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，下丘脑对于了解女性的健康以及与神经、精神、内分泌和睡眠障碍有关的性别差异具有重要意义。事实上，下丘脑核团是自主神经和内分泌功能的关键调节者，是大脑中性别差异最大的核团之一，与已知性别差异的精神疾病和医学疾病有关。我们认为，了解荷尔蒙对大脑的影响以及对其他器官和/或系统的调节，如心血管和生殖系统，对于下丘脑活动的下游影响至关重要。因此，了解下丘脑核团的神经解剖学，以及在特定疾病中它们是如何在男性和女性中受到差异破坏的，将有助于阐明临床医学中的性别差异。然而，在活体内识别人类下丘脑核团还没有实现。这一点很重要，因为研究表明，精神障碍与下丘脑、内分泌功能障碍和性别差异之间存在关联。事实上，重度抑郁障碍(MDD)患者的下丘脑室旁核(PVN)在皮质激素释放激素(CRH)和雌激素受体(ER)1密集的PVN神经元中增大。在我们最近对精神分裂症(SCZ)的工作中，我们利用MRI发现了下丘脑，特别是女性PVN的结构异常。此外，在健康女性中，我们使用功能磁共振显示，下丘脑核团(如PVN)中大脑活动的调节取决于性腺激素在月经周期中的变化。这项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)的神经成像数据和人类尸检验证。本研究的目的是利用高场强磁共振技术鉴定人下丘脑体内和体外的室旁核，探讨MRI方法学与组织学技术的关系，并建立其组织结构与MRI表现的相关性。除了PVN，它在下丘脑-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，我们还将确定视上核(SON)，它将被用作控制区。高分辨率7特斯拉磁共振成像将在30名健康受试者和4名体外人类下丘脑样本中进行。我们的首要目标是一种创新的方法：在活体内识别健康成年女性和男性下丘脑的室旁核。我们期望这种方法一旦确定，将被临床应用于MDD和SCZ的受试者。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)在活体人类和体外人类下丘脑组织中识别下丘脑核。核磁共振结果将与身体人体组织进行比较，以确保方法学验证。这些下丘脑核团是自主神经和内分泌功能的关键调节者，与许多已知性别差异的精神和内科疾病有关，如抑郁症和精神分裂症。了解性别差异和下丘脑参与与神经、精神、心血管、内分泌和睡眠障碍的关系，对一般公共健康，特别是妇女健康非常相关。

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.