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.
Lobo
Mary Kay
MK
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
Covington
Herbert E
HE
Chaudhury
Dipesh
D
Friedman
Allyson K
AK
Sun
HaoSheng
H
Damez-Werno
Diane
D
Dietz
David M
DM
Zaman
Samir
S
Koo
Ja Wook
JW
Kennedy
Pamela J
PJ
Mouzon
Ezekiell
E
Mogri
Murtaza
M
Neve
Rachael L
RL
Deisseroth
Karl
K
Han
Ming-Hu
MH
Nestler
Eric J
EJ
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