Hamdan Jameel N, Sierra-Fonseca Jorge A, Flores Rodolfo J, Saucedo Sigifredo, Miranda-Arango Manuel, O'Dell Laura E, Gosselink Kristin L
Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, United States.
Antharis Therapeutics, San Diego, CA, United States.
Front Behav Neurosci. 2022 Oct 19;16:1008556. doi: 10.3389/fnbeh.2022.1008556. eCollection 2022.
Early-life adversity (ELA) can induce persistent neurological changes and increase the risk for developing affective or substance use disorders. Disruptions to the reward circuitry of the brain and pathways serving motivation and emotion have been implicated in the link between ELA and altered adult behavior. The molecular mechanisms that mediate the long-term effects of ELA, however, are not fully understood. We examined whether ELA in the form of neonatal maternal separation (MatSep) modifies behavior and synaptic protein expression in adults. We hypothesized that MatSep would affect dopaminergic and glutamatergic signaling and enhance sensitivity to methamphetamine (Meth) reward or increase anxiety. Male Wistar rats were subjected to MatSep for 180 min/d on postnatal days (PND) 2-14 and allowed to grow to adulthood (PND 60) with no further manipulation. The hippocampus (Hipp), medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and caudate putamen (CPu) were isolated from one subgroup of animals and subjected to Western blot and protein quantitation for tyrosine hydroxylase (TH), α-synuclein (ALPHA), NMDA receptor (NMDAR), dopamine receptor-1 (D1) and -2 (D2), dopamine transporter (DAT), and postsynaptic density 95 (PSD95). Separate group of animals were tested for anxiety-like behavior and conditioned place preference (CPP) to Meth at 0.0, 0.1, and 1.0 mg/kg doses. MatSep rats displayed an increase in basal levels of anxiety-like behavior compared to control animals. MatSep rats also demonstrated CPP to Meth, but their responses did not differ significantly from controls at any drug dose. Increased NMDAR, D2, and ALPHA expression was observed in the NAc and CPu following MatSep; D2 and ALPHA levels were also elevated in the mPFC, along with DAT. MatSep rats had reduced D1 expression in the mPFC and Hipp, with the Hipp also showing a reduction in D2. Only the CPu showed elevated TH and decreased DAT expression levels. No significant changes were found in PSD95 expression in MatSep rats. In conclusion, ELA is associated with long-lasting and region-specific changes in synaptic protein expression that diminish dopamine neurotransmission and increase anxiety-like behavior in adults. These findings illustrate potential mechanisms through which ELA may increase vulnerability to stress-related illness.
早年逆境（ELA）可诱发持续的神经变化，并增加患情感障碍或物质使用障碍的风险。大脑奖赏回路以及服务于动机和情绪的通路的破坏与ELA和成年后行为改变之间的联系有关。然而，介导ELA长期影响的分子机制尚未完全明确。我们研究了以新生鼠母婴分离（MatSep）形式存在的ELA是否会改变成年鼠的行为和突触蛋白表达。我们假设MatSep会影响多巴胺能和谷氨酸能信号传导，并增强对甲基苯丙胺（Meth）奖赏的敏感性或增加焦虑。雄性Wistar大鼠在出生后第2 - 14天每天接受180分钟的MatSep处理，然后任其生长至成年（出生后第60天），不再进行进一步处理。从一组动物中分离出海马体（Hipp）、内侧前额叶皮质（mPFC）、伏隔核（NAc）和尾状壳核（CPu），进行蛋白质免疫印迹分析，并对酪氨酸羟化酶（TH）、α-突触核蛋白（ALPHA）、N-甲基-D-天冬氨酸受体（NMDAR）、多巴胺受体-1（D1）和-2（D2）、多巴胺转运体（DAT）以及突触后致密蛋白95（PSD95）进行蛋白质定量分析。另一组动物接受焦虑样行为测试以及对0.0、0.1和1.0mg/kg剂量Meth的条件性位置偏爱（CPP）测试。与对照动物相比，MatSep大鼠的基础焦虑样行为水平有所增加。MatSep大鼠也表现出对Meth的CPP，但在任何药物剂量下它们的反应与对照组相比均无显著差异。MatSep后在NAc和CPu中观察到NMDAR、D2和ALPHA表达增加；在mPFC中D2和ALPHA水平也升高，同时DAT也升高。MatSep大鼠在mPFC和Hipp中的D1表达降低，Hipp中的D2也降低。只有CPu显示TH升高且DAT表达水平降低。MatSep大鼠的PSD95表达未发现显著变化。总之，ELA与突触蛋白表达的持久且区域特异性变化有关，这些变化会减少多巴胺神经传递并增加成年鼠的焦虑样行为。这些发现阐明了ELA可能增加对与压力相关疾病易感性的潜在机制。
