Background

Activation of the mesolimbic dopamine system is positively reinforcing. After repeated activation, some individuals develop compulsive reward-seeking behavior, which is a core symptom of addiction. However, the underlying neural mechanism remains elusive.

Methods

We trained mice in a seek-take chain, rewarded by optogenetic dopamine neuron self-stimulation. After compulsivity was evaluated, AMPA/NMDA ratio was measured at three distinct corticostriatal pathways confirmed by retrograde labeling and anterograde synaptic connectivity. Fiber photometry method and chemogenetics were used to parse the contribution of orbitofrontal cortex afferents onto the dorsal striatum (DS) during the behavioral task. We established a causal link between DS activity and compulsivity using optogenetic inhibition.

Results

Mice that persevered when seeking was punished exhibited an increased AMPA/NMDA ratio selectively at orbitofrontal cortex to DS synapses. In addition, an activity peak of spiny projection neurons in the DS at the moment of signaled reward availability was detected. Chemogenetic inhibition of orbitofrontal cortex neurons curbed the activity peak and reduced punished reward seeking, as did optogenetic hyperpolarization of spiny projection neurons time-locked to the cue predicting reward availability.

Conclusions

Our results suggest that compulsive individuals display stronger neuronal activity in the DS during the cue predicting reward availability even when at the risk of punishment, nurturing further compulsive reward seeking.

中文翻译：

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皮质纹状体活动驱动强迫性奖励寻求

背景

中脑边缘多巴胺系统的激活是积极增强的。在反复激活后，一些人会出现强迫性的寻求奖励行为，这是成瘾的核心症状。然而，潜在的神经机制仍然难以捉摸。

方法

我们在一个寻求链中训练老鼠，通过光遗传学多巴胺神经元自我刺激来奖励。在对强迫性进行评估后，在通过逆行标记和顺行突触连接确认的三个不同皮质纹状体通路中测量 AMPA/NMDA 比率。纤维光度法和化学遗传学被用来解析眶额皮质传入神经在行为任务期间对背侧纹状体 (DS) 的贡献。我们使用光遗传学抑制在 DS 活动和强迫性之间建立了因果关系。

结果

在寻求惩罚时坚持不懈的小鼠在眶额皮层与 DS 突触之间选择性地表现出 AMPA/NMDA 比率增加。此外，检测到信号奖励可用性时刻 DS 中多刺投射神经元的活动峰值。眶额皮质神经元的化学遗传学抑制抑制了活动峰值并减少了惩罚性奖励寻求，多刺投射神经元的光遗传学超极化时间锁定于预测奖励可用性的线索。

结论

我们的结果表明，即使在面临惩罚风险时，强迫性个体在预测奖励可用性的提示期间也会在 DS 中表现出更强的神经元活动，从而进一步促进强迫性奖励寻求。