Genetic deletion of NAPE-PLD induces context-dependent dysregulation of anxiety-like behaviors, stress responsiveness, and HPA-axis functionality in mice

作者：Taylor J. Woodward, Diána Dimén, Emily Fender Sizemore, Sarah Stockman, Fezaan Kazi, Serge Luquet, Ken Mackie, István Katona, Andrea G. Hohmann · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.09.10.612324 · 被引用次数：6 · 研究领域：Cannabis and Cannabinoid Research、Aldose Reductase and Taurine、Polyamine Metabolism and Applications

Abstract The endocannabinoid (eCB) system regulates stress responsiveness and hypothalamic-pituitary-adrenal (HPA) axis activity. The enzyme N -acyl phosphatidylethanolamine phospholipase-D (NAPE-PLD) is primarily responsible for the synthesis of the endocannabinoid signaling molecule anandamide (AEA) and other structurally related lipid signaling molecules known as N -acylethanolamines (NAEs). However, little is known about how activity of this enzyme affects behavior. As AEA plays a regulatory role in stress adaptation, we hypothesized that reducing synthesis of AEA and other NAEs would dysregulate stress reactivity. To test this hypothesis, we evaluated wild type (WT) and NAPE-PLD knockout (KO) mice in behavioral assays that assess stress responsiveness and anxiety-like behavior. NAPE-PLD KO mice exhibited anxiety-like behaviors in the open field test and the light-dark box test after a period of single housing. NAPE-PLD KO mice exhibited a heightened freezing response to the testing environment that was further enhanced by exposure to 2,3,5-trimethyl-3-thiazoline (TMT) predator odor. NAPE-PLD KO mice exhibited an exaggerated freezing response at baseline but blunted response to TMT when compared to WT mice. NAPE-PLD KO mice also exhibited a context-dependent dysregulation of HPA axis in response to TMT in the paraventricular hypothalamic nucleus at a neuronal level, as measured by c-Fos immunohistochemstry. Male, but not female, NAPE-PLD knockout mice showed higher levels...