Center for Integrative Brain Research, Seattle Children's Research Institute, 1900 9th Ave, Seattle, WA, 98101, USA.
Graduate Program in Neuroscience, University of Washington, Seattle, WA, USA.
Eur J Neurosci. 2017 Aug;46(3):1850-1862. doi: 10.1111/ejn.13631. Epub 2017 Jul 26.
Drug addiction is a chronic disease that is shaped by alterations in neuronal function within the cortical-basal ganglia-thalamic circuit. However, our understanding of how this circuit regulates drug-seeking remains incomplete, and relapse rates remain high. The midline thalamic nuclei are an integral component of the cortical-basal ganglia-thalamic circuit and are poised to mediate addiction behaviors, including relapse. It is surprising that little research has examined the contribution of midline thalamic nuclei and their efferent projections in relapse. To address this, we expressed inhibitory, G -coupled DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in a subset of the midline thalamic nuclei or in midline thalamic nuclei neurons projecting to either the nucleus accumbens or the amygdala. We examined the effect of transiently decreasing activity of these neuronal populations on cue-induced and cocaine-primed reinstatement of cocaine-seeking. Reducing activity of midline thalamic nuclei neurons attenuated both cue-induced and cocaine-primed reinstatement, but had no effect on cue-induced reinstatement of sucrose-seeking or locomotor activity. Interestingly, attenuating activity of efferent projections from the anterior portion of midline thalamic nuclei to the nucleus accumbens blocked cocaine-primed reinstatement but enhanced cue-induced reinstatement. Decreasing activity of efferent projections from either the posterior midline thalamic nuclei to the nucleus accumbens or the midline thalamic nuclei to amygdala had no effect. These results reveal a novel contribution of subsets of midline thalamic nuclei neurons in drug-seeking behaviors and suggest that modulation of midline thalamic nuclei activity may be a promising therapeutic target for preventing relapse.
药物成瘾是一种慢性疾病，其特征是皮质-基底神经节-丘脑回路中的神经元功能改变。然而，我们对该回路如何调节觅药行为的理解仍然不完整，复发率仍然很高。中线丘脑核是皮质-基底神经节-丘脑回路的一个组成部分，有望介导包括复发在内的成瘾行为。令人惊讶的是，很少有研究检查中线丘脑核及其传出投射在复发中的贡献。为了解决这个问题，我们在中线丘脑核的一部分或投射到伏隔核或杏仁核的中线丘脑核神经元中表达了抑制性、G 偶联的 DREADDs（专门由设计药物激活的设计受体）。我们研究了这些神经元群体的活性短暂降低对线索诱导和可卡因引发的可卡因觅药复吸的影响。降低中线丘脑核神经元的活性减弱了线索诱导和可卡因引发的复吸，但对蔗糖觅药线索诱导复吸或运动活动没有影响。有趣的是，减弱中线丘脑核前部到伏隔核的传出投射的活性阻断了可卡因引发的复吸，但增强了线索诱导的复吸。降低来自后中线丘脑核到伏隔核或中线丘脑核到杏仁核的传出投射的活性没有影响。这些结果揭示了中线丘脑核神经元亚群在觅药行为中的新作用，并表明调节中线丘脑核活性可能是预防复发的有前途的治疗靶点。
