Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Departments of Psychiatry and of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Department of Pharmacology and Toxicology and the Research Institute on Addictions, State University of New York at Buffalo, New York, New York 14214, and Institut National de la Santé et de la Recherche Médicale, U952, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7224, UPMC, Paris, 75005, France.
J Neurosci. 2013 Nov 20;33(47):18381-95. doi: 10.1523/JNEUROSCI.1875-13.2013.
The transcription factor, ΔFosB, is robustly and persistently induced in striatum by several chronic stimuli, such as drugs of abuse, antipsychotic drugs, natural rewards, and stress. However, very few studies have examined the degree of ΔFosB induction in the two striatal medium spiny neuron (MSN) subtypes. We make use of fluorescent reporter BAC transgenic mice to evaluate induction of ΔFosB in dopamine receptor 1 (D1) enriched and dopamine receptor 2 (D2) enriched MSNs in ventral striatum, nucleus accumbens (NAc) shell and core, and in dorsal striatum (dStr) after chronic exposure to several drugs of abuse including cocaine, ethanol, Δ(9)-tetrahydrocannabinol, and opiates; the antipsychotic drug, haloperidol; juvenile enrichment; sucrose drinking; calorie restriction; the serotonin selective reuptake inhibitor antidepressant, fluoxetine; and social defeat stress. Our findings demonstrate that chronic exposure to many stimuli induces ΔFosB in an MSN-subtype selective pattern across all three striatal regions. To explore the circuit-mediated induction of ΔFosB in striatum, we use optogenetics to enhance activity in limbic brain regions that send synaptic inputs to NAc; these regions include the ventral tegmental area and several glutamatergic afferent regions: medial prefrontal cortex, amygdala, and ventral hippocampus. These optogenetic conditions lead to highly distinct patterns of ΔFosB induction in MSN subtypes in NAc core and shell. Together, these findings establish selective patterns of ΔFosB induction in striatal MSN subtypes in response to chronic stimuli and provide novel insight into the circuit-level mechanisms of ΔFosB induction in striatum.
转录因子 ΔFosB 可被多种慢性刺激（如滥用药物、抗精神病药物、天然奖赏和应激）强有力且持续地诱导于纹状体中。然而，仅有少数研究探讨了两种纹状体中间神经元（MSN）亚型中 ΔFosB 的诱导程度。我们利用荧光报告 BAC 转基因小鼠，评估了慢性暴露于可卡因、乙醇、Δ(9)-四氢大麻酚和阿片类药物等多种滥用药物、抗精神病药物氟哌啶醇、青少年富集、蔗糖摄入、热量限制、选择性 5-羟色胺再摄取抑制剂抗抑郁药氟西汀以及社交挫败应激后，腹侧纹状体、伏隔核壳和核仁以及背侧纹状体中多巴胺受体 1（D1）富集和多巴胺受体 2（D2）富集 MSN 中 ΔFosB 的诱导情况。我们的发现表明，慢性暴露于许多刺激会以 MSN 亚型选择性的方式诱导纹状体中 ΔFosB。为了探索纹状体中 ΔFosB 的环路介导诱导，我们利用光遗传学增强了向伏隔核投射突触输入的边缘脑区的活动；这些区域包括腹侧被盖区和几个谷氨酸能传入区域：内侧前额叶皮质、杏仁核和腹侧海马。这些光遗传学条件导致了伏隔核核心和壳中 MSN 亚型中 ΔFosB 的高度不同的诱导模式。总之，这些发现确立了慢性刺激下纹状体 MSN 亚型中 ΔFosB 诱导的选择性模式，并为纹状体中 ΔFosB 诱导的环路水平机制提供了新的见解。
