755–63.
Coley EJL, Demaestri C, Ganguly P, Honeycutt JA, Peterzell S, Rose N, et al. Cross-generational transmission of early life stress effects on HPA regulators and Bdnf are mediated by sex, lineage, and upbringing. Front Behav Neurosci. 2019;13:101.
Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314:140–3.
Caballero A, Granberg R, Tseng KY. Mechanisms contributing to prefrontal cortex maturation during adolescence. Neurosci Biobehav Rev. 2016;70:4–12.
Santiago AN, Lim KY, Opendak M, Sullivan RM, Aoki C. Early life trauma increases threat response of peri-weaning rats, reduction of axo-somatic synapses formed by parvalbumin cells and perineuronal net in the basolateral nucleus of amygdala. J Comp Neurol. 2018;526:2647–64.
Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do KQ. Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine. Biol Psychiatry. 2013;73:574–82.
Morishita H, Cabungcal JH, Chen Y, Do KQ, Hensch TK. Prolonged period of cortical plasticity upon redox dysregulation in fast-spiking interneurons. Biol Psychiatry. 2015;78:396–402.
White JD, Kaffman A. The moderating effects of sex on consequences of childhood maltreatment: from clinical studies to animal models. Front Neurosci. 2019;13:1082.
Bath KG. Synthesizing views to understand sex differences in response to early life adversity. Trends Neurosci. 2020;43:300–10.
Ellis SN, Honeycutt JA. Sex differences in affective dysfunction and alterations in parvalbumin in rodent models of early life adversity. Front Behav Neurosci. 2021;15:741454.
Manzano-Nieves G, Gaillard M, Gallo M, Bath KG. Early life stress impairs contextual threat expression in female, but not male, mice. Behav Neurosci. 2018;132:247–57.
Uematsu A, Matsui M, Tanaka C, Takahashi T, Noguchi K, Suzuki M, et al. Developmental trajectories of amygdala and hippocampus from infancy to early adulthood in healthy individuals. PLoS ONE. 2012;7:e46970.
Markham JA, Mullins SE, Koenig JI. Periadolescent maturation of the prefrontal cortex is sex-specific and is disrupted by prenatal stress. J Comp Neurol. 2013;521:1828–43.
McLean CP, Asnaani A, Litz BT, Hofmann SG. Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness. J Psychiatr Res. 2011;45:1027–35.
Keller SM, Nowak A, Roth TL. Female pups receive more maltreatment from stressed dams. Dev Psychobiol. 2019;61:824–31.
White JD, Kaffman A. Editorial perspective: Childhood maltreatment—the problematic unisex assumption. J Child Psychol Psychiatry Allied Discip. 2020;61:732–4.
Guadagno A, Verlezza S, Long H, Wong TP, Walker CD. It is all in the right amygdala: increased synaptic plasticity and perineuronal nets in male, but not female, juvenile rat pups after exposure to early-life stress. J Neurosci. 2020;40:8276–91.
White JD, Arefin TM, Pugliese A, Lee CH, Gassen J, Zhang J, et al. Early life stress causes sex-specific changes in adult fronto-limbic connectivity that differentially drive learning. Elife. 2020;9:e58301.
Lidia GM, Martina A, Silvia M, Veronica L, Paolo R, Emanuele P, et al. Autonomic vulnerability to biased perception of social inclusion in borderline personality disorder. Borderline Personal Disord Emot Dysregul. 2021;8:28.
Godbout N, Daspe M, Runtz M, Cyr G, Briere J. Childhood maltreatment, attachment, and borderline personality-related symptoms: gender-specific structural equation models. Psychol Trauma. 2019;11:90–8.
Waddington CH. Canalization of development and genetic assimilation of acquired characters. Nature. 1959;183:1654–5.
Cowan CSM, Richardson R. Early-life stress leads to sex-dependent changes in pubertal timing in rats that are reversed by a probiotic formulation. Dev Psychobiol. 2019;61:679–87.
Sun Y, Fang J, Wan Y, Su P, Tao F. Association of early-life adversity with measures of accelerated biological aging among children in China. JAMA Netw Open. 2020;3:e2013588.
