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CREB Binding at the Zfp189 Promoter Within Medium Spiny Neuron Subtypes Differentially Regulates Behavioral and Physiological Adaptations Over the Course of Cocaine Use
journal contribution
posted on 2023-02-21, 03:45 authored by CD Teague, JA Picone, WJ Wright, CJ Browne, GM Silva, R Futamura, A Minier-Toribio, ME Estill, A Ramakrishnan, FJ Martinez-Rivera, A Godino, EM Parise, KH Schmidt, NV Pulido, ZS Lorsch, Jee Hyun KimJee Hyun Kim, L Shen, RL Neve, Y Dong, EJ Nestler, PJ HamiltonBackground: Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice. Methods: To investigate the role of the CREB-Zfp189 interaction in cocaine use, we virally delivered modified clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 constructs capable of selectively localizing CREB to the Zfp189 gene promoter in the NAc of mice. Results: We observed that CREB binding to the Zfp189 promoter increased Zfp189 expression and diminished the reinforcing responses to cocaine. Furthermore, we showed that NAc Zfp189 expression increased within D1 medium spiny neurons in response to acute cocaine but increased in both D1- and D2-expressing medium spiny neurons in response to chronic cocaine. CREB-mediated induction of Zfp189 potentiated electrophysiological activity of D1- and D2-expressing medium spiny neurons, recapitulating the known effect of CREB on these neurons. Finally, targeting CREB to the Zfp189 promoter within NAc Drd2-expressing neurons, but not Drd1-expressing neurons, was sufficient to diminish cocaine-conditioned behaviors. Conclusions: Together, these findings point to the CREB-Zfp189 interaction within the NAc Drd2+ neurons as a molecular signature of chronic cocaine use that is causal in counteracting the reinforcing effects of cocaine.
History
Journal
Biological PsychiatryVolume
93Pagination
502-511Location
United StatesPublisher DOI
ISSN
0006-3223eISSN
1873-2402Language
enPublication classification
C1.1 Refereed article in a scholarly journalIssue
6Publisher
Elsevier BVUsage metrics
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No categories selectedKeywords
AddictionClustered regularly interspaced short palindromic repeatsCocaineNucleus accumbensTranscription factorZfp189Behavioral and Social ScienceDrug Abuse (NIDA Only)Substance AbuseNeurosciencesGeneticsBasic Behavioral and Social Science2.1 Biological and endogenous factors2 Aetiology3 Good Health and Well BeingBiological SciencesMedical and Health SciencesPsychology and Cognitive Sciences
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