Critical influence of neonatal testosterone on stress pathways in the adult brain.

新生儿睾酮对成人大脑应激途径的关键影响。

• 批准号: RGPIN-2014-05714
• 负责人: Viau, Victor
• 金额: $ 2.48万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630797
• 关键词: Critical; influence; neonatal; testosterone; stress

OBJECTIVES. Here we propose to test the requirements for and sites of involvement of neonatal sex steroids in programming the hypothalamic-pituitary-adrenal (HPA) neuroendocrine axis. Our current findings indicate that the activation of androgen receptors and the conversion of testosterone to estrogens during the neonatal period are both required for the normal development of the HPA axis to occur. Building on this success, all of the experiments of the current proposal will employ adult male rats (75 to 85 days) bearing subcutaneous implants of anti-androgen (flutamide) or an inhibitor of aromatase (ATD) within 12 h of birth, that are then removed on day 21 of weaning. We hypothesize that the capacity of testosterone to permanently alter or organize brain, behavior and physiology is linked to changes in androgen receptors, localized to brain regions located upstream from the principle driver of the HPA axis, the paraventricular nucleus (PVN) of the hypothalamus. In AIM-1, a battery of anatomical techniques will be employed to identify cells that project to the PVN region, respond to restraint-stress, and show androgen receptors. We also hypothesize that the enduring influence of testosterone to organize stress-related pathways to the PVN involves critical changes in the central activity of the neuropeptide arginine vasopressin (AVP) and its principle receptor, the V1A receptor. Importantly, this hypothesis is consistent with the stimulatory effect of testosterone on AVP synthesis in the brain, and the shared inhibitory characteristics by which central AVP-containing pathways and testosterone operate on the HPA axis. In AIM-2 we will compare HPA axis hormone responses to restraint-stress in animals receiving vehicle or V1A receptor antagonist injections into the lateral brain ventricles. Neonatal dependent changes in V1A receptors are not likely restricted to pathways regulating neuroendocrine responses, but might also occur within brain circuits generating active coping responses. Hence, we propose to use the same pharmacological approach to test for alterations in defensive burying behavior. In AIM-3, studies are designed to examine changes in AVP V1A receptor expression and function directly. We will employ in situ hybridization, receptor autoradiography and receptor coupling detection methods. Preceding experiments are geared towards unmasking processes related to the masculinization of stimulatory pathways driving PVN neuroendocrine responses. This may also include underlying changes in glucocorticoid negative-feedback regulation of the HPA axis. In AIM-4 we will test the extent to which neonatal manipulations alter the capacity of corticosterone to suppress the stress-induced activation of the HPA axis, in addition to glucocorticoid receptor expression and activation.SIGNIFICANCE. Using cellular, circuit, and system level approaches, the current proposal promises to provide novel findings and to increase our understanding of how neonatal testosterone contributes to the development of HPA axis and behavioral responses. What is emerging is that a variety of factors can influence the onset and duration of perinatal increases in testosterone (e.g. environmental stress, maternal behavior, nutrition, drugs). Based on the pervasive organizational effects of testosterone, we predict that any early life event that impacts testosterone release has the capacity to redirect any number of homeostatic processes. Thus, the work proposed is certain to impact several disciplines and fields of interest in physiology and neurobiology.

目标。在这里，我们建议测试新生儿性类固醇参与在编程下丘脑 - 垂体 - 肾上腺（HPA）神经内分泌轴的要求和部位。我们目前的发现表明，在新生儿时期，雄激素受体的激活以及睾丸激素向雌激素的转化都是HPA轴的正常发育所必需的。在这一成功的基础上，当前提案的所有实验将采用抗雄激素（Flutamide）的皮下植入物或芳香酶（ATD）抑制剂（ATD）的成年雄性大鼠（75至85天），然后在出生的12小时内，然后在WEANING的第21天将其移除。我们假设睾丸激素可以永久改变或组织大脑，行为和生理学的能力与雄激素受体的变化有关，雄激素受体的变化位于位于HPA轴的主要驱动器上游的脑部区域，HPA轴的主要驱动器（下丘脑的脊髓核（PVN））。在AIM-1中，将采用一系列解剖技术来识别投射到PVN区域的细胞，对约束压力做出反应并显示雄激素受体。我们还假设，睾丸激素组织应力相关途径的持久影响涉及神经肽精氨酸加压素（AVP）及其原理受体V1A受体的关键变化。重要的是，该假设与睾丸激素对大脑中AVP合成的刺激作用以及含AVP中央AVP途径和睾丸激素在HPA轴上运行的共同抑制特征是一致的。在AIM-2中，我们将将HPA轴激素反应与接收车辆或V1A受体拮抗剂注射的动物的约束压力进行比较。 V1A受体的新生儿依赖性变化不太可能仅限于调节神经内分泌反应的途径，但也可能发生在产生主动应对反应的脑电路中。因此，我们建议使用相同的药理方法来测试防御性埋葬行为的改变。在AIM-3中，研究旨在检查AVP V1A受体表达和功能的变化。我们将采用原位杂交，受体放射自显影和受体耦合检测方法。前面的实验旨在揭露与驱动PVN神经内分泌反应的刺激途径相关的过程。这也可能包括HPA轴的糖皮质激素负反馈调节的潜在变化。在AIM-4中，我们将测试新生儿操纵的程度，除了糖皮质激素受体的表达和激活外，除了糖皮质激素受体的表达和激活外，皮质酮抑制了应激诱导的HPA轴激活的能力。当前的提案使用蜂窝，电路和系统水平方法有望提供新的发现，并提高我们对新生儿睾丸激素如何有助于HPA轴和行为反应的发展的理解。正在出现的是，多种因素会影响睾丸激素围产期增加的发作和持续时间（例如，环境压力，孕产妇行为，营养，药物）。基于睾丸激素的普遍组织影响，我们预测，影响睾丸激素释放的任何早期生活事件都有能力重定向任何数量的稳态过程。因此，提出的工作肯定会影响生理学和神经生物学的几个学科和感兴趣的领域。