Anderson Kristin R, Rogu Peter J, Palumbo Talulla B, Miwa Julie M
Department of Biological and Chemical Sciences, Bethlehem, PA, United States.
Front Neurosci. 2025 Apr 1;19:1466166. doi: 10.3389/fnins.2025.1466166. eCollection 2025.
Nicotinic receptor signaling is influential in modulating appropriate responses to salient stimuli within a complex environment. The cholinergic neurotransmitter system drives attention to salient stimuli such as stressors, and aids in orchestrating the proper neural and behavioral responses. Dysregulation of this system, however, has been implicated in altered anxiety regulation and mood disorders. Among the multiple layers of regulation are protein modulators such as Lynx2/Lypd1, which provides negative nicotinic acetylcholine receptor regulation within anxiety-related circuits, such as the amygdala and medial prefrontal cortex, among other brain regions. Mice null for Lynx2/Lypd1 (Lynx2 KO) show elevated basal anxiety-like behavior in tests such as elevated plus maze, light-dark box and social interaction assays. Here, we queried how a line predisposed to basal anxiety-like behavior would respond to specific stressors, using validated models of experiential-based affective disorders such as fear extinction, acute and chronic social defeat stress assays. We discovered that Lynx2 KO mice demonstrate an inability to extinguish learned fear during fear extinction tests even during milder stress conditions. In social defeat studies, contrary to our predictions, the Lynx2 KO mice switched from a socially avoidant phenotype (which could be considered susceptible) before defeat to a social approach/resilient phenotype after defeat. Consistent with reports of the inverse relationship between resilience and BDNF levels, we observed reduced BDNF levels in the VTA of Lynx2 KO mice. Furthermore, we provide evidence for the functional role of α7 nicotinic receptor subtypes by phenotypic rescue of fear extinction and social defeat phenotypes by MLA antagonism of α7 nicotinic acetylcholine receptors, or by crossing with α7 nicotinic acetylcholine receptor null mutant mice. A stable physical interaction between LYNX2 and α7 nAChRs was observed by co-immunoprecipitation of complexes from mouse amygdalae extracts. Together, these data indicate that responses to specific stressors can become aberrant when baseline genetic factors predispose animals to anxiety dysregulation. These studies underscore the critical nature of well-regulated nicotinic receptor function in the adaptive response to environmental stressors.
烟碱型受体信号传导在调节对复杂环境中显著刺激的适当反应方面具有重要影响。胆碱能神经递质系统促使注意力集中于诸如应激源等显著刺激，并有助于协调适当的神经和行为反应。然而，该系统的失调与焦虑调节改变和情绪障碍有关。在多层调节中，存在诸如Lynx2/Lypd1等蛋白质调节剂，其在与焦虑相关的神经回路（如杏仁核和内侧前额叶皮质等其他脑区）内对烟碱型乙酰胆碱受体进行负调节。Lynx2/Lypd1基因敲除（Lynx2 KO）小鼠在高架十字迷宫、明暗箱和社交互动试验等测试中表现出基础焦虑样行为增加。在此，我们使用经过验证的基于经验的情感障碍模型（如恐惧消退、急性和慢性社会挫败应激试验），探究了一条易出现基础焦虑样行为的品系对特定应激源的反应。我们发现，即使在较轻的应激条件下，Lynx2 KO小鼠在恐惧消退试验中也表现出无法消除习得性恐惧。在社会挫败研究中，与我们的预测相反，Lynx KO小鼠在挫败前从社交回避型表型（可被认为是易感性的）转变为挫败后的社交接近/恢复力表型。与恢复力和脑源性神经营养因子（BDNF）水平之间呈负相关的报道一致，我们观察到Lynx2 KO小鼠腹侧被盖区的BDNF水平降低。此外，我们通过用α7烟碱型乙酰胆碱受体拮抗剂MLA挽救恐惧消退和社会挫败表型，或与α7烟碱型乙酰胆碱受体基因敲除突变小鼠杂交，为α7烟碱型受体亚型的功能作用提供了证据。通过从小鼠杏仁核提取物中共免疫沉淀复合物，观察到LYNX2与α7烟碱型乙酰胆碱受体之间存在稳定的物理相互作用。总之，这些数据表明，当基线遗传因素使动物易患焦虑失调时，对特定应激源的反应可能会变得异常。这些研究强调了在对环境应激源的适应性反应中，烟碱型受体功能良好调节的关键性质。
