Abstract
Background
Early-life adversities during development (e.g., child abuse and neglect) are linked to multiple behavioral and cognitive dysfunctions, such as attention deficit/hyperactivity disorder (ADHD) and anxiety disorders, which have high comorbidity. However, the impact of adversities during adolescence, a crucial period in early life for these disorders, is understudied. Using a chronic unpredictable stress (CUS) model in rats, we investigated whether adversities in adolescence could lead to increased anxiety and ADHD-like symptoms in adulthood.
Methods
Mid- to late-adolescent (5–7-week-old) male and female Sprague–Dawley rats underwent a mild CUS procedure for 2 weeks. Various stressors were applied in an unpredictable way. Rats of both sexes were then trained with a 2-choice reaction time (2-CRT) task during adulthood, which are designed to detect ADHD-like symptoms, including increased impulsivity and lapse of attention. In addition, an open field test was conducted to examine if CUS resulted in a persistent increase in anxiety-like behavior during adulthood.
Results
Both male and female rats with CUS exposure travelled shorter distances in the open field and spent less time in the center zone, indicating increased anxiety. In the 2-CRT task, rats of both sexes with CUS exposure showed increased impulsivity. Augmented lapses of attention were observed in female but not male rats.
Conclusion
Chronic unpredictable stress during adolescence increases anxiety and leads to ADHD-like symptoms in both male and female rats in adulthood. The deficits are more severe in females than in males. These observations support that adversities during adolescence persistently increase anxiety, which is comorbid with attention deficits.
Similar content being viewed by others
References
Adamo N, Michelini G, Cheung CHM, Buitelaar JK, Asherson P, Rijsdijk F, Kuntsi J (2021) Does co-occurring anxiety modulate ADHD-related cognitive and neurophysiological impairments? J Atten Disord 25:1135–1145
American Psychiatric Association (2013) American psychiatric association: diagnostic and statistical manual of mental disorders, fifth edition. Arlington, VA, American Psychiatric Publishing
Anisman H, Matheson K (2005) Stress, depression, and anhedonia: caveats concerning animal models. Neurosci Biobehav Rev 29:525–546
Antoniuk S, Bijata M, Ponimaskin E, Wlodarczyk J (2019) Chronic unpredictable mild stress for modeling depression in rodents: meta-analysis of model reliability. Neurosci Biobehav Rev 99:101–116
Arain M, Haque M, Johal L, Mathur P, Nel W, Rais A, Sandhu R, Sharma S (2013) Maturation of the adolescent brain. Neuropsychiatr Dis Treat 9:449
Arnold BC, Groeneveld RA (1995) Measuring skewness with respect to the mode. Am Stat 49:34–38
Arnsten AF (2009) Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 10:410–422
Arnsten AF, Pliszka SR (2011) Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders. Pharmacol Biochem Behav 99:211–216
Bale TL, Epperson CN (2015) Sex differences and stress across the lifespan. Nat Neurosci 18:1413–1420
Bari A, Robbins TW (2013) Inhibition and impulsivity: behavioral and neural basis of response control. Prog Neurobiol 108:44–79
Biederman J, Faraone S (2005) Attention-deficit hyperactivity disorder. Lancet 366:237–248
Biederman J, Faraone SV, Monuteaux MC (2002) Differential effect of environmental adversity by gender: Rutter’s index of adversity in a group of boys and girls with and without ADHD. Am J Psychiatry 159:1556–1562
