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

基本信息

批准号：
10447908
负责人：
LINDA K. MCLOON
金额：
$ 23.25万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/10447908
关键词：
Adult Affect Age Age-Months Agonist Androgen Antagonists Biological Markers Bipolar Disorder Birth Brain Brain Diseases Castration 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 Masculine Measurement Measures Methods Mucopolysaccharidosis I Mus Mutation N-Methyl-D-Aspartate Receptors N-Methylaspartate Neonatal Neuraxis Normalcy Operative Surgical Procedures Pattern Persons Photoreceptors Play Population Retina Retinal Diseases Risk Role Schizophrenia Serine Severities Sex Differences Sex Differentiation Symptoms Testing Testosterone Time 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

项目摘要

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.

项目概要研究使用视网膜电图（ERG）作为一种非侵入性方法检查视网膜功能，视网膜由与大脑相同的组织发育而来，有可能反映疾病中的大脑功能障碍。可以提供一个了解异常大脑功能的“窗口”，因此，视网膜功能的非侵入性测量已成为可能。因其在诊断和预测那些有患神经精神疾病风险的人方面的潜力而引起了人们的兴趣。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已经很困难了。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。我们在小鼠模型中检查了闪光 ERG (fERG)。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）基于人类与男性精神分裂症发病和严重程度的性别差异。对于女性，我们根据性别和基因型分析了数据，令我们惊讶的是，几乎所有差异都存在。这些基因型之间的 fERG 归因于雄性 SRKO 小鼠，雄性表现出降低的幅度。并且 a 波和 b 波的隐式时间延迟，而 SRKO 女性主要不受影响。鉴于已知的发病和死亡差异，SRKO 小鼠 fERG 反应的显着降低非常重要。与女性相比，男性精神分裂症的严重程度更高，而我们观察到 SRKO 中的性别差异。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。表明性激素在正常视网膜功能中发挥作用，但尚不清楚性激素如何改变驱动 fERG 的场电位暗示，仅在小鼠研究中观察到性别差异。在中间光适应期间，而不是传统的暗视和明视适应期间。视网膜网络中的性别差异主要由视杆细胞和视锥细胞主导，而不仅仅是一种类型视网膜水平上这些性别差异的基础尚不清楚，但如果已知，则可能是这样。用于在因性别而异的疾病中利用 fERG。卵巢切除术或去势将消除 fERG 中的性别差异。出生时的性腺激素可能在正常时期使视网膜和大脑男性化或女性化为了检验这一假设，我们将用氟他胺（一种抗- 雄激素）或具有睾酮的新生雌性小鼠，并确定 fERG 中的性别差异是否存在这种阻止性别分化的早期治疗废除了这一点，从而改变了我们的大脑发育。目前的假设是，性腺激素在视网膜功能的性别差异中发挥着关键作用。