Reduced resting-state functional connectivity of the basolateral amygdala to the medial prefrontal cortex in preweaning rats exposed to chronic early-life stress
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Early-life stress (ELS) exposure has long-term consequences for both brain structure and function and impacts cognitive and emotional behavior. The basolateral amygdala (BLA) plays an important role in anxiety and fear conditioning through its extensive anatomical and functional connections, in particular to the medial prefrontal cortex (mPFC). However, how ELS affects amygdala function and connectivity in developing rats is unknown. We used the naturalistic limited bedding/nesting (LB) paradigm to induce chronic stress in the pups between postnatal day (PND) 1–10. Male normal bedding (NB, control) or LB offspring underwent structural and resting-state functional MRI (rs-fMRI) on PND18 and in adulthood (PND74–76). Adult male rats were tested for fear conditioning and extinction behavior prior to scanning. Seed-based functional connectivity maps were generated based on four BLA seeds (left, right, anterior and posterior). At both ages, LB induced different effects on anterior and posterior BLA networks, with significant reductions in rs-fMRI connectivity between the anterior BLA and mPFC in LB compared to NB offspring. BLA connectivity was lateralized by preweaning age, with the right hemisphere displaying more connectivity changes than the left. Weak negative volumetric correlations between the BLA and mPFC were also present, mostly in preweaning LB animals. rs-fMRI connectivity and volumetric changes were associated with enhanced fear behaviors in adult LB offspring. Activation of the LB-exposed neonatal amygdala described previously might accelerate the maturation of BLA–mPFC projections and/or modify the activity of reciprocal connections between these structures, leading to a net reduction in rs-fMRI connectivity and increased fear behavior.
KeywordsBasolateral amygdala Resting-state connectivity Neonatal stress Medial prefrontal cortex Preweaning Imaging Volumetry Behavior
We thank Dr Jürgen Germann and Ms Elisa Guma (Douglas Institute, Imaging Center) for their assistance with the Display software package for manual segmentation analyses and preliminary co-registration analyses, respectively.
This study was funded by an NSERC Grant to CDW (Grant #138199) and an internal McGill-Faculty of Medicine studentship award to AG.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving animals and ethical approval
All experimental procedures carried out on Sprague–Dawley rats were approved by the University Animal Care Committee at McGill University in accordance with the guidelines of the Canadian Council on Animal Care.
- Arp JM, Ter Horst JP, Loi M, den Blaauwen J, Bangert E, Fernandez G, Joels M, Oitzl MS, Krugers HJ (2016) Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress. Neurobiol Learn Mem 133:30–38. https://doi.org/10.1016/j.nlm.2016.05.009 CrossRefPubMedGoogle Scholar
- Bolton JL, Molet J, Regev L, Chen Y, Rismanchi N, Haddad E, Yang DZ, Obenaus A, Baram TZ (2018) 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 83(2):137–147. https://doi.org/10.1016/j.biopsych.2017.08.023 CrossRefPubMedGoogle Scholar
- Burghy CA, Stodola DE, Ruttle PL, Molloy EK, Armstrong JM, Oler JA, Fox ME, Hayes AS, Kalin NH, Essex MJ, Davidson RJ, Birn RM (2012) Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence. Nat Neurosci 15(12):1736–1741. https://doi.org/10.1038/nn.3257 CrossRefPubMedPubMedCentralGoogle Scholar
- Eiland L, Ramroop J, Hill MN, Manley J, McEwen BS (2012) Chronic juvenile stress produces corticolimbic dendritic architectural remodeling and modulates emotional behavior in male and female rats. Psychoneuroendocrinology 37(1):39–47. https://doi.org/10.1016/j.psyneuen.2011.04.015 CrossRefPubMedGoogle Scholar
- Essex MJ, Shirtcliff EA, Burk LR, Ruttle PL, Klein MH, Slattery MJ, Kalin NH, Armstrong JM (2011) Influence of early life stress on later hypothalamic–pituitary–adrenal axis functioning and its covariation with mental health symptoms: a study of the allostatic process from childhood into adolescence. Dev Psychopathol 23(4):1039–1058. https://doi.org/10.1017/s0954579411000484 CrossRefPubMedPubMedCentralGoogle Scholar
- Felix-Ortiz AC, Burgos-Robles A, Bhagat ND, Leppla CA, Tye KM (2016) Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex. Neuroscience 321:197–209. https://doi.org/10.1016/j.neuroscience.2015.07.041 CrossRefPubMedGoogle Scholar
- Guadagno A, Wong TP, Walker CD (2018) 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 Neuropsychopharmacol Biol Psychiatry 81:25–37. https://doi.org/10.1016/j.pnpbp.2017.09.025 CrossRefPubMedGoogle Scholar
