Heun-Johnson Hanke, Levitt Pat
Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA.
Institute for the Developing Mind, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Neurobiol Stress. 2017 Nov 26;8:10-20. doi: 10.1016/j.ynstr.2017.11.003. eCollection 2018 Feb.
Early adversity in childhood increases the risk of anxiety, mood, and post-traumatic stress disorders in adulthood, and specific gene-by-environment interactions may increase risk further. A common functional variant in the promoter region of the gene encoding the human MET receptor tyrosine kinase (rs1858830 ' allele) reduces expression of and is associated with altered cortical circuit function and structural connectivity. Mice with reduced expression exhibit changes in anxiety-like and conditioned fear behavior, precocious synaptic maturation in the hippocampus, and reduced neuronal arbor complexity and synaptogenesis. These phenotypes also can be produced independently by early adversity in wild-type mice. The present study addresses the outcome of combining early-life stress and genetic influences that alter timing of maturation on enduring functional and structural phenotypes. Using a model of reduced expression ( ) and early-life stress from postnatal day 2-9, social, anxiety-like, and contextual fear behaviors in later life were measured. Mice that experienced early-life stress exhibited impairments in social interaction, whereas alterations in anxiety-like behavior and fear learning were driven by haploinsufficiency, independent of rearing condition. Early-life stress or reduced expression decreased arbor complexity of ventral hippocampal CA1 pyramidal neurons projecting to basolateral amygdala. Paradoxically, arbor complexity in mice was increased following early-life stress, and thus not different from arbors in wild-type mice raised in control conditions. The changes in dendritic morphology are consistent with the hypothesis that the physiological state of maturation of CA1 neurons in mice influences their responsiveness to early-life stress. The dissociation of behavioral and structural changes suggests that there may be phenotype-specific sensitivities to early-life stress.
童年早期的逆境会增加成年后患焦虑症、情绪障碍和创伤后应激障碍的风险，特定的基因与环境相互作用可能会进一步增加风险。人类MET受体酪氨酸激酶编码基因（rs1858830 '等位基因）启动子区域的一个常见功能变体可降低其表达，并与皮质回路功能和结构连接性改变有关。MET表达降低的小鼠表现出焦虑样和条件性恐惧行为的变化、海马体中突触早熟、神经元树突复杂性降低和突触形成减少。这些表型也可由野生型小鼠的早期逆境独立产生。本研究探讨了早期生活压力和改变成熟时间的遗传影响相结合对持久的功能和结构表型的影响。使用MET表达降低（MET+/-）的模型和出生后第2至9天的早期生活压力，测量了后期生活中的社交、焦虑样和情境恐惧行为。经历过早期生活压力的小鼠在社交互动方面表现出缺陷，而焦虑样行为和恐惧学习的改变是由MET单倍剂量不足驱动的，与饲养条件无关。早期生活压力或MET表达降低会降低投射到基底外侧杏仁核的腹侧海马CA1锥体神经元的树突复杂性。矛盾的是，MET+/-小鼠在经历早期生活压力后树突复杂性增加，因此与在对照条件下饲养的野生型小鼠的树突没有差异。树突形态的变化与以下假设一致，即MET+/-小鼠中CA1神经元的成熟生理状态会影响它们对早期生活压力的反应。行为和结构变化的分离表明，对早期生活压力可能存在表型特异性敏感性。
