Impact of acute and persistent excitation of prelimbic pyramidal neurons on motor activity and trace fear learning

Timothy R Rose, Ezequiel Marron Fernandez de Velasco, Baovi Vo, Megan E Tipps, Kevin Wickman

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Drug-induced neuroadaptations in the mPFC have been implicated in addictive behaviors. Repeated cocaine exposure has been shown to increase pyramidal neuron excitability in the prelimbic (PL) region of the mouse mPFC, an adaptation attributable to a suppression of G protein-gated inwardly rectifying K + (GIRK) channel activity. After establishing that this neuroadaptation is not seen in adjacent GABA neurons, we used viral GIRK channel ablation and complementary chemogenetic approaches to selectively enhance PL pyramidal neuron excitability in adult mice, to evaluate the impact of this form of plasticity on PL-dependent behaviors. GIRK channel ablation decreased somatodendritic GABA B receptor-dependent signaling and rheobase in PL pyramidal neurons. This manipulation also enhanced the motor-stimulatory effect of cocaine but did not impact baseline activity or trace fear learning. In contrast, selective chemogenetic excitation of PL pyramidal neurons, or chemogenetic inhibition of PL GABA neurons, increased baseline and cocaine-induced activity and disrupted trace fear learning. These effects were mirrored in male mice by selective excitation of PL pyramidal neurons projecting to the VTA, but not NAc or BLA. Collectively, these data show that manipulations enhancing the excitability of PL pyramidal neurons, and specifically those projecting to the VTA, recapitulate behavioral hallmarks of repeated cocaine exposure in mice. SIGNIFICANCE STATEMENT Prolonged exposure to drugs of abuse triggers neuroadaptations that promote core features of addiction. Understanding these neuroadaptations and their implications may suggest interventions capable of preventing or treating addiction. While previous work showed that repeated cocaine exposure increased the excitability of pyramidal neurons in the prelimbic cortex (PL), the behavioral implications of this neuroadaptation remained unclear. Here, we used neuron-specific manipulations to evaluate the impact of increased PL pyramidal neuron excitability on PL-dependent behaviors. Acute or persistent excitation of PL pyramidal neurons potentiated cocaine-induced motor activity and disrupted trace fear conditioning, effects replicated by selective excitation of the PL projection to the VTA. Our work suggests that hyperexcitability of this projection drives key behavioral hallmarks of addiction.

Original languageEnglish (US)
Pages (from-to)960-971
Number of pages12
JournalJournal of Neuroscience
Issue number5
StatePublished - Feb 3 2021

Bibliographical note

Funding Information:
Received Oct. 8, 2020; revised Dec. 11, 2020; accepted Dec. 16, 2020. Author contributions: K.W., T.R.R., E.M.F.d.V., and M.E.T. designed research; K.W., T.R.R., E.M.F.d.V., B.N.V., and M.E.T. analyzed data; K.W., T.R.R., E.M.F.d.V., B.N.V., and M.E.T. edited the paper; T.R.R., E.M.F.d.V., B.N.V., and M.E.T. performed research; T.R.R. wrote the first draft of the paper; E.M.F.d.V. contributed unpublished reagents/analytic tools. pT.R.R. and E.M.F.d.V. contributed equally to this work. This work was supported by National Institutes of Health Grants MH061933, DA034696, and AA027544 to K.W., AA025978 to M.E.T., and DA007234 to T.R.R.; Wallin Neuroscience Discovery Fund Award to K.W.; and University of Minnesota Doctoral Dissertation Fellowship to B.N.V. We thank Zhilian Xia, Nicholas Carlblom, Hannah Oberle, and Mehrsa Zahiremami for exceptional care of the mouse colony. The authors declare no competing financial interests. Correspondence should be addressed to Kevin Wickman at Copyright © 2021 the authors

Publisher Copyright:
Copyright © 2021 the authors


  • Chemogenetics
  • Cocaine
  • Fear conditioning
  • GIRK
  • Motor activity
  • Cocaine/pharmacology
  • Fear/drug effects
  • Pyramidal Cells/drug effects
  • Learning/drug effects
  • Mice, Inbred C57BL
  • Male
  • Mice, Transgenic
  • Dopamine Uptake Inhibitors/pharmacology
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism
  • Animals
  • Mice
  • Motor Activity/drug effects
  • Ventral Tegmental Area/drug effects

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural


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