Michopoulos V, Perez Diaz M, Embree M, Reding K, Votaw J R, Mun J, Voll R J, Goodman M M, Wilson M, Sanchez M, Toufexis D
Division of Developmental & Cognitive Neuroscience, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Psychiatry & Behavioural Sciences, School of Medicine, Emory University, Atlanta, GA, USA.
J Neuroendocrinol. 2014 Feb;26(2):80-8. doi: 10.1111/jne.12129.
Social subordination in female macaques represents a well-described model of chronic psychosocial stress. Additionally, a length polymorphism (5-HTTLPR) in the regulatory region of the serotonin (5-HT) transporter (5-HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to that described in humans with an analogous 5-HTTLPR polymorphism. The present study determined the effects of social status and the 5-HTTLPR genotype on 5-HT1A receptor binding potential (5-HT1A BP(ND)) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17β-oestradiol (E(2)) treatment. Areas analysed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography using p-[(18) F]MPPF was performed to determine the levels of 5-HT1A BP(ND) under a non-E(2) and a 3-week E(2) treatment condition. The short variant (s-variant) 5-HTTLPR genotype produced a significant reduction in 5-HT1A BP(ND) in the mPFC regardless of social status, and subordinate s-variant females showed a reduction in 5-HT1A BP(ND) within the ACC. Both these effects of 5-HTTLPR were unaffected by E(2). Additionally, E(2) reduced 5-HT1A BP(ND) in the dorsal raphe of all females irrespective of psychosocial stress or 5-HTTLPR genotype. Hippocampal 5-HT1A BP(ND) was attenuated in subordinate females regardless of 5-HTTLPR genotype during the non-E(2) condition, an effect that was normalised with E(2). Similarly, 5-HT1A BP(ND) in the hypothalamus was significantly lower in subordinate females regardless of 5-HTTLPR genotype, an effect reversed with E(2). Taken together, the data indicate that the effect of E(2) on modulation of central 5HT1A BP(ND) may only occur in brain regions that show no 5-HTTLPR genotype-linked control of 5-HT1A binding.
雌性猕猴的社会从属地位是一种描述详尽的慢性心理社会应激模型。此外，恒河猴体内存在血清素（5-羟色胺，5-HT）转运体（5-HTT）基因（SLC6A4）调控区域的长度多态性（5-HTTLPR），这与具有类似5-HTTLPR多态性的人类所描述的不良后果有关。本研究确定了社会地位和5-HTTLPR基因型对去卵巢雌性猴子大脑中涉及情绪调节和应激反应性区域的5-HT1A受体结合潜能（5-HT1A BP(ND)）的影响，然后评估了17β-雌二醇（E(2)）治疗如何改变这些影响。分析的区域包括前额叶皮质[前扣带回（ACC）；内侧前额叶皮质（mPFC）；背外侧前额叶皮质；眶额前额叶皮质]、杏仁核、海马体、下丘脑和中缝核。使用p-[(18)F]MPPF进行正电子发射断层扫描，以确定在非E(2)和3周E(2)治疗条件下的5-HT1A BP(ND)水平。无论社会地位如何，短变体（s-变体）5-HTTLPR基因型均使mPFC中的5-HT1A BP(ND)显著降低，而处于从属地位的s-变体雌性ACC内的5-HT1A BP(ND)也降低。5-HTTLPR的这两种效应均不受E(2)影响。此外，无论心理社会应激或5-HTTLPR基因型如何，E(2)均降低了所有雌性背中缝核中的5-HT1A BP(ND)。在非E(2)条件下，无论5-HTTLPR基因型如何，从属雌性的海马体5-HT1A BP(ND)均减弱，E(2)可使其恢复正常。同样，无论5-HTTLPR基因型如何，从属雌性下丘脑的5-HT1A BP(ND)均显著较低，E(2)可逆转这一效应。综上所述，数据表明E(2)对中枢5HT1A BP(ND)的调节作用可能仅发生在那些未显示出5-HTTLPR基因型对5-HT1A结合的相关控制的脑区。
