期刊
JOURNAL OF NEUROSCIENCE
卷 41, 期 5, 页码 960-971出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2606-20.2020
关键词
chemogenetics; cocaine; fear conditioning; GIRK; motor activity
资金
- National Institutes of Health [MH061933, DA034696, AA027544, AA025978, DA007234]
- Wallin Neuroscience Discovery Fund
- University of Minnesota Doctoral Dissertation Fellowship
Drug-induced neuroadaptations in the mouse mPFC, specifically affecting pyramidal neurons in the prelimbic region, have been shown to increase cocaine-induced activity and disrupt trace fear learning. Enhancing the excitability of these neurons selectively replicates behavioral hallmarks of repeated cocaine exposure in mice.
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.
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