Center Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.
Faculty of Psychology, Università Telematica Internazionale "Uninettuno", Rome, Italy.
Genes Brain Behav. 2021 Apr;20(4):e12709. doi: 10.1111/gbb.12709. Epub 2020 Oct 27.
Alterations in dopamine (DA) reuptake are involved in several psychiatric disorders whose symptoms can be investigated in knock out rats for the DA transporter (DAT-KO). Recent studies evidenced the role of epigenetic DAT modulation in depressive-like behavior. Accordingly, we used heterozygous (HET) rats born from both HET parents (termed MIX-HET), compared to HET rats born from WT-mother and KO-father (MAT-HET), implementing the role of maternal care on DAT modulation. We developed a "sudden fright" paradigm (based on dark-light test) to study reaction to fearful inputs in the DAT-KO, MAT-HET, MIX-HET, and WT groups. Rats could freely explore the whole 3-chambers apparatus; then, they were gently confined in one room where they experienced the fright; finally, they could freely move again. As expected, after the fearful stimulus only MAT-HET rats showed a different behavior consisting of avoidance towards the fear-associated chamber, compared to WT rats. Furthermore, ex-vivo immuno-fluorescence reveals higher prefrontal DAT levels in MAT-HET compared to MIX-HET and WT rats. Immuno-fluorescence shows also a different histone deacetylase (HDAC) enzymes concentration. Since HDAC concentration could modulate gene expression, within MAT-HET fore brain, the enhanced expression of DAT could well impair the corticostriatal-thalamic circuit, thus causing aberrant avoidance behavior (observed only in MAT-HET rats). DAT expression seems to be linked to a simply different breeding condition, which points to a reduced care by HET dams for epigenetic regulation. This could imply significant prefronto-cortical influences onto the emotional processes: hence an excessively frightful response, even to mild stressful agents, may draw developmental trajectories toward anxious and depressed-like behavior.
多巴胺（DA）再摄取的改变与几种精神疾病有关，其症状可以在 DA 转运体（DAT-KO）敲除大鼠中进行研究。最近的研究表明表观遗传 DAT 调节在抑郁样行为中起作用。因此，我们使用来自 HET 父母的杂合子（HET）大鼠（称为 MIX-HET），与来自 WT 母亲和 KO 父亲的 HET 大鼠（MAT-HET）进行比较，实施了母性关怀对 DAT 调节的作用。我们开发了一种“突然惊吓”范式（基于明暗测试），以研究 DAT-KO、MAT-HET、MIX-HET 和 WT 组对恐惧性输入的反应。大鼠可以自由探索整个 3 室仪器；然后，他们被轻轻地限制在一个房间里，在那里他们经历了惊吓；最后，他们可以再次自由移动。正如预期的那样，在恐惧刺激后，只有 MAT-HET 大鼠表现出一种不同的行为，即回避与恐惧相关的房间，与 WT 大鼠相比。此外，离体免疫荧光显示 MAT-HET 大鼠前额叶 DAT 水平高于 MIX-HET 和 WT 大鼠。免疫荧光还显示不同的组蛋白去乙酰化酶（HDAC）酶浓度。由于 HDAC 浓度可以调节基因表达，在 MAT-HET 大脑中，DAT 的增强表达可能会损害皮质纹状体-丘脑回路，从而导致异常的回避行为（仅在 MAT-HET 大鼠中观察到）。DAT 表达似乎与一种简单的不同繁殖条件有关，这表明 HET 母鼠对表观遗传调节的关怀减少。这可能意味着对情绪过程有显著的前额叶皮质影响：因此，即使是对轻度应激源的过度惊吓反应，也可能导致焦虑和抑郁样行为的发展轨迹。