Deardorff J, Hayward C, Wilson KA, Bryson S, Hammer LD, Agras S. Puberty and gender interact to predict social anxiety symptoms in early adolescence. J Adolesc Health. 2007;41:102–4.
Sheridan MA, Peverill M, Finn AS, McLaughlin KA. Dimensions of childhood adversity have distinct associations with neural systems underlying executive functioning. Dev Psychopathol. 2017;29:1777–94.
Arnsten AF. Stress weakens prefrontal networks: molecular insults to higher cognition. Nat Neurosci. 2015;18:1376–85.
Delpech JC, Wei L, Hao J, Yu X, Madore C, Butovsky O, et al. Early life stress perturbs the maturation of microglia in the developing hippocampus. Brain Behav Immun. 2016;57:79–93.
Roque A, Ochoa-Zarzosa A, Torner L. Maternal separation activates microglial cells and induces an inflammatory response in the hippocampus of male rat pups, independently of hypothalamic and peripheral cytokine levels. Brain Behav Immun. 2016;55:39–48.
Hennessy MB, Deak T, Sensenbaugh JD, Gallimore DM, Garybush AM, Mondello JE, et al. Central neuroimmune activity and depressive-like behavior in response to repeated maternal separation and injection of LPS. Physiol Behav. 2019;199:366–74.
Richardson R, Bowers J, Callaghan BL, Baker KD. Does maternal separation accelerate maturation of perineuronal nets and parvalbumin-containing inhibitory interneurons in male and female rats? Dev Cogn Neurosci. 2021;47:100905.
Guadagno A, Wong TP, Walker CD. 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-Psychopharmacol Biol Psychiatry. 2018;81:25–37.
Hill MN, Eiland L, Lee TTY, Hillard CJ, McEwen BS. Early life stress alters the developmental trajectory of corticolimbic endocannabinoid signaling in male rats. Neuropharmacology. 2019;146:154–62.
Rincón-Cortés M, Sullivan RM. Emergence of social behavior deficit, blunted corticolimbic activity and adult depression-like behavior in a rodent model of maternal maltreatment. Transl Psychiatry. 2016;6:e930.
Holland FH, Ganguly P, Potter DN, Chartoff EH, Brenhouse HC. Early life stress disrupts social behavior and prefrontal cortex parvalbumin interneurons at an earlier time-point in females than in males. Neurosci Lett. 2014;566:131–6.
Ganguly P, Holland FH, Brenhouse HC. Functional uncoupling NMDAR NR2A subunit from PSD-95 in the prefrontal cortex: effects on behavioral dysfunction and parvalbumin loss after early-life stress. Neuropsychopharmacology. 2015;40:2666–75.
Brenhouse HC, Andersen SL. Nonsteroidal anti-inflammatory treatment prevents delayed effects of early life stress in rats. Biol Psychiatry. 2011;70:434–40.
Reincke SA, Hanganu-Opatz IL. Early-life stress impairs recognition memory and perturbs the functional maturation of prefrontal-hippocampal-perirhinal networks. Sci Rep. 2017;7:42042.
Farrell MR, Holland FH, Shansky RM, Brenhouse HC. Sex-specific effects of early life stress on social interaction and prefrontal cortex dendritic morphology in young rats. Behav Brain Res. 2016;310:119–25.
Heydari A, Esmaeilpour K, Sheibani V. Maternal separation impairs long term-potentiation in CA3-CA1 synapses in adolescent female rats. Behav Brain Res. 2019;376:112239.
McCarthy MM. Sex differences in the developing brain as a source of inherent risk. Dialogues Clin Neurosci. 2016;18:361–72.
Blair C, Raver CC. Child development in the context of adversity: experiential canalization of brain and behavior. Am Psychologist. 2012;67:309–18.
Gottlieb G. Experiential canalization of behavioral development: theory. Dev Psychol. 1991;27:4.
This work was partially funded by NIMH R01MH127850. The author thanks Dr. Laurel Gabard-Durnam for her invaluable editorial assistance with the manuscript. Artistic contribution from Jennifer Leigh at Creative Outlaw Design.
The author declares no competing interests.
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Brenhouse, H.C. Points of divergence on a bumpy road: early development of brain and immune threat processing systems following postnatal adversity. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01658-9