Graduate Program in Pharmacology.
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455.
J Neurosci. 2021 Feb 3;41(5):960-971. doi: 10.1523/JNEUROSCI.2606-20.2020. Epub 2021 Jan 5.
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 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. 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.
药物诱导的 mPFC 神经适应性与成瘾行为有关。反复可卡因暴露已被证明会增加小鼠 mPFC 额前皮质（PL）区域的锥体神经元兴奋性，这种适应性归因于 G 蛋白门控内向整流钾（GIRK）通道活性的抑制。在确定这种神经适应性不会出现在相邻的 GABA 神经元中后，我们使用病毒 GIRK 通道消融和互补的化学遗传学方法，选择性增强成年小鼠 PL 锥体神经元的兴奋性，以评估这种形式的可塑性对 PL 依赖性行为的影响。GIRK 通道消融降低了 PL 锥体神经元的树突体 GABA 受体依赖性信号和阈值。这种操作还增强了可卡因的运动刺激作用，但不影响基线活动或痕迹恐惧学习。相比之下，选择性化学遗传兴奋 PL 锥体神经元，或化学遗传抑制 PL GABA 神经元，增加了基线和可卡因诱导的活动，并破坏了痕迹恐惧学习。这些影响在雄性小鼠中通过选择性兴奋投射到 VTA 的 PL 锥体神经元得到了反映，但在 NAc 或 BLA 中则没有。总的来说，这些数据表明，增强 PL 锥体神经元兴奋性的操作，特别是那些投射到 VTA 的，重现了小鼠中反复可卡因暴露的行为特征。长期滥用药物会引发促进成瘾核心特征的神经适应性。了解这些神经适应性及其影响可能会提出能够预防或治疗成瘾的干预措施。虽然以前的工作表明，反复可卡因暴露会增加额前皮质（PL）锥体神经元的兴奋性，但这种神经适应性的行为意义仍不清楚。在这里，我们使用神经元特异性操作来评估增加 PL 锥体神经元兴奋性对 PL 依赖性行为的影响。急性或持续兴奋 PL 锥体神经元增强了可卡因诱导的运动活动，并破坏了痕迹恐惧条件反射，选择性兴奋 PL 投射到 VTA 可复制这些影响。我们的工作表明，这种投射的过度兴奋驱动了成瘾的关键行为特征。
