Novick Andrew M, Mears Mackenzie, Forster Gina L, Lei Yanlin, Tejani-Butt Shanaz M, Watt Michael J
Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD 57069, USA.
Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD 57069, USA.
Behav Brain Res. 2016 May 1;304:51-9. doi: 10.1016/j.bbr.2016.02.013. Epub 2016 Feb 10.
Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies.
青春期雄性大鼠反复遭受社会挫败会导致成年期内侧前额叶皮质多巴胺功能减退、工作记忆受损以及情境性焦虑样行为增加。鉴于谷氨酸在多巴胺调节、认知以及恐惧和焦虑方面的作用，我们研究了青春期社会挫败后N-甲基-D-天冬氨酸（NMDA）受体的潜在变化。由于NMDA受体和内侧前额叶皮质多巴胺都与条件性恐惧的表达和消退有关，另一组大鼠接受经典恐惧条件反射范式的刺激，以研究青春期挫败是否会改变恐惧学习。采用定量放射自显影法测量内侧前额叶皮质、尾壳核、伏隔核、杏仁核和海马体区域中3H-MK-801与NMDA受体的结合情况。使用听觉恐惧条件反射范式评估恐惧学习，将对听觉音调的僵住反应用作条件性恐惧的指标。与对照组相比，青春期社会挫败使成年大鼠前额叶皮质腹内侧区和中央杏仁核中的NMDA受体表达减少，而海马体CA3区的表达增加。先前遭受挫败的大鼠在回忆期和首次消退期的条件性僵住反应也有所降低，这可能分别与中央杏仁核和CA3区中观察到的NMDA受体减少和增加有关。青春期社会挫败后NMDA受体的改变表明，谷氨酸能系统功能障碍与内侧前额叶皮质多巴胺缺乏相结合，可能在临床前和临床研究中均可见的青春期社会应激源的一些长期行为后果中发挥作用。
