Anderson Kristin R, Rogu Peter J, Palumbo Talulla B, Miwa Julie M
Lehigh University.
Res Sq. 2023 Jan 30:rs.3.rs-2492514. doi: 10.21203/rs.3.rs-2492514/v1.
Cholinergic signaling is critical for an individual to react appropriately and adaptably to salient stimuli while navigating a complex environment. The cholinergic neurotransmitter system drives attention to salient stimuli, such as stressors, and aids in orchestrating the proper neural and behavioral response. Fine-tuned regulation of the cholinergic system has been linked to appropriate stress responses and subsequent mood regulation while dysregulation has been implicated in mood disorders. Among the multiple layers of regulation are cholinergic protein modulators. Here, we use validated models of experiential-based affective disorders to investigate differences in responses to stress in a genetic mouse model of cholinergic dysregulation based on the loss of protein modulator. The lynx2 nicotinic receptor modulatory protein provides negative cholinergic regulation within the amygdala, medial prefrontal cortex, and other brain regions. We discovered here that lynx2 knockout (KO) mice demonstrate an inability to update behavior with an inability to extinguish learned fear during a fear extinction test. We also observed, under an increased stress load following exposure to chronic social defeat stress (CSDS) paradigm, there was a unified resilience phenotype in lynx2KO mice, as opposed to the wild-type cohort which was split between resilience and susceptible phenotypes. Furthermore, we provide evidence for the functional role of α7 nicotinic receptor subtypes by phenotypic rescue with MLA or crossing with an α7 null mutant mouse (e.g. lynx2/α7 double KO mice). We demonstrate a direct physical interaction between lynx2 and α7 nAChR by co-immunoprecipitation of complexes from mouse BLA extracts. The genetic predisposition to heightened basal anxiety-like behavior and altered cholinergic signaling impairs individual behavior responses stressors. Together, these data indicate that the effects of social stress can be influenced by baseline genetic factors involved in anxiety regulation.
胆碱能信号传导对于个体在复杂环境中导航时对显著刺激做出适当且适应性的反应至关重要。胆碱能神经递质系统促使个体关注显著刺激，如应激源，并有助于协调适当的神经和行为反应。胆碱能系统的精细调节与适当的应激反应及随后的情绪调节相关，而调节异常则与情绪障碍有关。胆碱能蛋白调节剂是多层调节中的一部分。在此，我们使用经过验证的基于经验的情感障碍模型，来研究在基于蛋白调节剂缺失的胆碱能调节异常的基因小鼠模型中对应激反应的差异。lynx2烟碱受体调节蛋白在杏仁核、内侧前额叶皮质和其他脑区提供负性胆碱能调节。我们在此发现，lynx2基因敲除（KO）小鼠在恐惧消退测试中表现出无法更新行为且无法消除习得性恐惧。我们还观察到，在暴露于慢性社会挫败应激（CSDS）范式后增加的应激负荷下，lynx2 KO小鼠呈现出统一的恢复力表型，而野生型群体则分为恢复力和易感表型。此外，我们通过用MLA进行表型挽救或与α7基因敲除突变小鼠（如lynx2/α7双基因敲除小鼠）杂交，为α7烟碱受体亚型的功能作用提供了证据。我们通过从小鼠杏仁核基底外侧核提取物中共免疫沉淀复合物，证明了lynx2与α7 nAChR之间存在直接的物理相互作用。基础焦虑样行为增强和胆碱能信号改变的遗传易感性会损害个体对应激源的行为反应。总之，这些数据表明社会应激的影响可能受到参与焦虑调节的基线遗传因素的影响。
