Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex.
Brain stimulation and imaging studies in humans have highlighted a key role for the prefrontal cortex in clinical depression; however, it remains unknown whether excitation or inhibition of prefrontal cortical neuronal activity is associated with antidepressant responses. Here, we examined cellular indicators of functional activity, including the immediate early genes (IEGs) zif268 (egr1), c-fos, and arc, in the prefrontal cortex of clinically depressed humans obtained postmortem. We also examined these genes in the ventral portion of the medial prefrontal cortex (mPFC) of mice after chronic social defeat stress, a mouse model of depression. In addition, we used viral vectors to overexpress channel rhodopsin 2 (a light-activated cation channel) in mouse mPFC to optogenetically drive "burst" patterns of cortical firing in vivo and examine the behavioral consequences. Prefrontal cortical tissue derived from clinically depressed humans displayed significant reductions in IEG expression, consistent with a deficit in neuronal activity within this brain region. Mice subjected to chronic social defeat stress exhibited similar reductions in levels of IEG expression in mPFC. Interestingly, some of these changes were not observed in defeated mice that escape the deleterious consequences of the stress, i.e., resilient animals. In those mice that expressed a strong depressive-like phenotype, i.e., susceptible animals, optogenetic stimulation of mPFC exerted potent antidepressant-like effects, without affecting general locomotor activity, anxiety-like behaviors, or social memory. These results indicate that the activity of the mPFC is a key determinant of depression-like behavior, as well as antidepressant responses.
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
Herbert E
HE
Covington
Mary Kay
MK
Lobo
Ian
I
Maze
Vincent
V
Vialou
James M
JM
Hyman
Samir
S
Zaman
Quincey
Q
LaPlant
Ezekiel
E
Mouzon
Subroto
S
Ghose
Carol A
CA
Tamminga
Rachael L
RL
Neve
Karl
K
Deisseroth
Eric J
EJ
Nestler
D000818:Animals; D000075402:Channelrhodopsins; D003866:Depressive Disorder / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early / Q000502:physiology*; D006801:Humans; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000473:pathology / Q000502:physiology*
D000075402:Channelrhodopsins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse