Identification and Validation of Human Hypothalamic Nuclei in-vivo and ex-vivo Us

描述（由申请人提供）：越来越多的证据表明，下丘脑对于理解女性健康和与神经、精神、内分泌和睡眠障碍相关的性别差异的重要性。事实上，下丘脑核是自主神经和内分泌功能的关键调节器，是大脑中性别差异最大的核之一，与已知性别差异的精神和医学疾病有关。我们认为，了解激素对大脑的影响以及对其他器官和/或系统（如心血管和生殖系统）的调节，对于下丘脑活动的下游影响至关重要。因此，了解下丘脑核的神经解剖学，以及它们在特定疾病中如何在男性和女性中被不同地破坏，将有助于阐明临床医学中的性别差异。然而，下丘脑核在人体内的鉴定尚未实现。这一点很重要，因为研究表明，在精神疾病中，下丘脑、内分泌功能障碍和性别差异存在关联。事实上，在重度抑郁症（MDD）患者中，室旁下丘脑核（PVN）增大，PVN神经元密集于促肾上腺皮质激素释放激素（CRH）和雌激素受体（ER）1。在我们最近对精神分裂症（SCZ）的研究中，我们使用MRI识别了下丘脑的结构异常，特别是女性的PVN。此外，在健康女性中，我们通过功能性核磁共振显示，下丘脑核（如PVN）的大脑活动调节依赖于月经周期中性腺激素的变化。本研究的主要重点是使用一种新的体内方法来评估下丘脑，比较使用7特斯拉磁共振成像（MRI）和人类死后验证的神经成像数据。本研究旨在利用高场MRI识别人下丘脑体内和离体PVN，探讨MRI方法与组织学技术的关系，并建立组织学结构与MRI表征的相关性。PVN对于其在下丘脑-垂体-肾上腺（HPA）轴中的作用及其在MDD和SCZ中的功能障碍至关重要，除此之外，我们还将确定视上核（SON），这将被用作对照区域。高分辨率特斯拉核磁共振成像将在30名健康受试者和4名离体人类下丘脑样本中进行。我们的首要目标是一个创新的方法之一：确定人类下丘脑的PVN在健康成年女性和男性体内。我们期望这种方法一旦确定，将在临床应用于重度抑郁症和重度焦虑症患者。公共卫生相关性：将使用高场磁共振成像（MRI）（即7特斯拉扫描仪）和离体人下丘脑组织识别活人下丘脑核。MRI结果将与死后的人体组织进行比较，以确保方法学的验证。这些下丘脑核是自主神经和内分泌功能的关键调节器，与许多具有已知性别差异的精神和医学疾病（如抑郁症和精神分裂症）有关。了解与神经、精神、心血管、内分泌和睡眠障碍有关的性别差异和下丘脑的参与对一般公众健康，特别是妇女健康非常重要。

DESCRIPTION (provided by applicant): There is increasing evidence regarding the importance of the hypothalamus for understanding women's health and sex differences in relation to neurological, psychiatric, endocrine and sleep disorders. In fact, hypothalamic nuclei, key regulators of autonomic and endocrine functions, are some of the most highly sexually dimorphic nuclei in the brain and implicated in psychiatric and medical disorders with known sex differences. We would argue that an understanding of hormonal effects on the brain and the regulation of other organs and/or systems, such as the cardiovascular and reproductive systems, are critical as downstream effects of hypothalamic activity. Thus an understanding of the neuroanatomy of hypothalamic nuclei and how they are differentially disrupted in men and women in specific disorders will contribute to elucidating sex differences in clinical medicine. However, the identification of hypothalamic nuclei in-vivo in humans has not been realized. This is important since studies have shown the association of the hypothalamus, endocrine dysfunction and sex differences in psychiatric disorders. In fact, the paraventricular hypothalamic nucleus (PVN) is enlarged in patients with major depressive disorder (MDD), in PVN neurons that are dense in corticotropin releasing hormone (CRH) and estrogen receptor (ER)1. In our recent work in schizophrenia (SCZ) we identified structural abnormalities using MRI in the hypothalamus particularly in the PVN in women. Furthermore, in healthy women we showed, using functional MRI, regulation of brain activity in hypothalamic nuclei such as the PVN, dependent on gonadal hormone changes over the menstrual cycle. The principal focus of this study is to use a new in-vivo methodology for the assessment of the hypothalamus comparing neuroimaging data using 7 Tesla magnetic resonance imaging (MRI) and human postmortem validation. The proposed study aims to identify the PVN in-vivo and ex-vivo in the human hypothalamus using high field MRI, to investigate the relationship of the MRI methodology and the histological technique, and to establish the correlates of the histological structures with the MRI representations. In addition to the PVN, which is critical for its role within the hypothalamic-pituitary-adrenal (HPA) axis and its dysfunction in MDD and SCZ, we will identify the supraoptic nucleus (SON), which will be used as a control region. High-resolution 7 Tesla MRI will be carried out in thirty healthy subjects, and four ex-vivo human hypothalamic samples. Our overarching goal is an innovative methodological one: to identify the PVN of the human hypothalamus in healthy adult women and men in-vivo. We expect this method, once defined, to be applied clinically in subjects with MDD and SCZ. PUBLIC HEALTH RELEVANCE: Hypothalamic nuclei will be identified in living humans using high field magnetic resonance imaging (MRI) (i.e., a 7 Tesla scanner) and in ex-vivo human hypothalamic tissue. The MRI results will be compared with postmortem human tissue to assure methodological validation. These hypothalamic nuclei are key regulators of autonomic and endocrine functions implicated in numerous psychiatric and medical disorders with known sex differences such as depression and schizophrenia. Understanding sex differences and the hypothalamic involvement in relation to neurological, psychiatric, cardiovascular, endocrine and sleep disorders is very relevant for public health in general and women's health in particular.