Dunn Geoffrey A, Thompson Jacqueline R, Mitchell A J, Papadakis Samantha, Selby Matthew, Fair Damien, Gustafsson Hanna C, Sullivan Elinor L
Department of Human Physiology, University of Oregon, Eugene, OR, United States.
Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, United States.
Front Neurosci. 2023 Jan 10;16:1067479. doi: 10.3389/fnins.2022.1067479. eCollection 2022.
The neurotransmitter serotonin is a key regulator of neurotransmission, mood, and behavior and is essential in neurodevelopment. Dysfunction in this important neurotransmitter system is connected to behavioral disorders such as depression and anxiety. We have previously shown that the developing serotonin system is sensitive to perinatal exposure to Western-style diet (WSD).
To advance our hypothesis that perinatal WSD has a long-term impact on the serotonergic system, we designed a fluorescent immunohistochemistry experiment using antibodies against tryptophan hydroxylase 2 (TPH2) and vesicular glutamate transporter 3 (VGLUT3) to probe protein expression in the raphe subnuclei in 13-month-old Japanese macaques (; = 22). VGLUT3 has been shown to be coexpressed in TPH2+ cells in the dorsal raphe (DR) and median raphe nucleus (MnR) of rodent raphe nuclei and may provide information about the projection site of serotonergic fibers into the forebrain. We also sought to improve scientific understanding of the heterogeneity of the serotonin production center for the central nervous system, the midbrain raphe nuclei.
In this immunohistochemical study, we provide the most detailed characterization of the developing primate raphe to date. We utilize multi-level modeling (MLM) to simultaneously probe the contribution of WSD, offspring sex, and raphe anatomical location, to raphe neuronal measurements. Our molecular and morphological characterization revealed that the 13-month-old macaque DR is remarkably similar to that of adult macaques and humans. We demonstrate that vesicular glutamate transporter 3 (VGLUT3), which rodent studies have recently shown can distinguish raphe populations with distinct projection targets and behavioral functions, likewise contributes to the heterogeneity of the primate raphe.
This study provides evidence that perinatal WSD has a long-term impact on the density of serotonin-producing neurons, potentially limiting serotonin availability throughout the brain. Due to the critical involvement of serotonin in development and behavior, these findings provide important insight into the mechanisms by which maternal nutrition and metabolic state influence offspring behavioral outcomes. Finally, these findings could inform future research focused on designing therapeutic interventions to optimize neural development and decrease a child's risk of developing a mental health disorder.
神经递质血清素是神经传递、情绪和行为的关键调节因子，对神经发育至关重要。这一重要神经递质系统的功能障碍与抑郁症和焦虑症等行为障碍有关。我们之前已经表明，发育中的血清素系统对围产期接触西式饮食（WSD）敏感。
为了推进我们的假设，即围产期WSD对血清素能系统有长期影响，我们设计了一项荧光免疫组织化学实验，使用针对色氨酸羟化酶2（TPH2）和囊泡谷氨酸转运体3（VGLUT3）的抗体，来探测13个月大的日本猕猴（n = 22）中缝核亚核中的蛋白质表达。啮齿动物中缝核的研究表明，VGLUT3在背侧中缝核（DR）和中缝正中核（MnR）的TPH2+细胞中共表达，可能提供血清素能纤维向前脑投射部位的信息。我们还试图增进对中枢神经系统血清素产生中心——中脑缝核——异质性的科学理解。
在这项免疫组织化学研究中，我们提供了迄今为止对发育中的灵长类中缝核最详细的特征描述。我们利用多层次建模（MLM）同时探究WSD、后代性别和中缝核解剖位置对中缝核神经元测量的影响。我们的分子和形态学特征表明，13个月大的猕猴DR与成年猕猴和人类的DR非常相似。我们证明，啮齿动物研究最近表明，囊泡谷氨酸转运体3（VGLUT3）可以区分具有不同投射靶点和行为功能的中缝核群体，同样它也有助于灵长类中缝核的异质性。
这项研究提供了证据，表明围产期WSD对血清素产生神经元的密度有长期影响，可能会限制整个大脑中血清素的可用性。由于血清素在发育和行为中至关重要，这些发现为母体营养和代谢状态影响后代行为结果的机制提供了重要见解。最后，这些发现可以为未来的研究提供参考，这些研究专注于设计治疗干预措施，以优化神经发育并降低儿童患精神健康障碍的风险。
