Siemsen Benjamin M, Barry Sarah M, Vollmer Kelsey M, Green Lisa M, Brock Ashley G, Westphal Annaka M, King Raven A, DeVries Derek M, Otis James M, Cowan Christopher W, Scofield Michael D
Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, Charleston, SC, United States.
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, United States.
Front Cell Neurosci. 2022 Feb 24;16:844243. doi: 10.3389/fncel.2022.844243. eCollection 2022.
Prelimbic cortical projections to the nucleus accumbens core are critical for cue-induced cocaine seeking, but the identity of the accumbens neuron(s) targeted by this projection, and the transient neuroadaptations contributing to relapse within these cells, remain unknown.
Male Sprague-Dawley rats underwent cocaine or sucrose self-administration, extinction, and cue-induced reinstatement. Pathway-specific chemogenetics, patch-clamp electrophysiology, electrochemistry, and high-resolution confocal microscopy were used to identify and characterize a small population of nucleus accumbens core neurons that receive dense prelimbic cortical input to determine their role in regulating cue-induced cocaine and natural reward seeking.
Chemogenetic inhibition of prelimbic cortical projections to the nucleus accumbens core suppressed cue-induced cocaine relapse and normalized real-time cue-evoked increases in accumbens glutamate release to that of sucrose seeking animals. Furthermore, chemogenetic inhibition of the population of nucleus accumbens core neurons receiving the densest prelimbic cortical input suppressed cocaine, but not sucrose seeking. These neurons also underwent morphological plasticity during the peak of cocaine seeking in the form of dendritic spine expansion and increased ensheathment by astroglial processes at large spines.
We identified and characterized a unique subpopulation of nucleus accumbens neurons that receive dense prelimbic cortical input. The functional specificity of this subpopulation is underscored by their ability to mediate cue-induced cocaine relapse, but not sucrose seeking. This subset of cells represents a novel target for addiction therapeutics revealed by anterograde targeting to interrogate functional circuits imbedded within a known network.
前边缘皮质向伏隔核核心的投射对于线索诱导的可卡因觅求至关重要，但该投射所靶向的伏隔核神经元的身份，以及这些细胞内导致复吸的短暂神经适应性变化仍不清楚。
雄性Sprague-Dawley大鼠接受可卡因或蔗糖自我给药、消退以及线索诱导的复吸实验。采用通路特异性化学遗传学、膜片钳电生理学、电化学和高分辨率共聚焦显微镜来识别和表征一小群接受密集前边缘皮质输入的伏隔核核心神经元，以确定它们在调节线索诱导的可卡因和自然奖赏觅求中的作用。
对前边缘皮质向伏隔核核心的投射进行化学遗传学抑制可抑制线索诱导的可卡因复吸，并使伏隔核谷氨酸释放的实时线索诱发增加恢复到与蔗糖觅求动物相同的水平。此外，对接受最密集前边缘皮质输入的伏隔核核心神经元群体进行化学遗传学抑制可抑制可卡因觅求，但不影响蔗糖觅求。在可卡因觅求高峰期，这些神经元还经历了形态可塑性变化，表现为树突棘扩张以及大棘突处星形胶质细胞过程的包裹增加。
我们识别并表征了一群接受密集前边缘皮质输入的独特伏隔核神经元亚群。该亚群的功能特异性体现在它们能够介导线索诱导的可卡因复吸，但不能介导蔗糖觅求。这一细胞亚群代表了成瘾治疗的一个新靶点，通过顺行靶向揭示了嵌入已知网络中的功能回路。
