Direct regulation of diurnal drd3 expression and cocaine reward by npas2

Angela R. Ozburn, Edgardo Falcon, Alan Twaddle, Alexandria L. Nugent, Andrea G. Gillman, Sade M. Spencer, Rachel N. Arey, Shibani Mukherjee, James Lyons-Weiler, David W. Self, Colleen A. McClung

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate reward remain poorly understood. Methods We used mice with a mutation in Npas2 and adeno-associated virus-short hairpin RNA mediated knockdown of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference assays. We utilized cell sorting quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation followed by deep sequencing. Results Npas2 mutants exhibit decreased sensitivity to cocaine reward, which is recapitulated with a knockdown of neuronal PAS domain protein 2 (NPAS2) specifically in the NAc, demonstrating the importance of NPAS2 in this region. Interestingly, reducing circadian locomotor output cycles kaput (CLOCK) (a homologue of NPAS2) in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we found that NPAS2 expression is restricted to Drd1 expressing neurons while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and found that NPAS2 knockdown in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine. Conclusions Together, these findings identify an important role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward.

Original languageEnglish (US)
Pages (from-to)425-433
Number of pages9
JournalBiological Psychiatry
Volume77
Issue number5
DOIs
StatePublished - Mar 1 2015

Fingerprint

Reward
Cocaine
Nucleus Accumbens
CLOCK Proteins
Dopamine Receptors
High-Throughput Nucleotide Sequencing
Dependovirus
Dopamine Agents
Chromatin Immunoprecipitation
Circadian Rhythm
Protein Domains
Small Interfering RNA
Genes
Psychiatry
Real-Time Polymerase Chain Reaction
Proteins
Binding Sites
Neurons
Mutation
DNA

Keywords

  • Circadian
  • Clock
  • Cocaine
  • Drd3
  • Npas2
  • Reward

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Ozburn, A. R., Falcon, E., Twaddle, A., Nugent, A. L., Gillman, A. G., Spencer, S. M., ... McClung, C. A. (2015). Direct regulation of diurnal drd3 expression and cocaine reward by npas2. Biological Psychiatry, 77(5), 425-433. https://doi.org/10.1016/j.biopsych.2014.07.030

Direct regulation of diurnal drd3 expression and cocaine reward by npas2. / Ozburn, Angela R.; Falcon, Edgardo; Twaddle, Alan; Nugent, Alexandria L.; Gillman, Andrea G.; Spencer, Sade M.; Arey, Rachel N.; Mukherjee, Shibani; Lyons-Weiler, James; Self, David W.; McClung, Colleen A.

In: Biological Psychiatry, Vol. 77, No. 5, 01.03.2015, p. 425-433.

Research output: Contribution to journalArticle

Ozburn, AR, Falcon, E, Twaddle, A, Nugent, AL, Gillman, AG, Spencer, SM, Arey, RN, Mukherjee, S, Lyons-Weiler, J, Self, DW & McClung, CA 2015, 'Direct regulation of diurnal drd3 expression and cocaine reward by npas2', Biological Psychiatry, vol. 77, no. 5, pp. 425-433. https://doi.org/10.1016/j.biopsych.2014.07.030
Ozburn AR, Falcon E, Twaddle A, Nugent AL, Gillman AG, Spencer SM et al. Direct regulation of diurnal drd3 expression and cocaine reward by npas2. Biological Psychiatry. 2015 Mar 1;77(5):425-433. https://doi.org/10.1016/j.biopsych.2014.07.030
Ozburn, Angela R. ; Falcon, Edgardo ; Twaddle, Alan ; Nugent, Alexandria L. ; Gillman, Andrea G. ; Spencer, Sade M. ; Arey, Rachel N. ; Mukherjee, Shibani ; Lyons-Weiler, James ; Self, David W. ; McClung, Colleen A. / Direct regulation of diurnal drd3 expression and cocaine reward by npas2. In: Biological Psychiatry. 2015 ; Vol. 77, No. 5. pp. 425-433.
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abstract = "Background Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate reward remain poorly understood. Methods We used mice with a mutation in Npas2 and adeno-associated virus-short hairpin RNA mediated knockdown of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference assays. We utilized cell sorting quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation followed by deep sequencing. Results Npas2 mutants exhibit decreased sensitivity to cocaine reward, which is recapitulated with a knockdown of neuronal PAS domain protein 2 (NPAS2) specifically in the NAc, demonstrating the importance of NPAS2 in this region. Interestingly, reducing circadian locomotor output cycles kaput (CLOCK) (a homologue of NPAS2) in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we found that NPAS2 expression is restricted to Drd1 expressing neurons while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and found that NPAS2 knockdown in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine. Conclusions Together, these findings identify an important role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward.",
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AU - Spencer, Sade M.

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N2 - Background Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate reward remain poorly understood. Methods We used mice with a mutation in Npas2 and adeno-associated virus-short hairpin RNA mediated knockdown of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference assays. We utilized cell sorting quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation followed by deep sequencing. Results Npas2 mutants exhibit decreased sensitivity to cocaine reward, which is recapitulated with a knockdown of neuronal PAS domain protein 2 (NPAS2) specifically in the NAc, demonstrating the importance of NPAS2 in this region. Interestingly, reducing circadian locomotor output cycles kaput (CLOCK) (a homologue of NPAS2) in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we found that NPAS2 expression is restricted to Drd1 expressing neurons while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and found that NPAS2 knockdown in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine. Conclusions Together, these findings identify an important role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward.

AB - Background Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate reward remain poorly understood. Methods We used mice with a mutation in Npas2 and adeno-associated virus-short hairpin RNA mediated knockdown of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference assays. We utilized cell sorting quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation followed by deep sequencing. Results Npas2 mutants exhibit decreased sensitivity to cocaine reward, which is recapitulated with a knockdown of neuronal PAS domain protein 2 (NPAS2) specifically in the NAc, demonstrating the importance of NPAS2 in this region. Interestingly, reducing circadian locomotor output cycles kaput (CLOCK) (a homologue of NPAS2) in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we found that NPAS2 expression is restricted to Drd1 expressing neurons while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and found that NPAS2 knockdown in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine. Conclusions Together, these findings identify an important role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward.

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