title: Synaptic modifications in the medial prefrontal cortex in susceptibility and resilience to stress.
abstract: When facing stress, most individuals are resilient whereas others are prone to developing mood disorders. The brain mechanisms underlying such divergent behavioral responses remain unclear. Here we used the learned helplessness procedure in mice to examine the role of the medial prefrontal cortex (mPFC), a brain region highly implicated in both clinical and animal models of depression, in adaptive and maladaptive behavioral responses to stress. We found that uncontrollable and inescapable stress induced behavioral state-dependent changes in the excitatory synapses onto a subset of mPFC neurons: those that were activated during behavioral responses as indicated by their expression of the activity reporter c-Fos. Whereas synaptic potentiation was linked to learned helplessness, a depression-like behavior, synaptic weakening, was associated with resilience to stress. Notably, enhancing the activity of mPFC neurons using a chemical-genetic method was sufficient to convert the resilient behavior into helplessness. Our results provide direct evidence that mPFC dysfunction is linked to maladaptive behavioral responses to stress, and suggest that enhanced excitatory synaptic drive onto mPFC neurons may underlie the previously reported hyperactivity of this brain region in depression.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724.
authors.forename: Minghui
authors.initials: M
authors.lastname: Wang
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, and.
authors.forename: Zinaida
authors.initials: Z
authors.lastname: Perova
authors.affiliation: Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Arenkiel
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, and bli@cshl.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D006380:Helplessness, Learned; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017397:Prefrontal Cortex / Q000473:pathology / Q000503:physiopathology*; D055500:Resilience, Psychological; D013315:Stress, Psychological / Q000473:pathology / Q000503:physiopathology*; D013569:Synapses / Q000473:pathology / Q000502:physiology*
keywords: c-Fos; chemical–genetic; depression; excitatory synapses; learned helplessness; mPFC