Sex as a Factor in Normal Retinal Function and Schizophrenia

性别是正常视网膜功能和精神分裂症的一个因素

• 批准号: 10598084
• 负责人: LINDA K. MCLOON
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598084
• 关键词: Adult; Affect; Age; Age Months; Agonist; Androgen Antagonists; Biological Markers; Bipolar Disorder; Birth; Brain; Brain Diseases; Castration; Central Nervous System; Collaborations; Data; Development; Diagnosis; Disease; Early treatment; Electrodes; Electroretinography; Estrogens; Female; Feminization; Flutamide; Genes; Genetic; Genotype; Gonadal Hormones; Gonadal Steroid Hormones; Hormonal; Hormones; Individual; Knowledge; Laboratories; Light; Light Adaptations; Lighting; Male Castration; Masculine; Measurement; Measures; Methods; Mucopolysaccharidosis I; Mus; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neonatal; Normalcy; Operative Surgical Procedures; Pattern; Persons; Photoreceptors; Play; Population; Retina; Retinal Diseases; Risk; Role; Schizophrenia; Serine; Severities; Sex Differences; Sex Differentiation; Symptoms; Testing; Testosterone; Tissues; Transgenic Mice; Vertebrate Photoreceptors; Wild Type Mouse; Woman; aspartate receptor; base; brain dysfunction; diagnostic tool; early onset; efficacy study; human data; human male; human subject; insight; interest; male; men; mouse model; neonatal mice; nervous system disorder; neuropsychiatric disorder; novel; prevent; prognostic indicator; receptor expression; response; retinal neuron; risk variant; serine racemase; severe mental illness; sex; success

Project Summary Studies have examined retinal function using the electroretinogram (ERG) as a non-invasive method that has the potential to mirror brain dysfunction in disease. The retina, which develops from the same tissue as the brain, can provide a “window” into abnormal brain function. Thus, non-invasive measurements of retinal function have garnered interest for their potential to diagnose and predict those at risk of developing neuropsychiatric diseases. However, understanding how sex differences play a role in normal and diseased retinal function have been understudied. This lack of knowledge limits proper interpretation and analysis of results in neurological diseases conditions where sex differences are well established. We examined the flash ERG (fERG) in a mouse model of schizophrenia with a mutation in serine racemase (SRKO), resulting in hypofunction of the N-methyl-D-aspartate receptor (NMDAR). Based on sex differences in onset and severity of schizophrenia in human males versus females, we analyzed our data based on sex and genotype. To our surprise, almost all the differences in the fERG between these genotypes were due to the male SRKO mice. The males showed decreased amplitudes and delayed implicit times in the a- and b-waves, while SRKO females were mainly unaffected. This male- dominated reduction of the fERG response of SRKO mice is important in light of known differences in onset and severity in human males with schizophrenia compared to females. While we observed sex differences in SRKO mice, we also observed sex differences in the fERG between male and female wildtype (WT) mice. These results suggest that sex hormones play a role in normal retinal function, but it is unclear how gonadal hormones alter the field-potentials that drive the fERG. Interestingly, the sex differences in the mouse studies were only observed during mesopic-light adaptation, rather than the traditional scotopic and photopic adaptation. This suggests that sex differences in the retinal network are dominated by both rods and cones, rather than by just one type of photoreceptor. The basis for these sex differences at the level of the retina is unknown, but if known, could be used to leverage the use of fERG in disease conditions that differ depending on sex. We will determine if ovarectomy or castration will eliminate the sex differences in the fERG. It is also possible that the presence of gonadal hormones from birth may have masculinized or feminized the retina and brain during the normal period of sexual differentiation. To test this hypothesis, we will treat neonatal male mice with flutamide (an anti- androgen) or neonatal female mice with testosterone and determine if the sex differences in the fERG are abolished by this early treatment that prevents sexual differentiation, which in turn alters brain development. Our working hypothesis is that gonadal hormones play a critical role in sex differences in retinal function.

项目摘要 研究已经使用视网膜电图（ERG）作为一种非侵入性方法检查了视网膜功能， 反映疾病中大脑功能障碍的潜力。视网膜与大脑是由同一组织发育而来的， 可以提供一个观察异常大脑功能的窗口。因此，视网膜功能的非侵入性测量具有 他们对诊断和预测那些有患神经精神疾病风险的人的潜力产生了兴趣。 然而，了解性别差异如何在正常和患病的视网膜功能中发挥作用一直是 替补演员这种知识的缺乏限制了对神经系统疾病结果的正确解释和分析 性别差异得到充分确立的条件。我们检查了闪光视网膜电图（fERG）在小鼠模型， 丝氨酸消旋酶（SRKO）突变导致N-甲基-D-天冬氨酸功能减退的精神分裂症 受体（NMDAR）。基于男性精神分裂症发病和严重程度的性别差异， 女性，我们根据性别和基因型分析了我们的数据。令我们惊讶的是，几乎所有的差异， 这些基因型之间的fERG是由于雄性SRKO小鼠造成的。雄性的脑电波振幅 和延迟的内隐时间在a-和b-波，而SRKO女性主要是不受影响。这只公的 SRKO小鼠的fERG反应的主导性降低是重要的，因为已知的发病差异和 与女性相比，男性精神分裂症患者的严重程度。虽然我们观察到SRKO的性别差异， 在小鼠中，我们还观察到雄性和雌性野生型（WT）小鼠之间fERG的性别差异。这些结果 这表明性激素在正常视网膜功能中起作用，但尚不清楚性腺激素如何改变 驱动fERG的场电位有趣的是，在小鼠研究中， 在中间光适应期间，而不是传统的暗适应和明适应。这表明 视网膜网络中的性别差异由杆和锥两者主导，而不是仅仅由一种类型的 光感受器视网膜水平上这些性别差异的基础尚不清楚，但如果知道，可能是 用于在因性别而异的疾病条件下利用fERG。我们将确定是否 卵巢切除术或去势将消除fERG的性别差异。也有可能， 在正常时期，出生时的性腺激素可能使视网膜和大脑男性化或女性化 性别差异。为了验证这一假设，我们将用氟替卡松（一种抗- 雄激素）或新生雌性小鼠与睾酮，并确定是否性别差异fERG是 这种早期治疗可以阻止性别分化，从而改变大脑发育。我们 工作假设是，性腺激素在视网膜功能的性别差异中起关键作用。