Tavakoli Navid S, Malone Samantha G, Anderson Tanner L, Neeley Ryson E, Asadipooya Artin, Bardo Michael T, Ortinski Pavel I
Department of Neuroscience, University of Kentucky, Lexington, KY, United States.
Department of Psychology, University of Kentucky, Lexington, KY, United States.
Front Cell Neurosci. 2024 Aug 29;18:1347491. doi: 10.3389/fncel.2024.1347491. eCollection 2024.
Recent literature supports a prominent role for astrocytes in regulation of drug-seeking behaviors. The dorsal striatum, specifically, is known to play a role in reward processing with neuronal activity that can be influenced by astrocyte Ca. However, the manner in which Ca in dorsal striatum astrocytes impacts neuronal signaling after exposure to self-administered cocaine remains unclear. We addressed this question following over-expression of the Ca extrusion pump, hPMCA2w/b, in dorsal striatum astrocytes and the Ca indicator, GCaMP6f, in dorsal striatum neurons of rats that were trained to self-administer cocaine. Following extinction of cocaine-seeking behavior, the rats over-expressing hMPCA2w/b showed a significant increase in cue-induced reinstatement of cocaine seeking. Suppression of astrocyte Ca increased the amplitude of neuronal Ca transients in brain slices, but only after cocaine self-administration. This was accompanied by decreased duration of neuronal Ca events in the cocaine group and no changes in Ca event frequency. Acute administration of cocaine to brain slices decreased amplitude of neuronal Ca in both the control and cocaine self-administration groups regardless of hPMCA2w/b expression. These results indicated that astrocyte Ca control over neuronal Ca transients was enhanced by cocaine self-administration experience, although sensitivity to acutely applied cocaine remained comparable across all groups. To explore this further, we found that neither the hMPCA2w/b expression nor the cocaine self-administration experience altered regulation of neuronal Ca events by NPS-2143, a Ca sensing receptor (CaSR) antagonist, suggesting that plasticity of neuronal signaling after hPMCA2w/b over-expression was unlikely to result from elevated extracellular Ca. We conclude that astrocyte Ca in the dorsal striatum impacts neurons via cell-intrinsic mechanisms (e.g., gliotransmission, metabolic coupling, etc.) and impacts long-term neuronal plasticity after cocaine self-administration differently from neuronal response to acute cocaine. Overall, astrocyte Ca influences neuronal output in the dorsal striatum to promote resistance to cue-induced reinstatement of cocaine seeking.
近期文献支持星形胶质细胞在调节觅药行为中发挥重要作用。具体而言，背侧纹状体在奖赏处理中发挥作用，其神经元活动会受到星形胶质细胞钙的影响。然而，背侧纹状体星形胶质细胞中的钙在暴露于自我给药的可卡因后影响神经元信号传导的方式仍不清楚。我们在训练自我给药可卡因的大鼠的背侧纹状体星形胶质细胞中过表达钙外排泵hPMCA2w/b，并在背侧纹状体神经元中过表达钙指示剂GCaMP6f后解决了这个问题。在可卡因觅药行为消退后，过表达hPMCA2w/b的大鼠在提示诱导的可卡因觅药恢复方面显著增加。星形胶质细胞钙的抑制增加了脑片神经元钙瞬变的幅度，但仅在可卡因自我给药后。这伴随着可卡因组神经元钙事件持续时间的缩短以及钙事件频率的无变化。对脑片急性给予可卡因会降低对照组和可卡因自我给药组神经元钙的幅度，无论hPMCA2w/b的表达如何。这些结果表明，尽管所有组对急性给予可卡因的敏感性仍然相当，但可卡因自我给药经历增强了星形胶质细胞钙对神经元钙瞬变的控制。为了进一步探究这一点，我们发现hPMCA2w/b的表达和可卡因自我给药经历均未改变钙敏感受体（CaSR）拮抗剂NPS - 2143对神经元钙事件的调节，这表明hPMCA2w/b过表达后神经元信号传导的可塑性不太可能是由细胞外钙升高引起的。我们得出结论，背侧纹状体中的星形胶质细胞钙通过细胞内机制（如胶质递质传递、代谢偶联等）影响神经元，并以不同于神经元对急性可卡因反应的方式影响可卡因自我给药后的长期神经元可塑性。总体而言，星形胶质细胞钙影响背侧纹状体中的神经元输出，以促进对提示诱导的可卡因觅药恢复的抵抗力。
