Gorman-Sandler Erin, Robertson Breanna, Crawford Jesseca, Wood Gabrielle, Ramesh Archana, Arishe Olufunke O, Webb R Clinton, Hollis Fiona
Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
Columbia VA Health Care Systems, Columbia, SC, 29208, USA.
Neurobiol Stress. 2023 Aug 14;26:100563. doi: 10.1016/j.ynstr.2023.100563. eCollection 2023 Sep.
Postpartum depression (PPD) is a major psychiatric complication of childbirth, affecting up to 20% of mothers, yet remains understudied. Mitochondria, dynamic organelles crucial for cell homeostasis and energy production, share links with many of the proposed mechanisms underlying PPD pathology. Brain mitochondrial function is affected by stress, a major risk factor for development of PPD, and is linked to anxiety-like and social behaviors. Considering the importance of mitochondria in regulating brain function and behavior, we hypothesized that mitochondrial dysfunction is associated with behavioral alterations in a chronic stress-induced rat model of PPD. Using a validated and translationally relevant chronic mild unpredictable stress paradigm during late gestation, we induced PPD-relevant behaviors in adult postpartum Wistar rats. In the mid-postpartum, we measured mitochondrial function in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using high-resolution respirometry. We then measured protein expression of mitochondrial complex proteins and 4-hydroxynonenal (a marker of oxidative stress), and Th1/Th2 cytokine levels in PFC and plasma. We report novel findings that gestational stress decreased mitochondrial function in the PFC, but not the NAc of postpartum dams. However, in groups controlling for the effects of either stress or parity alone, no differences in mitochondrial respiration measured in either brain regions were observed compared to nulliparous controls. This decrease in PFC mitochondrial function in stressed dams was accompanied by negative behavioral consequences in the postpartum, complex-I specific deficits in protein expression, and increased Tumor Necrosis Factor alpha cytokine levels in plasma and PFC. Overall, we report an association between PFC mitochondrial respiration, PPD-relevant behaviors, and inflammation following gestational stress, highlighting a potential role for mitochondrial function in postpartum health.
产后抑郁症（PPD）是分娩后的一种主要精神并发症，影响多达20%的母亲，但仍未得到充分研究。线粒体是对细胞稳态和能量产生至关重要的动态细胞器，与PPD病理学的许多潜在机制存在联系。脑线粒体功能受应激影响，应激是PPD发生的主要危险因素，且与焦虑样行为和社交行为有关。考虑到线粒体在调节脑功能和行为方面的重要性，我们假设线粒体功能障碍与慢性应激诱导的PPD大鼠模型中的行为改变有关。在妊娠后期使用经过验证且与转化相关的慢性轻度不可预测应激范式，我们在成年产后Wistar大鼠中诱导出与PPD相关的行为。在产后中期，我们使用高分辨率呼吸测定法测量前额叶皮质（PFC）和伏隔核（NAc）中的线粒体功能。然后我们测量PFC和血浆中线粒体复合物蛋白和4-羟基壬烯醛（氧化应激标志物）的蛋白表达以及Th1/Th2细胞因子水平。我们报告了新的发现，即妊娠应激会降低产后母鼠PFC中的线粒体功能，但不会降低NAc中的线粒体功能。然而，在单独控制应激或产次影响的组中，与未生育的对照组相比，在这两个脑区测量的线粒体呼吸没有差异。应激母鼠PFC线粒体功能的这种下降伴随着产后的负面行为后果、蛋白表达中复合物I特异性缺陷以及血浆和PFC中肿瘤坏死因子α细胞因子水平的升高。总体而言，我们报告了妊娠应激后PFC线粒体呼吸、与PPD相关的行为和炎症之间的关联，突出了线粒体功能在产后健康中的潜在作用。
