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The dynamics of stress: a longitudinal MRI study of rat brain structure and connectome

Abstract

Stress is a well-established trigger for a number of neuropsychiatric disorders, as it alters both structure and function of several brain regions and its networks. Herein, we conduct a longitudinal neuroimaging study to assess how a chronic unpredictable stress protocol impacts the structure of the rat brain and its functional connectome in both high and low responders to stress. Our results reveal the changes that stress triggers in the brain, with structural atrophy affecting key regions such as the prelimbic, cingulate, insular and retrosplenial, somatosensory, motor, auditory and perirhinal/entorhinal cortices, the hippocampus, the dorsomedial striatum, nucleus accumbens, the septum, the bed nucleus of the stria terminalis, the thalamus and several brain stem nuclei. These structural changes are associated with increasing functional connectivity within a network composed by these regions. Moreover, using a clustering based on endocrine and behavioural outcomes, animals were classified as high and low responders to stress. We reveal that susceptible animals (high responders) develop local atrophy of the ventral tegmental area and an increase in functional connectivity between this area and the thalamus, further spreading to other areas that link the cognitive system with the fight-or-flight system. Through a longitudinal approach we were able to establish two distinct patterns, with functional changes occurring during the exposure to stress, but with an inflection point after the first week of stress when more prominent changes were seen. Finally, our study revealed differences in functional connectivity in a brainstem–limbic network that distinguishes resistant and susceptible responders before any exposure to stress, providing the first potential imaging-based predictive biomarkers of an individual’s resilience/vulnerability to stressful conditions.

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References

  1. deKloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005; 6: 463–475.

    Article  CAS  Google Scholar 

  2. Russo SJ, Murrough JW, Han MH, Charney DS, Nestler EJ. Neurobiology of resilience. Nat Neurosci 2012; 15: 1475–1484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Southwick SM, Charney DS. The science of resilience: implications for the prevention and treatment of depression. Science 2012; 338: 79–82.

    Article  CAS  PubMed  Google Scholar 

  4. Fleshner M, Maier SF, Lyons DM, Raskind MA. The neurobiology of the stress-resistant brain. Stress 2011; 14: 498–502.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Brewin CR, Andrews B, Valentine JD. Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J Consul Clin Psychol 2000; 68: 748–766.

    Article  CAS  Google Scholar 

  6. Hammen C. Stress and depression. Annu Rev Clin Psychol 2005; 1: 293–319.

    Article  PubMed  Google Scholar 

  7. Melchior M, Caspi A, Milne BJ, Danese A, Poulton R, Moffitt TE. Work stress precipitates depression and anxiety in young, working women and men. Psychol Med 2007; 37: 1119–1129.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Welberg L. Psychiatric disorders: a REDD line from stress to depression. Nat Rev Neurosci 2014; 15: 350–351.

    Article  PubMed  Google Scholar 

  9. Fride E, Dan Y, Feldon J, Halevy G, Weinstock M. Effects of prenatal stress on vulnerability to stress in prepubertal and adult rats. Physiol Behav 1986; 37: 681–687.

    Article  CAS  PubMed  Google Scholar 

  10. Hougaard KS, Andersen MB, Kjaer SL, Hansen AM, Werge T, Lund SP. Prenatal stress may increase vulnerability to life events: comparison with the effects of prenatal dexamethasone. Brain Res Dev Brain Res 2005; 159: 55–63.

    Article  CAS  PubMed  Google Scholar 

  11. Rodrigues AJ, Leao P, Carvalho M, Almeida OF, Sousa N. Potential programming of dopaminergic circuits by early life stress. Psychopharmacology (Berl) 2011; 214: 107–120.

    Article  CAS  Google Scholar 

  12. Castro JE, Diessler S, Varea E, Marquez C, Larsen MH, Cordero MI et al. Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity. Psychoneuroendocrinology 2012; 37: 1209–1223.

    Article  CAS  PubMed  Google Scholar 

  13. Duclot F, Kabbaj M. Individual differences in novelty seeking predict subsequent vulnerability to social defeat through a differential epigenetic regulation of brain-derived neurotrophic factor expression. J Neurosci 2013; 33: 11048–11060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sandi C, Cordero MI, Ugolini A, Varea E, Caberlotto L, Large CH. Chronic stress-induced alterations in amygdala responsiveness and behavior—modulation by trait anxiety and corticotropin-releasing factor systems. Eur J Neurosci 2008; 28: 1836–1848.

    Article  PubMed  Google Scholar 

  15. Dudley KJ, Li X, Kobor MS, Kippin TE, Bredy TW. Epigenetic mechanisms mediating vulnerability and resilience to psychiatric disorders. Neurosci Biobehav Rev 2011; 35: 1544–1551.

    Article  PubMed  Google Scholar 

  16. Arentsen T, Qian Y, Gkotzis S, Femenia T, Wang T, Udekwu K et al. The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior. Mol Psychiatry 2017; 22: 257–266.

    Article  CAS  PubMed  Google Scholar 

  17. Kelly JR, Clarke G, Cryan JF, Dinan TG. Brain-gut-microbiota axis: challenges for translation in psychiatry. Ann Epidemiol 2016; 26: 366–372.

    Article  PubMed  Google Scholar 

  18. Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015; 9: 392.

