Ebner Karl, Fontebasso Veronica, Ferro Federico, Singewald Nicolas, Hannibal Jens
Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
Faculty of Health and Medical Sciences, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Neuropsychopharmacology. 2025 Feb;50(3):519-530. doi: 10.1038/s41386-024-02016-9. Epub 2024 Oct 29.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed in the brain including the hypothalamic paraventricular nucleus (PVN) implying a regulatory role in stress function. Recent evidence indicates that one of the main targets of PACAP within the PVN are corticotropin-releasing factor (CRF) neurons, which are key regulators of the hypothalamic-pituitary-adrenal (HPA) axis. However, the neural correlates that mediate PACAP effects on stress function are not fully understood. In the present study, we characterized the neuronal mechanism by which PACAP regulates neuroendocrine and behavioral stress responses in rats. We found that intracerebroventricular administration of PACAP increased the swim stress-induced c-Fos expression in distinct brain areas of the stress and anxiety circuitry including the parvocellular part of the PVN and changed behavioral stress coping during forced swimming to a more passive coping style (i.e., indicated by increased floating and reduced struggling behavior). Subsequently, PACAP administration directly into the PVN mimicked these behavioral effects and potentiated the plasma ACTH response to forced swim stress suggesting an excitatory role of PACAP on HPA stress axis reactivity. In addition, immunohistochemical analysis revealed a considerable portion of stress-activated CRF neurons in the medial parvocellular part of the PVN that co-localized PAC1 receptors suggesting that PACAP-induced effects on stress function are likely mediated directly by activation of CRF neurons in the PVN. Thus, these findings suggest that the PVN may represent one of the key areas where PACAP regulates the neuroendocrine and behavioral stress response.
垂体腺苷酸环化酶激活多肽（PACAP）是一种广泛分布于大脑中的神经肽，包括下丘脑室旁核（PVN），这意味着它在应激功能中具有调节作用。最近的证据表明，PVN内PACAP的主要靶点之一是促肾上腺皮质激素释放因子（CRF）神经元，它们是下丘脑-垂体-肾上腺（HPA）轴的关键调节因子。然而，介导PACAP对应激功能影响的神经关联尚未完全了解。在本研究中，我们对PACAP调节大鼠神经内分泌和行为应激反应的神经元机制进行了表征。我们发现，脑室内注射PACAP可增加应激和焦虑回路不同脑区中游泳应激诱导的c-Fos表达，包括PVN的小细胞部分，并在强迫游泳期间将行为应激应对方式转变为更被动的应对方式（即，表现为漂浮增加和挣扎行为减少）。随后，直接向PVN注射PACAP模拟了这些行为效应，并增强了血浆促肾上腺皮质激素对强迫游泳应激的反应，表明PACAP对HPA应激轴反应性具有兴奋作用。此外，免疫组织化学分析显示，PVN内侧小细胞部分中相当一部分应激激活的CRF神经元共定位有PAC1受体，这表明PACAP对应激功能的诱导作用可能直接由PVN中CRF神经元的激活介导。因此，这些发现表明，PVN可能是PACAP调节神经内分泌和行为应激反应的关键区域之一。
