Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, Genoa, Italy.
School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
Transl Psychiatry. 2023 Feb 18;13(1):62. doi: 10.1038/s41398-023-02366-w.
Stress represents a main risk factor for psychiatric disorders. Whereas it is known that even a single trauma may induce psychiatric disorders in humans, the mechanisms of vulnerability to acute stressors have been little investigated. In this study, we generated a new animal model of resilience/vulnerability to acute footshock (FS) stress in rats and analyzed early functional, molecular, and morphological determinants of stress vulnerability at tripartite glutamate synapses in the prefrontal cortex (PFC). We found that adult male rats subjected to FS can be deemed resilient (FS-R) or vulnerable (FS-V), based on their anhedonic phenotype 24 h after stress exposure, and that these two populations are phenotypically distinguishable up to two weeks afterwards. Basal presynaptic glutamate release was increased in the PFC of FS-V rats, while depolarization-evoked glutamate release and synapsin I phosphorylation at Ser were increased in both FS-R and FS-V. In FS-R and FS-V rats the synaptic expression of GluN2A and apical dendritic length of prelimbic PFC layers II-III pyramidal neurons were decreased, while BDNF expression was selectively reduced in FS-V. Depolarization-evoked (carrier-mediated) glutamate release from astroglia perisynaptic processes (gliosomes) was selectively increased in the PFC of FS-V rats, while GLT1 and xCt levels were higher and GS expression reduced in purified PFC gliosomes from FS-R. Overall, we show for the first time that the application of the sucrose intake test to rats exposed to acute FS led to the generation of a novel animal model of resilience/vulnerability to acute stress, which we used to identify early determinants of maladaptive response related to behavioral vulnerability to stress.
压力是精神疾病的主要风险因素。虽然已知单次创伤即可在人类中诱发精神疾病，但急性应激源易感性的机制仍鲜有研究。在这项研究中，我们在大鼠中产生了一种新的急性足底电击（FS）应激的弹性/易感性动物模型，并分析了前额叶皮质（PFC）三价谷氨酸突触中应激易感性的早期功能、分子和形态学决定因素。我们发现，根据应激暴露后 24 小时的快感缺失表型，成年雄性大鼠可被认为是有弹性（FS-R）或易感性（FS-V），并且这两种群体在两周后仍可区分。FS-V 大鼠的 PFC 中基础突触前谷氨酸释放增加，而 FS-R 和 FS-V 大鼠的去极化诱发谷氨酸释放和突触素 I 在 Ser 上的磷酸化均增加。在 FS-R 和 FS-V 大鼠中，PFC 的突触表达 GluN2A 和额前皮质 II-III 层锥体神经元的树突长度减少，而 BDNF 表达仅在 FS-V 中减少。FS-V 大鼠 PFC 中，星形胶质细胞突触周过程（神经胶质体）的去极化诱发（载体介导）谷氨酸释放选择性增加，而纯化的 PFC 神经胶质体中的 GLT1 和 xCt 水平升高，GS 表达减少。总体而言，我们首次表明，将蔗糖摄入量测试应用于急性 FS 暴露的大鼠，产生了一种新的急性应激弹性/易感性动物模型，我们用该模型来确定与应激易感性相关的行为易感性的适应性反应的早期决定因素。
