Magalhães R1,2, Barrière DA3, Novais A1,2, Marques F1,2, Marques P1,2, Cerqueira J1,2, Sousa JC1,2, Cachia A3,4,5,6, Boumezbeur F7, Bottlaender M7, Jay TM3,4,8, Mériaux S7, Sousa N1,2.
1 / Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
2 / ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
3 / Physiopathologie des Maladies Psychiatriques, UMR_S 894 Inserm, Centre de Psychiatrie et Neurosciences, Paris, France.
4 / Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
5 / Laboratoire de Psychologie du développement et de l'Education de l'Enfant, CNRS UMR, Paris, France.
6 / Institut Universitaire de France, Paris, France.
7 / Neurospin, JOLIOT, CEA, Gif/Yvette, France.
8 / Faculté de Médecine Paris Descartes, Service Hospitalo-Universitaire, Centre Hospitalier Sainte-Anne, Paris, France.
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.Molecular Psychiatry advance online publication, 5 December 2017; doi:10.1038/mp.2017.244.
Mol Psychiatry. 2017 Dec 5. doi: 10.1038/mp.2017.244. [Epub ahead of print]
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