title: In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward.
abstract: The reinforcing and rewarding properties of cocaine are attributed to its ability to increase dopaminergic transmission in nucleus accumbens (NAc). This action reinforces drug taking and seeking and leads to potent and long-lasting associations between the rewarding effects of the drug and the cues associated with its availability. The inability to extinguish these associations is a key factor contributing to relapse. Dopamine produces these effects by controlling the activity of two subpopulations of NAc medium spiny neurons (MSNs) that are defined by their predominant expression of either dopamine D1 or D2 receptors. Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion. However, we still lack a clear understanding of how the endogenous activity of these cell types is affected by cocaine and encodes information that drives drug-associated behaviors. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in NAc that encodes information about drug associations and elucidate the temporal profile with which D1 activity is increased to drive drug seeking in response to contextual cues. Chronic cocaine exposure dysregulates these D1 signals to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Directly manipulating these D1 signals using designer receptors exclusively activated by designer drugs prevents contextual associations. Together, these data elucidate the responses of D1- and D2-type MSNs in NAc to acute cocaine and during the formation of context-reward associations and define how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Erin S
authors.initials: ES
authors.lastname: Calipari
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Bagot
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Immanuel
authors.initials: I
authors.lastname: Purushothaman
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Davidson
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, OR 97239;
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Yorgason
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Peña
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Deena M
authors.initials: DM
authors.lastname: Walker
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Pirpinias
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Guise
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305;
authors.forename: Charu
authors.initials: C
authors.lastname: Ramakrishnan
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305; Department of Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA 94305.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; eric.nestler@mssm.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003463:Cues; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D058999:Drug-Seeking Behavior / Q000187:drug effects; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D059906:Neuroimaging / Q000379:methods; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003042:Cocaine
keywords: associative learning; calcium imaging; cocaine; medium spiny neuron; reward
references.citation: Proc Natl Acad Sci U S A. 1988 Jul;85(14):5274-8
references.pmid: 2899326
references.citation: Neuropharmacology. 2014 Jan;76 Pt B:351-9
references.pmid: 23578393
references.citation: Brain Res. 1993 Oct 29;626(1-2):14-22
references.pmid: 8281424
references.citation: Science. 1996 Mar 15;271(5255):1586-9
references.pmid: 8599115
references.citation: Curr Opin Neurobiol. 1996 Apr;6(2):228-36
references.pmid: 8725965
references.citation: Science. 1997 Mar 14;275(5306):1593-9
references.pmid: 9054347
references.citation: Science. 1998 Oct 9;282(5387):298-300
references.pmid: 9765157
references.citation: Annu Rev Psychol. 2006;57:87-115
references.pmid: 16318590
references.citation: Psychopharmacology (Berl). 2007 Apr;191(3):719-30
references.pmid: 16835769
references.citation: J Neurosci. 2007 Mar 28;27(13):3535-9
references.pmid: 17392469
references.citation: Br J Pharmacol. 2008 May;154(2):327-42
references.pmid: 18345022
references.citation: Philos Trans R Soc Lond B Biol Sci. 2008 Oct 12;363(1507):3233-43
references.pmid: 18640922
references.citation: Neuropharmacology. 2009;56 Suppl 1:149-59
references.pmid: 18625253
references.citation: Prog Neurobiol. 2010 Apr;90(4):385-417
references.pmid: 19941931
references.citation: Trends Neurosci. 2010 Jun;33(6):267-76
references.pmid: 20207024
references.citation: Science. 2010 Oct 15;330(6002):385-90
references.pmid: 20947769
references.citation: Annu Rev Neurosci. 2011;34:441-66
references.pmid: 21469956
references.citation: Nat Rev Neurosci. 2011 Nov;12(11):623-37
references.pmid: 21989194
references.citation: Science. 2012 Apr 13;336(6078):241-5
references.pmid: 22499948
references.citation: Handb Clin Neurol. 2012;106:419-31
references.pmid: 22608635
references.citation: Nat Neurosci. 2013 Jul;16(7):966-73
references.pmid: 23708143
references.citation: Ann N Y Acad Sci. 1992 Jun 28;654:400-15
references.pmid: 1632593
references.citation: Cell. 2014 Jun 19;157(7):1535-51
references.pmid: 24949967
references.citation: Nat Neurosci. 2014 Sep;17(9):1198-207
references.pmid: 25108911
references.citation: J Neurosci. 2014 Oct 22;34(43):14349-64
references.pmid: 25339748
references.citation: Neuropsychopharmacology. 2000 Sep;23(3):335-44
references.pmid: 10942857
references.citation: Nature. 2001 Jul 12;412(6843):141-2
references.pmid: 11449260
references.citation: Neuropsychopharmacology. 2002 Jun;26(6):703-15
references.pmid: 12007741
references.citation: Science. 2003 Mar 21;299(5614):1898-902
references.pmid: 12649484
references.citation: Nature. 2003 Apr 10;422(6932):614-8
references.pmid: 12687000
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14282-7
references.pmid: 15375209
references.citation: J Neurosci. 2012 May 30;32(22):7577-84
references.pmid: 22649236
references.citation: Nat Neurosci. 2012 Jun;15(6):816-8
references.pmid: 22544310
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1923-8
references.pmid: 23319622
references.citation: Nature. 2013 Feb 14;494(7436):238-42
references.pmid: 23354054
references.citation: J Neurosci. 2013 Apr 17;33(16):6759-65
references.pmid: 23595734
references.citation: Annu Rev Pharmacol Toxicol. 2015;55:399-417
references.pmid: 25292433