- Magnuson ME, Thompson GJ, Pan WJ, Keilholz SD (2014) Time-dependent effects of isoflurane and dexmedetomidine on functional connectivity, spectral characteristics, and spatial distribution of spontaneous BOLD fluctuations. NMR Biomed 27(3):291–303. https://doi.org/10.1002/nbm.3062 CrossRefPubMedPubMedCentralGoogle Scholar
- McLaughlin RJ, Verlezza S, Gray JM, Hill MN, Walker CD (2016) Inhibition of anandamide hydrolysis dampens the neuroendocrine response to stress in neonatal rats subjected to suboptimal rearing conditions. Stress 19(1):114–124. https://doi.org/10.3109/10253890.2015.1117448 CrossRefPubMedGoogle Scholar
- Molet J, Maras PM, Kinney-Lang E, Harris NG, Rashid F, Ivy AS, Solodkin A, Obenaus A, Baram TZ (2016) MRI uncovers disrupted hippocampal microstructure that underlies memory impairments after early-life adversity. Hippocampus 26(12):1618–1632. https://doi.org/10.1002/hipo.22661 CrossRefPubMedPubMedCentralGoogle Scholar
- Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. Elsevier Academic Press, AmsterdamGoogle Scholar
- Raineki C, Cortes MR, Belnoue L, Sullivan RM (2012) 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 32(22):7758–7765. https://doi.org/10.1523/JNEUROSCI.5843-11.2012 CrossRefPubMedPubMedCentralGoogle Scholar
- Scicli AP, Petrovich GD, Swanson LW, Thompson RF (2004) Contextual fear conditioning is associated with lateralized expression of the immediate early gene c-fos in the central and basolateral amygdalar nuclei. Behav Neurosci 118(1):5–14. https://doi.org/10.1037/0735-7044.118.1.5 CrossRefPubMedGoogle Scholar
- Sherwood NM, Timiras PS (1970) A stereotaxic atlas of the developing rat brain. University of California Press, BerkeleyGoogle Scholar
- Sierra-Mercado D, Padilla-Coreano N, Quirk GJ (2011) Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology 36(2):529–538. https://doi.org/10.1038/npp.2010.184 CrossRefPubMedGoogle Scholar
- Silvers JA, Goff B, Gabard-Durnam LJ, Gee DG, Fareri DS, Caldera C, Tottenham N (2017) Vigilance, the amygdala, and anxiety in youths with a history of institutional care. Biol Psychiatry Cogn Neurosci Neuroimaging 2(6):493–501. https://doi.org/10.1016/j.bpsc.2017.03.016 CrossRefPubMedPubMedCentralGoogle Scholar
- Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C (2017) Resting state fMRI: a review on methods in resting state connectivity analysis and resting state networks. Neuroradiol J 30(4):305–317. https://doi.org/10.1177/1971400917697342 CrossRefPubMedPubMedCentralGoogle Scholar
- Sperry MM, Kandel BM, Wehrli S, Bass KN, Das SR, Dhillon PS, Gee JC, Barr GA (2017) Mapping of pain circuitry in early post-natal development using manganese-enhanced MRI in rats. Neuroscience 352:180–189. https://doi.org/10.1016/j.neuroscience.2017.03.052 CrossRefPubMedGoogle Scholar
- Venkatraghavan L, Bharadwaj S, Wourms V, Tan A, Jurkiewicz MT, Mikulis DJ, Crawley AP (2017) Brain resting-state functional connectivity is preserved under sevoflurane anesthesia in patients with pervasive developmental disorders: a pilot study. Brain Connect 7(4):250–257. https://doi.org/10.1089/brain.2016.0448 CrossRefPubMedGoogle Scholar
- Verwer RW, Vulpen EH Van, Uum JF Van (1996) Postnatal development of amygdaloid projections to the prefrontal cortex in the rat studied with retrograde and anterograde tracers. J Comp Neurol 376(1):75–96. https://doi.org/10.1002/(SICI)1096-9861(19961202)376:1<75::AID-CNE5>3.0.CO;2-LCrossRefPubMedGoogle Scholar
- Vyas A, Jadhav S, Chattarji S (2006) Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala. Neuroscience 143(2):387–393. https://doi.org/10.1016/j.neuroscience.2006.08.003 CrossRefPubMedGoogle Scholar
- Walker CD, Bath K, Joels M, Korosi A, Larauche M, Lucassen PJ, Morris M, Raineki C, Roth TL, Sullivan RM, Tache Y, Baram TZ (2017) Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential. Stress 20(5):421–448. https://doi.org/10.1080/10253890.2017.1343296 CrossRefPubMedPubMedCentralGoogle Scholar
- Wilber AA, Walker AG, Southwood CJ, Farrell MR, Lin GL, Rebec GV, Wellman CL (2011) Chronic stress alters neural activity in medial prefrontal cortex during retrieval of extinction. Neuroscience 174:115–131. https://doi.org/10.1016/j.neuroscience.2010.10.070 CrossRefPubMedGoogle Scholar
- Yan CG, Rincon-Cortes M, Raineki C, Sarro E, Colcombe S, Guilfoyle DN, Yang Z, Gerum S, Biswal BB, Milham MP, Sullivan RM, Castellanos FX (2017) Aberrant development of intrinsic brain activity in a rat model of caregiver maltreatment of offspring. Transl Psychiatry 7(1):e1005. https://doi.org/10.1038/tp.2016.276 CrossRefPubMedPubMedCentralGoogle Scholar