    PubMed  PubMed Central  Google Scholar 

  19. Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron 2012; 73: 962–977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gray JD, Rubin TG, Kogan JF, Marrocco J, Weidmann J, Lindkvist S et al. Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice. Mol Psychiatry 2016 e-pub ahead of print 13 December 2016; 10.1038/mp.2016.219.

  21. Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 2011; 13: 22–37.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sousa N, Lukoyanov NV, Madeira MD, Almeida OF, Paula-Barbosa MM. Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement. Neuroscience 2000; 97: 253–266.

    Article  CAS  PubMed  Google Scholar 

  23. Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N. The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci 2007; 27: 2781–2787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science 2009; 325: 621–625.

    Article  CAS  PubMed  Google Scholar 

  25. Soares J, Sampaio A, Ferreira LM, Santos NC, Marques P, Marques F et al. Stress Impact on Resting State Brain Networks. PLoS ONE 2013; 8: 6.

    Google Scholar 

  26. Henckens MJ, van der Marel K, van der Toorn A, Pillai AG, Fernandez G, Dijkhuizen RM et al. Stress-induced alterations in large-scale functional networks of the rodent brain. Neuroimage 2015; 105: 312–322.

    Article  PubMed  Google Scholar 

  27. Franklin TB, Saab BJ, Mansuy IM. Neural mechanisms of stress resilience and vulnerability. Neuron 2012; 75: 747–761.

    Article  CAS  PubMed  Google Scholar 

  28. Anacker C, Scholz J, O'Donnell KJ, Allemang-Grand R, Diorio J, Bagot RC et al. Neuroanatomic differences associated with stress susceptibility and resilience. Biol Psychiatry 2016; 79: 840–849.

    Article  PubMed  Google Scholar 

  29. Magalhaes R, Bourgin J, Boumezbeur F, Marques P, Bottlaender M, Poupon C et al. White matter changes in microstructure associated with a maladaptive response to stress in rats. Transl Psychiatry 2017; 7: e1009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Savitz JB, Rauch SL, Drevets WC. Clinical application of brain imaging for the diagnosis of mood disorders: the current state of play. Mol Psychiatry 2013; 18: 528–539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Loeser JD, Melzack R. Pain: an overview. Lancet 1999; 353: 1607–1609.

    Article  CAS  PubMed  Google Scholar 

  32. Sousa N. The dynamics of the stress neuromatrix. Mol Psychiatry 2016; 21: 302–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bourgin J, Cachia A, Boumezbeur F, Djemaï B, Bottlaender M, Duchesnay E et al. Hyper-responsivity to stress in rats is associated with a large increase in amygdala volume. A 7T MRI study. Eur Neuropsychopharmacol 2015; 25: 828–835.

    Article  CAS  PubMed  Google Scholar 

  34. Cerqueira JJ, Pêgo J, Taipa R, Bessa JM, Almeida OFX, Sousa N. Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors. J Neurosci 2005; 25: 7792–7800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Soares JM, Sampaio A, Ferreira LM, Santos NC, Marques F, Palha JA et al. Stress-induced changes in human decision-making are reversible. Transl Psychiatry 2012; 2: e131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci 1999; 22: 105–122.

    Article  CAS  PubMed  Google Scholar 

  37. Sauro MD, Jorgensen RS, Pedlow CT. Stress, glucocorticoids, and memory: a meta-analytic review. Stress 2003; 6: 235–245.

    Article  CAS  PubMed  Google Scholar 

  38. Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 2013; 493: 532–536.

    Article  CAS  PubMed  Google Scholar 

  39. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 2007; 131: 391–404.

    Article  CAS  PubMed  Google Scholar 

  40. Wilkinson MB, Xiao G, Kumar A, LaPlant Q, Renthal W, Sikder D et al. Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models. J Neurosci 2009; 29: 7820–7832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pego JM, Morgado P, Pinto LG, Cerqueira JJ, Almeida OF, Sousa N. Dissociation of the morphological correlates of stress-induced anxiety and fear. Eur J Neurosci 2008; 27: 1503–1516.

    Article  CAS  PubMed  Google Scholar 

  42. Cameron HA, McEwen BS, Gould E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci 1995; 15: 4687–4692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci 2007; 10: 1110–1115.

    Article  CAS  PubMed  Google Scholar 

  44. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 2009; 10: 397–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work is part of the Sigma project with the reference FCT-ANR/NEU-OSD/0258/2012 co-financed by the French public funding agency ANR (Agence National pour la Recherche, APP Blanc International II 2012), the Portuguese FCT (Fundação para a Ciência e Tecnologia) and by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER) as well as the Projecto Estratégico co-funded by FCT (PEst-C/SAU/LA0026-/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298). DAB and AN were funded by grants from FCT-ANR/NEU-OSD/0258/2012. RM is supported by the FCT fellowship grant with the reference PDE/BDE/113604/2015 from the PhD-iHES program; AC was supported by a grant from the foundation NRJ. PM was funded by Fundação Calouste Gulbenkian (Portugal; ‘Better mental health during ageing based on temporal prediction of individual brain ageing trajectories (TEMPO)’), Grant Number P-139977. We thank Drs Patrício Costa and Pedro Moreira for support on the various statistical analyses.

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Magalhães, R., Barrière, D.A., Novais, A. et al. The dynamics of stress: a longitudinal MRI study of rat brain structure and connectome. Mol Psychiatry 23, 1998–2006 (2018). https://doi.org/10.1038/mp.2017.244

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