Pennington Zachary T, LaBanca Alexa R, Sompolpong Patlapa, Abdel-Raheim Shereen D, Ko Bumjin, Christenson Wick Zoe, Feng Yu, Dong Zhe, Francisco Taylor R, Bacon Madeline E, Chen Lingxuan, Fulton Sasha L, Maze Ian, Shuman Tristan, Cai Denise Jade
bioRxiv. 2024 May 8:2023.02.27.530077. doi: 10.1101/2023.02.27.530077.
Severe stress can produce multiple persistent changes in defensive behavior relevant to psychiatric illness. While much is known about the circuits supporting stress-induced associative fear, how stress-induced circuit plasticity supports non-associative changes in defensive behavior remains unclear.
Mice were exposed to an acute severe stressor, and subsequently, both associative and non-associative defensive behavioral responses were assessed. A mixture of local protein synthesis inhibition, pan-neuronal chemogenetic inhibition, and projection-specific chemogenetic inhibition were utilized to isolate the roles of the basolateral amygdala (BLA) and ventral hippocampus (vHC) to the induction and expression of associative and non-associative defensive behavioral changes.
Stress-induced protein synthesis in the BLA was necessary for enhancements in stress sensitivity but not enhancements in anxiety-related behaviors, whereas protein synthesis in the vHC was necessary for enhancements in anxiety-related behavior but not enhancements in stress sensitivity. Like protein synthesis, neuronal activity of the BLA and vHC were found to differentially support the expression of these same defensive behaviors. Additionally, projection-specific inhibition of BLA-vHC connections failed to alter these behaviors, indicating that these defensive behaviors are regulated by distinct BLA and vHC circuits. Lastly, contributions of the BLA and vHC to stress sensitivity and anxiety-related behavior were independent of their contributions to associative fear.
Stress-induced plasticity in the BLA and vHC were found to support dissociable non-associative behavioral changes, with BLA supporting enhancements in stress sensitivity and vHC supporting increased anxiety-related behavior. These findings demonstrate that independent BLA and vHC circuits are critical for stress-induced defensive behaviors, and that differential targeting of BLA and vHC circuits may be needed in disease treatment.
严重应激可导致与精神疾病相关的防御行为发生多种持续性改变。虽然人们对支持应激诱导的联想性恐惧的神经回路了解很多，但应激诱导的神经回路可塑性如何支持防御行为的非联想性改变仍不清楚。
将小鼠暴露于急性严重应激源，随后评估联想性和非联想性防御行为反应。利用局部蛋白质合成抑制、泛神经元化学遗传抑制和投射特异性化学遗传抑制的组合，来分离基底外侧杏仁核（BLA）和腹侧海马体（vHC）在联想性和非联想性防御行为变化的诱导和表达中的作用。
BLA中应激诱导的蛋白质合成对于应激敏感性的增强是必要的，但对于焦虑相关行为的增强不是必要的，而vHC中的蛋白质合成对于焦虑相关行为的增强是必要的，但对于应激敏感性的增强不是必要的。与蛋白质合成一样，发现BLA和vHC的神经元活动差异支持这些相同防御行为的表达。此外，对BLA-vHC连接的投射特异性抑制未能改变这些行为，表明这些防御行为由不同的BLA和vHC神经回路调节。最后，BLA和vHC对应激敏感性和焦虑相关行为的贡献独立于它们对联想性恐惧的贡献。
发现BLA和vHC中应激诱导的可塑性支持可分离的非联想性行为变化，BLA支持应激敏感性增强，vHC支持焦虑相关行为增加。这些发现表明，独立的BLA和vHC神经回路对应激诱导的防御行为至关重要，并且在疾病治疗中可能需要对BLA和vHC神经回路进行差异靶向治疗。
