Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward.
The nucleus accumbens is a key mediator of cocaine reward, but the distinct roles of the two subpopulations of nucleus accumbens projection neurons, those expressing dopamine D1 versus D2 receptors, are poorly understood. We show that deletion of TrkB, the brain-derived neurotrophic factor (BDNF) receptor, selectively from D1+ or D2+ neurons oppositely affects cocaine reward. Because loss of TrkB in D2+ neurons increases their neuronal excitability, we next used optogenetic tools to control selectively the firing rate of D1+ and D2+ nucleus accumbens neurons and studied consequent effects on cocaine reward. Activation of D2+ neurons, mimicking the loss of TrkB, suppresses cocaine reward, with opposite effects induced by activation of D1+ neurons. These results provide insight into the molecular control of D1+ and D2+ neuronal activity as well as the circuit-level contribution of these cell types to cocaine reward.
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
Mary Kay
MK
Lobo
Herbert E
HE
Covington
Dipesh
D
Chaudhury
Allyson K
AK
Friedman
HaoSheng
H
Sun
Diane
D
Damez-Werno
David M
DM
Dietz
Samir
S
Zaman
Ja Wook
JW
Koo
Pamela J
PJ
Kennedy
Ezekiell
E
Mouzon
Murtaza
M
Mogri
Rachael L
RL
Neve
Karl
K
Deisseroth
Ming-Hu
MH
Han
Eric J
EJ
Nestler
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D000075402:Channelrhodopsins; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D003213:Conditioning, Psychological; D008027:Light; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012201:Reward; D015398:Signal Transduction
D019208:Brain-Derived Neurotrophic Factor; D000075402:Channelrhodopsins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D020813:Receptor, trkB; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003042:Cocaine