Abstract
Parallel clinical and preclinical research have begun to illuminate the biological basis of stress-related disorders, including major depression, but translational bridges informing discrete mechanistic targets for intervention are missing. To address this critical need, we used structural MRI in a mouse model and in a large human sample to examine stress effects on brain structure that may be conserved across species. Specifically, we focused on a previously unexplored approach, whole-brain structural covariance, as it reflects synchronized changes in neuroanatomy, potentially due to mutual trophic influences or shared plasticity across regions. Using the unpredictable chronic mild stress (UCMS) paradigm in mouse we first demonstrate that UCMS-induced elevated behavioral emotionality correlates with increased size of the amygdala and other corticolimbic regions. We further identify focal increases in the amygdala’s ‘hubness’ (degree and strength) set against the background of a global stress-related loss of network clustering and modularity. These macroscopic changes are supported on the molecular level by increased postsynaptic density-95 protein in the amygdala, consistent with stress-induced plastic changes and synaptic strengthening. Finally, we provide clinical evidence that strikingly similar structural network reorganization patterns exist in young adults reporting high childhood trauma and increased mood symptoms. Collectively, we provide initial translational evidence for a conserved stress-related increase in amygdala-centered structural synchrony, as measured by enhanced structural covariance, which is paralleled by a decrease in global structural synchrony. This putative trade-off reflected in increased amygdala-centered plastic changes at the expense of global structural dedifferentiation may represent a mechanistic pathway for depression and related psychopathology.
Highlights
Major depressive disorder (MDD) is a chronic debilitating illness characterized by low mood, anhedonia, and emotion dysregulation.[1]
UCMSexposed mice displayed increased anxiety-like deficits in the elevated plus maze (EPM) (Fig. 1h) and novelty suppressed feeding (NSF) tests (Supplementary Figure 2)
Using a novel translational approach centered on parallel applications of structural neuroimaging, we provide initial cross-species evidence for large-scale behavioral and brain network alterations associated with chronic stress
Summary
Major depressive disorder (MDD) is a chronic debilitating illness characterized by low mood, anhedonia, and emotion dysregulation.[1].
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