Biederman J, Faraone SV, Spencer T, Wilens T, Norman D, Lapey KA, Mick E, Lehman BK, Doyle A (1993) Patterns of psychiatric comorbidity, cognition, and psychosocial functioning in adults with attention deficit hyperactivity disorder. Am J Psychiatry 150:1792–1798
Bock J, Breuer S, Poeggel G, Braun K (2017) Early life stress induces attention-deficit hyperactivity disorder (ADHD)-like behavioral and brain metabolic dysfunctions: functional imaging of methylphenidate treatment in a novel rodent model. Brain Struct Funct 222:765–780
Brenhouse HC, Lukkes JL, Andersen SL (2013) Early life adversity alters the developmental profiles of addiction-related prefrontal cortex circuitry. Brain Sci 3:143–158
Caye A, Rocha TB, Anselmi L, Murray J, Menezes AM, Barros FC, Goncalves H, Wehrmeister F, Jensen CM, Steinhausen HC, Swanson JM, Kieling C, Rohde LA (2016) Attention-deficit/hyperactivity disorder trajectories from childhood to young adulthood: evidence from a birth cohort supporting a late-onset syndrome. JAMA Psychiat 73:705–712
Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N (2007) The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci 27:2781–2787
Chaby LE, Cavigelli SA, Hirrlinger AM, Caruso MJ, Braithwaite VA (2015) Chronic unpredictable stress during adolescence causes long-term anxiety. Behav Brain Res 278:492–495
Cheng J, Liu A, Shi MY, Yan Z (2017) Disrupted glutamatergic transmission in prefrontal cortex contributes to behavioral abnormality in an animal model of ADHD. Neuropsychopharmacology 42:2096–2104
Chocyk A, Bobula B, Dudys D, Przyborowska A, Majcher-Maślanka I, Hess G, Wędzony K (2013) Early-life stress affects the structural and functional plasticity of the medial prefrontal cortex in adolescent rats. Eur J Neurosci 38:2089–2107
Cooper M, Hammerton G, Collishaw S, Langley K, Thapar A, Dalsgaard S, Stergiakouli E, Tilling K, Davey Smith G, Maughan B, O’Donovan M, Thapar A, Riglin L (2018) Investigating late-onset ADHD: a population cohort investigation. J Child Psychol Psychiatry 59:1105–1113
Cortese S, Kelly C, Chabernaud C, Proal E, Di Martino A, Milham MP, Castellanos FX (2012) Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies. Am J Psychiatry 169:1038–1055
Corwin RL (2006) Bingeing rats: a model of intermittent excessive behavior? Appetite 46:11–15
Danielson ML, Bitsko RH, Ghandour RM, Holbrook JR, Kogan MD, Blumberg SJ (2018) Prevalence of parent-reported ADHD diagnosis and associated treatment among US children and adolescents, 2016. J Clin Child Adolesc Psychol 47:199–212
Faraone SV, Biederman J, Mick E, Williamson S, Wilens T, Spencer T, Weber W, Jetton J, Kraus I, Pert J (2000) Family study of girls with attention deficit hyperactivity disorder. Am J Psychiatry 157:1077–1083
Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiat 57:1313–1323
Fernández A, Quintero J, Hornero R, Zuluaga P, Navas M, Gómez C, Escudero J, García-Campos N, Biederman J, Ortiz T (2009) Complexity analysis of spontaneous brain activity in attention-deficit/hyperactivity disorder: diagnostic implications. Biol Psychiat 65:571–577
Gallo M, Shleifer DG, Godoy LD, Ofray D, Olaniyan A, Campbell T, Bath KG (2019) Limited bedding and nesting induces maternal behavior resembling both hypervigilance and abuse. Front Behav Neurosci 13:167
Ghosal S, Hare BD, Duman RS (2017) Prefrontal cortex GABAergic deficits and circuit dysfunction in the pathophysiology and treatment of chronic stress and depression. Curr Opin Behav Sci 14:1–8
Hausknecht KA, Acheson A, Kieres AK, Sabol KESR-Y, Richards JB (2005) Prenatal alcohol exposure causes attention deficits in male rats. Behav Neurosci 119:302–310
Hausknecht K, Haj-Dahmane S, Shen RY (2013) Prenatal stress exposure increases the excitation of dopamine neurons in the ventral tegmental area and alters their reponses to psychostimulants. Neuropsychopharmacology 38:293–301
