Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Psychoneuroendocrinology. 2022 Feb;136:105599. doi: 10.1016/j.psyneuen.2021.105599. Epub 2021 Nov 20.
Male and females appear equally capable of showing habituated hypothalamic-pituitary-adrenal (HPA) axis output responses to repeated exposures of the same challenge. Whether this reflects, within males and females, common mechanisms of decreased neuronal activity within stress responding, afferents to the paraventricular hypothalamic nucleus (PVH), the final common pathway to the HPA axis, has not been examined. Here we compared in adult male and female rats the extent to which declines in HPA axis responses to repeated restraint are met by habituated cellular (Fos) responses, in addition to changes in serotonin (5-hydroxytryptamine; 5-HT) expression and signaling, which normally stimulates the HPA axis. Thus, alterations in this component of HPA axis drive could provide an underlying basis for sex differences in adaptive responses. Males and females showed reliable declines in ACTH and corticosterone responses after 10 daily episodes of repeated restraint, recapitulated, in largest part, by similar regional patterns of Fos habituation, including within the PVH, several stress sensitive cell groups of the limbic forebrain, as well as within the raphe nucleus. Serotonin staining in the dorsal raphe and terminal profiles in the forebrain continued to reflect a higher pre-synaptic capacity for the 5-HT system in females. The sexual dimorphism encountered within the lateral septum and medial preoptic area of control animals was less distinguished in the repeat condition, however, whereas 5-HT varicosities in the PVH increased after repeated restraint only in females. Relative to their singly restrained counterparts, males displayed an increase in 5-HT 1 A receptor expression in the raphe nucleus after repeated restraint, whereas females showed a decrease in 5-HT 1 A mRNA levels in the hippocampus and in the zona incerta, representing the most proximal of cell groups expressing the 5-HT 1 A receptor in the vicinity of the PVH. In conclusion, similar regional profiles of cellular habituation in males and females suggest common CNS substrates of neuroendocrine adaptation. However, this process may be met by underlying sex differences in serotonergic control, given the respective roles for pre- and postsynaptic 5-HT 1 A receptors in mediating serotonin availability and signal transfer.
男性和女性在反复暴露于相同挑战时，表现出同样有能力显示出习惯化的下丘脑-垂体-肾上腺（HPA）轴输出反应。这是否反映了在男性和女性中，应激反应中神经元活动减少的共同机制，传入室旁下丘脑核（PVH）的传入神经，是通向 HPA 轴的最终共同途径，尚未被研究。在这里，我们比较了成年雄性和雌性大鼠在反复束缚应激后，HPA 轴反应的下降程度与习惯化细胞（Fos）反应之间的关系，以及 5-羟色胺（5-HT）表达和信号的变化，5-HT 通常会刺激 HPA 轴。因此，HPA 轴驱动的这种成分的改变可能为性别差异的适应性反应提供了一个潜在的基础。雄性和雌性大鼠在 10 次重复束缚应激后，ACTH 和皮质酮反应均出现可靠下降，最大程度上由类似的 Fos 习惯化区域模式重现，包括 PVH 内、边缘前脑的几个应激敏感细胞群以及中缝核内。背缝核中的 5-HT 染色和前脑中的终末轮廓继续反映了女性中 5-HT 系统的更高的前突触容量。然而，在重复应激条件下，控制动物的外侧隔核和内侧视前区的性二态性不太明显，而只有在雌性大鼠中，反复束缚应激后 PVH 中的 5-HT 轴突增多。与单独束缚的对应物相比，雄性大鼠在反复束缚应激后，中缝核中的 5-HT1A 受体表达增加，而雌性大鼠在海马和未定带中的 5-HT1A mRNA 水平降低，这代表了靠近 PVH 的表达 5-HT1A 受体的最近端细胞群。总之，雄性和雌性大鼠中类似的细胞习惯化区域模式表明，神经内分泌适应有共同的中枢神经系统基础。然而，鉴于 5-HT1A 受体在调节 5-HT 可用性和信号传递中的前突触和后突触作用，5-HT 能控制的潜在性别差异可能会导致这一过程。
