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在下丘脑-垂体-肾上腺（HPA）神经内分泌轴编程中的需求和参与部位。我们目前的研究结果表明，新生儿时期雄激素受体的激活和睾酮向雌激素的转化都是 HPA 轴正常发育所必需的。在此成功的基础上，当前提案的所有实验将采用成年雄性大鼠（75至85天），在出生后12小时内皮下植入抗雄激素（氟他胺）或芳香酶抑制剂（ATD），即然后在断奶第 21 天取出。我们假设睾酮永久改变或组织大脑、行为和生理的能力与雄激素受体的变化有关，雄激素受体定位于位于 HPA 轴主要驱动因素、下丘脑室旁核 (PVN) 上游的大脑区域。在 AIM-1 中，将采用一系列解剖技术来识别投射到 PVN 区域、对约束压力做出反应并显示雄激素受体的细胞。我们还假设，睾酮对组织与 PVN 的应激相关通路的持久影响涉及神经肽精氨酸加压素 (AVP) 及其主要受体 V1A 受体的中枢活性的关键变化。重要的是，这一假设与睾酮对大脑 AVP 合成的刺激作用以及含有 AVP 的中枢通路和睾酮在 HPA 轴上发挥作用的共同抑制特征一致。在 AIM-2 中，我们将比较接受媒介物或 V1A 受体拮抗剂注射到侧脑室的动物的 HPA 轴激素对约束应激的反应。 V1A 受体的新生儿依赖性变化可能并不局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大脑回路中。因此，我们建议使用相同的药理学方法来测试防御性掩埋行为的改变。在 AIM-3 中，研究旨在直接检查 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偶联检测方法。前述实验旨在揭示与驱动 PVN 神经内分泌反应的刺激途径男性化相关的过程。这可能还包括糖皮质激素对 HPA 轴负反馈调节的潜在变化。在 AIM-4 中，除了糖皮质激素受体的表达和激活之外，我们还将测试新生儿操作改变皮质酮抑制应激诱导的 HPA 轴激活的能力的程度。意义。使用细胞、电路和系统级方法，当前的提案有望提供新的发现，并增加我们对新生儿睾酮如何促进 HPA 轴和行为反应的发展的理解。正在出现的情况是，多种因素可以影响围产期睾酮增加的发生和持续时间（例如环境压力、母亲行为、营养、药物）。根据睾酮普遍存在的组织效应，我们预测任何影响睾酮释放的早期生命事件都有能力改变许多体内平衡过程。因此，所提出的工作肯定会影响生理学和神经生物学的多个学科和感兴趣的领域。