Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens.
Chronic stress is a strong diathesis for depression in humans and is used to generate animal models of depression. It commonly leads to several major symptoms of depression, including dysregulated feeding behaviour, anhedonia and behavioural despair. Although hypotheses defining the neural pathophysiology of depression have been proposed, the critical synaptic adaptations in key brain circuits that mediate stress-induced depressive symptoms remain poorly understood. Here we show that chronic stress in mice decreases the strength of excitatory synapses on D1 dopamine receptor-expressing nucleus accumbens medium spiny neurons owing to activation of the melanocortin 4 receptor. Stress-elicited increases in behavioural measurements of anhedonia, but not increases in measurements of behavioural despair, are prevented by blocking these melanocortin 4 receptor-mediated synaptic changes in vivo. These results establish that stress-elicited anhedonia requires a neuropeptide-triggered, cell-type-specific synaptic adaptation in the nucleus accumbens and that distinct circuit adaptations mediate other major symptoms of stress-elicited depression.
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA.
Byung Kook
BK
Lim
Kee Wui
KW
Huang
Brad A
BA
Grueter
Patrick E
PE
Rothwell
Robert C
RC
Malenka
D059445:Anhedonia / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology; D003863:Depression / Q000473:pathology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D054351:Electrical Synapses / Q000235:genetics / Q000378:metabolism*; D005247:Feeding Behavior / Q000502:physiology; D055785:Gene Knockdown Techniques; D051379:Mice; D009714:Nucleus Accumbens / Q000473:pathology*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013315:Stress, Psychological / Q000473:pathology*; D015431:Weight Loss / Q000235:genetics; D000521:alpha-MSH / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; D003042:Cocaine