Hodes GE, Epperson CN (2019) Sex differences in vulnerability and resilience to stress across the life span. Biol Psychiat 86:421–432
Hollis F, Isgor C, Kabbaj M (2013) The consequences of adolescent chronic unpredictable stress exposure on brain and behavior. Neuroscience 249:232–241
Honeycutt JA, Demaestri C, Peterzell S, Silveri MM, Cai X, Kulkarni P, Cunningham MG, Ferris CF, Brenhouse HC (2020) Altered corticolimbic connectivity reveals sex-specific adolescent outcomes in a rat model of early life adversity. Elife 9:e52651
Howard ARH, Lynch AK, Call CD, Cross DR (2020) Sensory processing in children with a history of maltreatment: an occupational therapy perspective. Vulnerable Children and Youth Studies 15:60–67
Jarrett MA, Ollendick TH (2008) A conceptual review of the comorbidity of attention-deficit/hyperactivity disorder and anxiety: implications for future research and practice. Clin Psychol Rev 28:1266–1280
Kolb B, Gibb R (2015) Plasticity in the prefrontal cortex of adult rats. Front Cell Neurosci 9:15
Lam VY, Raineki C, Ellis L, Yu W, Weinberg J (2018) Interactive effects of prenatal alcohol exposure and chronic stress in adulthood on anxiety-like behavior and central stress-related receptor mRNA expression: sex-and time-dependent effects. Psychoneuroendocrinology 97:8–19
Leth-Steensen C, Elbaz ZK, Douglas VI (2000) Mean response times, variability, and skew in the responding of ADHD children: a response time distributional approach. Acta Physiol (oxf) 104:167–190
Levy F (2004) Synaptic gating and ADHD: a biological theory of comorbidity of ADHD and anxiety. Neuropsychopharmacology 29:1589–1596
Liebsch G, Montkowski A, Holsboer F, Landgraf R (1998) Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety-related behaviour. Behav Brain Res 94:301–310
Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445
Malhi GS, Das P, Bell E, Mattingly G, Mannie Z (2019) Modelling resilience in adolescence and adversity: a novel framework to inform research and practice. Transl Psychiatry 9:316
Mallo T, Alttoa A, Koiv K, Tonissaar M, Eller M, Harro J (2007) Rats with persistently low or high exploratory activity: behaviour in tests of anxiety and depression, and extracellular levels of dopamine. Behav Brain Res 177:269–281
McCormick CM, Mathews IZ (2007) HPA function in adolescence: role of sex hormones in its regulation and the enduring consequences of exposure to stressors. Pharmacol Biochem Behav 86:220–233
McEwen BS, Morrison JH (2013) The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 79:16–29
McEwen BS, Nasca C, Gray JD (2016) Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 41:3–23
McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM, Kessler RC (2012) Childhood adversities and first onset of psychiatric disorders in a national sample of US adolescents. Arch Gen Psychiatry 69:1151–1160
McLaughlin KA, Sheridan MA, Lambert HK (2014) Childhood adversity and neural development: deprivation and threat as distinct dimensions of early experience. Neurosci Biobehav Rev 47:578–591
Musazzi L, Treccani G, Popoli M (2015) Functional and structural remodeling of glutamate synapses in prefrontal and frontal cortex induced by behavioral stress. Front Psych 6:60
Negrón-Oyarzo I, Dagnino-Subiabre A, Muñoz Carvajal P (2015) Synaptic impairment in layer 1 of the prefrontal cortex induced by repeated stress during adolescence is reversed in adulthood. Front Cell Neurosci 9:442
Negrón-Oyarzo I, Aboitiz F, Fuentealba P (2016) Impaired functional connectivity in the prefrontal cortex: a mechanism for chronic stress-induced neuropsychiatric disorders. Neural plasticity
Nigg JT, Sibley MH, Thapar A, Karalunas SL (2020) Development of ADHD: etiology, heterogeneity, and early life course. Annu Rev Dev Psychol 2:559–583
Page CE, Coutellier L (2019) Prefrontal excitatory/inhibitory balance in stress and emotional disorders: evidence for over-inhibition. Neurosci Biobehav Rev 105:39–51
Parihar VK, Hattiangady B, Kuruba R, Shuai B, Shetty AK (2011) Predictable chronic mild stress improves mood, hippocampal neurogenesis and memory. Mol Psychiatry 16:171–183
Park J, Moghaddam B (2017) Impact of anxiety on prefrontal cortex encoding of cognitive flexibility. Neuroscience 345:193–202
Pavlova I, Broshevitskaya N, Onufriev M, Moiseeva YV (2020) Sex-related differences in anxious-depressive and defensive behavior in Wistar rats. Neurosci Behav Physiol 50:1163–1175
Planchez B, Surget A, Belzung C (2019) Animal models of major depression: drawbacks and challenges. J Neural Transm 126:1383–1408
Popoli M, Yan Z, McEwen BS, Sanacora G (2012) The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13:22–37
Prager EM, Bergstrom HC, Grunberg NE, Johnson LR (2011) The importance of reporting housing and husbandry in rat research. Front Behav Neurosci 5:38
Punzi EH (2016) Excessive behaviors in clinical practice—a state of the art article. Int J Qual Stud Health Well Being 11:30055
Quan M, Zheng C, Zhang N, Han D, Tian Y, Zhang T, Yang Z (2011) Impairments of behavior, information flow between thalamus and cortex, and prefrontal cortical synaptic plasticity in an animal model of depression. Brain Res Bull 85:109–116
Reimherr FW, Marchant BK, Gift TE, Steans TA (2017) ADHD and anxiety: clinical significance and treatment implications. Curr Psychiatry Rep 19:109
Sabol K, Richards J, Broom S, Roach J, Hausknecht K (2003) Effects of stimulus salience and methamphetamine on choice reaction time in the rat: central tendency versus distribution skew. Behav Pharmacol 14:489–500
Schatz DB, Rostain AL (2006) ADHD with comorbid anxiety: a review of the current literature. J Atten Disord 10:141–149
Scholl JL, Afzal A, Fox LC, Watt MJ, Forster GL (2019) Sex differences in anxiety-like behaviors in rats. Physiol Behav 211:112670
Sequeira-Cordero A, Salas-Bastos A, Fornaguera J, Brenes J (2019) Behavioural characterisation of chronic unpredictable stress based on ethologically relevant paradigms in rats. Sci Rep 9:1–21
Sequeira-Cordero A, Salas-Bastos A, Fornaguera J, Brenes JC (2019) Behavioural characterisation of chronic unpredictable stress based on ethologically relevant paradigms in rats. Sci Rep 9:17403
Sestakova N, Puzserova A, Kluknavsky M, Bernatova I (2013) Determination of motor activity and anxiety-related behaviour in rodents: methodological aspects and role of nitric oxide. Interdiscip Toxicol 6:126–135
Shaw P, Eckstrand K, Sharp W, Blumenthal J, Lerch J, Greenstein D, Clasen L, Evans A, Giedd J, Rapoport J (2007) Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci 104:19649–19654
Shi R, Sharpe L, Abbott M (2019) A meta-analysis of the relationship between anxiety and attentional control. Clin Psychol Rev 72:101754
Sibley MH, Rohde LA, Swanson JM, Hechtman LT, Molina BSG, Mitchell JT, Arnold LE, Caye A, Kennedy TM, Roy A, Stehli A, Multimodal Treatment Study of Children with ACG (2018) Late-onset ADHD reconsidered with comprehensive repeated assessments between ages 10 and 25. Am J Psychiatry 175:140–149
Sørensen L, Plessen KJ, Nicholas J, Lundervold AJ (2011) Is behavioral regulation in children with ADHD aggravated by comorbid anxiety disorder? J Atten Disord 15:56–66
