Dept. of Pharmacology & Systems Physiology, University of Cincinnati, Cincinnati, OH 45220, United States; Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45220, United States.
Dept. of Pharmacology & Systems Physiology, University of Cincinnati, Cincinnati, OH 45220, United States.
Neuroscience. 2023 Sep 15;528:75-88. doi: 10.1016/j.neuroscience.2023.07.022. Epub 2023 Jul 28.
There is a growing interest for studying the impact of chronic inflammation, particularly lung inflammation, on the brain and behavior. This includes asthma, a chronic inflammatory condition, that has been associated with psychiatric conditions such as posttraumatic stress disorder (PTSD). Although asthma is driven by elevated production of Th2 cytokines (IL-4, IL-5 and IL-13), which drive asthma symptomology, recent work demonstrates that concomitant Th1 or Th17 cytokine production can worsen asthma severity. We previously demonstrated a detrimental link between PTSD-relevant fear behavior and allergen-induced lung inflammation associated with a mixed Th2/Th17-inflammatory profile in mice. However, the behavioral effects of Th2-skewed airway inflammation, typical to mild/moderate asthma, are unknown. Therefore, we investigated fear conditioning/extinction in allergen house dust mite (HDM)-exposed C57Bl/6 mice, a model of Th2-skewed allergic asthma. Behaviors relevant to panic, anxiety, and depression were also assessed. Furthermore, we investigated the accumulation of Th2/Th17-cytokine-expressing cells in lung and brain, and the neuronal activation marker, ΔFosB, in fear regulatory brain areas. HDM-exposed mice elicited lower freezing during fear extinction with no effects on acquisition and conditioned fear. No HDM effect on panic, anxiety or depression-relevant behaviors was observed. While HDM evoked a Th2-skewed immune response in lung tissue, no significant alterations in brain Th cell subsets were observed. Significantly reduced ΔFosB+ cells in the basolateral amygdala of HDM mice were observed post extinction. Our data indicate that allergen-driven Th2-skewed responses may induce fear extinction promoting effects, highlighting beneficial interactions of Th2-associated immune mediators with fear regulatory circuits.
人们对于研究慢性炎症（尤其是肺部炎症）对大脑和行为的影响越来越感兴趣。这包括哮喘，一种慢性炎症性疾病，它与创伤后应激障碍（PTSD）等精神疾病有关。虽然哮喘是由 Th2 细胞因子（IL-4、IL-5 和 IL-13）的过度产生驱动的，这些细胞因子会导致哮喘症状，但最近的研究表明，同时产生 Th1 或 Th17 细胞因子会加重哮喘的严重程度。我们之前证明了 PTSD 相关的恐惧行为与过敏原引起的肺部炎症之间存在有害联系，这种炎症与小鼠中的混合 Th2/Th17 炎症特征有关。然而，Th2 偏向性气道炎症（典型的轻度/中度哮喘）的行为影响尚不清楚。因此，我们在过敏原屋尘螨（HDM）暴露的 C57Bl/6 小鼠中研究了恐惧条件反射/消退，这是一种 Th2 偏向性过敏哮喘模型。还评估了与恐慌、焦虑和抑郁相关的行为。此外，我们研究了 Th2/Th17 细胞因子表达细胞在肺部和大脑中的积累，以及恐惧调节脑区中的神经元激活标记物 ΔFosB。HDM 暴露的小鼠在恐惧消退期间的冻结反应较低，而对获得和条件性恐惧没有影响。没有观察到 HDM 对恐慌、焦虑或抑郁相关行为的影响。虽然 HDM 在肺部组织中引起了 Th2 偏向性免疫反应，但在大脑 Th 细胞亚群中没有观察到明显的变化。在 HDM 小鼠的外侧杏仁核中观察到显著减少的 ΔFosB+细胞。我们的数据表明，过敏原驱动的 Th2 偏向性反应可能会诱导恐惧消退促进作用，突出了 Th2 相关免疫介质与恐惧调节回路的有益相互作用。
