Meadows K L, Byrnes E M
Tufts University Cummings School of Veterinary Medicine, 200 Westboro Road, Grafton, MA 01536, United States.
Neuroscience. 2015 Jan 22;284:337-348. doi: 10.1016/j.neuroscience.2014.10.006. Epub 2014 Oct 13.
Relaxin is an essential pregnancy-related hormone with broad peripheral effects mediated by activation of relaxin-like family peptide 1 receptors (RXFP1). More recent studies suggest an additional role for relaxin as a neuropeptide, with RXFP1 receptors expressed in numerous brain regions. Neurons in an area of the brainstem known as the nucleus incertus (NI) produce relaxin 3 (RLN3), the most recently identified neuropeptide in the relaxin family. RLN3 has been shown to activate both RXFP1 and relaxin-like family peptide receptor 3 (RXFP3) receptor subtypes. Studies suggest wide-ranging neuromodulatory effects of both RXFP1 and RXFP3 activation, although to date the majority of studies have been conducted in young males. In the current study, we examined potential sex- and age-related changes in RLN3 gene expression in the NI as well as RXFP1 and RXFP3 gene expression in the dorsal hippocampus (HI), ventral hippocampus (vHI) and amygdala (AMYG) using young adult (9-12weeks) and middle-aged (9-12months) male and female rats. In addition, regional changes in RXFP1 and RXFP3 protein expression were examined in the CA1, CA2/CA3 and dentate gyrus (DG) as well as within basolateral (BLA), central (CeA), and medial (MeA) amygdaloid nuclei. In the NI, RLN3 showed an age-related decrease in males. In the HI, only the RXFP3 receptor showed an age-related change in gene expression, however, both receptor subtypes showed age-related changes in protein expression that were region specific. Additionally, while gene and protein expression of both receptors increased with age in AMYG, these effects were both region- and sex-specific. Finally, overall males displayed a greater number of cells that express the RXFP3 protein in all of the amygdaloid nuclei examined. Cognitive and emotional processes regulated by activity within the HI and AMYG are modulated by both sex and age. The vast majority of studies exploring the influence of sex on age-related changes in the HI and AMYG have focused on sex hormones, with few studies examining the role of neuropeptides. The current findings suggest that changes in relaxin family peptides may contribute to the significant sex differences observed in these brain regions as a function of aging.
松弛素是一种与妊娠相关的重要激素，通过激活松弛素样家族肽1受体（RXFP1）介导广泛的外周效应。最近的研究表明，松弛素作为一种神经肽还有额外的作用，RXFP1受体在许多脑区表达。脑干中一个称为不确定核（NI）的区域的神经元产生松弛素3（RLN3），这是松弛素家族中最近发现的神经肽。已证明RLN3可激活RXFP1和松弛素样家族肽受体3（RXFP3）受体亚型。研究表明，激活RXFP1和RXFP3具有广泛的神经调节作用，尽管迄今为止大多数研究是在年轻男性中进行的。在本研究中，我们使用年轻成年（9 - 12周）和中年（9 - 12个月）的雄性和雌性大鼠，研究了NI中RLN3基因表达以及背侧海马体（HI）、腹侧海马体（vHI）和杏仁核（AMYG）中RXFP1和RXFP3基因表达的潜在性别和年龄相关变化。此外，还检查了CA1、CA2/CA3和齿状回（DG）以及基底外侧（BLA）、中央（CeA）和内侧（MeA）杏仁核内RXFP1和RXFP3蛋白表达的区域变化。在NI中，RLN3在雄性中显示出与年龄相关的下降。在HI中，只有RXFP3受体在基因表达上显示出与年龄相关的变化，然而，两种受体亚型在蛋白表达上都显示出与年龄相关的区域特异性变化。此外，虽然两种受体的基因和蛋白表达在AMYG中都随年龄增加，但这些效应都是区域和性别特异性的。最后，在所有检查的杏仁核中，总体上雄性显示出表达RXFP3蛋白的细胞数量更多。由HI和AMYG内的活动调节的认知和情感过程受到性别和年龄的调节。绝大多数探索性别对HI和AMYG中与年龄相关变化的影响的研究都集中在性激素上，很少有研究考察神经肽的作用。目前的研究结果表明，松弛素家族肽的变化可能导致在这些脑区中观察到的随年龄增长而出现的显著性别差异。