Suo L, Zhao L, Si J, Liu J, Zhu W, Chai B, Zhang Y, Feng J, Ding Z, Luo Y (2013) Predictable chronic mild stress in adolescence increases resilience in adulthood. Neuropsychopharmacology 38:1387–1400
Tannock R (2000) Attention-deficit/hyperactivity disorder with anxiety disorders. In: Brown TE (ed) Attention-deficit disorders and comorbidities in children, adolescents, and adults. American Psychiatric Press, Washington, DC, pp 125–170
Thapar A (2018) Discoveries on the genetics of ADHD in the 21st century: new findings and their implications. Am J Psychiatry 175:943–950
Thapar A, Cooper M, Eyre O, Langley K (2013) Practitioner review: what have we learnt about the causes of ADHD? J Child Psychol Psychiatry 54:3–16
Tirelli E, Laviola G, Adriani W (2003) Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in laboratory rodents. Neurosci Biobehav Rev 27:163–178
Underwood MD, Bakalian MJ, Escobar T, Kassir S, Mann JJ, Arango V (2019) Early-life adversity, but not suicide, is associated with less prefrontal cortex gray matter in adulthood. Int J Neuropsychopharmacol 22:349–357
Wang R, Hausknecht K, Haj-Dahmane S, Shen R-Y, Richards JB (2018) Decreased environmental complexity during development impairs habituation of reinforcer effectiveness of sensory stimuli. Behav Brain Res 337:53–60
Wang R, Hausknecht KA, Gancarz-Kausch AM, Oubraim S, Shen RY, Haj-Dahmane S (2020) Cocaine self-administration abolishes endocannabinoid-mediated long-term depression of glutamatergic synapses in the ventral tegmental area. Eur J Neurosci. 52(11):4517–4524
Wang R, Martin CD, Lei AL, Hausknecht KA, Ishiwari K, Richards JB, Haj-Dahmane S, Shen R-Y (2020) Prenatal ethanol exposure leads to attention deficits in both male and female rats. Front Neurosci 14:12
Wang R, Martin CD, Lei AL, Hausknecht KA, Ishiwari K, Oubraim S, Wang A-L, Richards JB, Haj-Dahmane S, Shen R-Y (2021) Moderate prenatal ethanol exposure leads to attention deficits in both male and female rats. Alcohol Clin Exp Res 45(5):1122–1135. https://doi.org/10.1111/acer.14599
Wang R, Martin CD, Lei AL, Hausknecht KA, Turk M, Micov V, Kwarteng F, Ishiwari K, Oubraim S, Wang AL, Richards JB, Haj-Dahmane S, Shen RY (2022) Prenatal ethanol exposure impairs sensory processing and habituation to visual stimuli, effects normalized by enrichment of postnatal environmental. Alcohol Clin Exp Res 46(5):894–906. https://doi.org/10.1111/acer.14818
Weissman DH, Roberts K, Visscher K, Woldorff M (2006) The neural bases of momentary lapses in attention. Nat Neurosci 9:971
Yetnikoff L, Reichard RA, Schwartz ZM, Parsely KP, Zahm DS (2014) Protracted maturation of forebrain afferent connections of the ventral tegmental area in the rat. J Comp Neurol 522:1031–1047
Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z (2012) Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron 73:962–977
Zimmerberg B, Farley MJ (1993) Sex differences in anxiety behavior in rats: role of gonadal hormones. Physiol Behav 54:1119–1124
Zorrilla EP (1997) Multiparous species present problems (and possibilities) to developmentalists. Dev Psychobiol 30:141–150
Acknowledgements
The authors thank Mark Kogutowski for his technical support.
Funding
This work was supported by the National Institutes of Health (Grant AA026421 to RS).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Kwarteng, F., Wang, R., Micov, V. et al. Adolescent chronic unpredictable stress leads to increased anxiety and attention deficit/hyperactivity-like symptoms in adulthood. Psychopharmacology 239, 3779–3791 (2022). https://doi.org/10.1007/s00213-022-06242-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-022-06242-1