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

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

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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.

项目摘要研究已使用电视图（ERG）作为一种非侵入性方法检查了视网膜功能反映疾病中脑功能障碍的潜力。视网膜从与大脑同一组织发展的视网膜可以为异常的大脑功能提供“窗口”。那是残留功能的非侵入性测量值引起了人们对诊断和预测有神经精神疾病风险的潜力的兴趣。但是，了解性别差异如何在正常和否认的视网膜功能中发挥作用研究了。缺乏知识限制了神经疾病结果的正确解释和分析性别差异的条件已建立得很好。我们在鼠标模型中检查了Flash ERG（FERG）精神分裂症具有丝氨酸种族酶（SRKO）突变的精神分裂症，导致N-甲基-D-天冬氨酸的功能不全接收器（NMDAR）。基于人类男性的精神分裂症的发作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小鼠引起的。雄性显示放大器减少在A和B波中延迟隐式时间，而SRKO女性主要不受影响。这个男性 - 鉴于发作的已知差异和与女性相比，精神分裂症男性的严重程度。当我们观察到srko的性别差异时小鼠，我们还观察到男性和雌性野生型（WT）小鼠之间的性别差异。这些结果表明性激素在正常残留功能中起作用，但目前尚不清楚性腺激素如何改变驱动FERG的现场潜力。有趣的是，仅观察到小鼠研究中的性别差异在介质轻度适应期间，而不是传统的Scotopic和Photopic适应。这表明这一点视网膜网络中的性别差异都由杆和锥体主导，而不是仅以一种类型的感光器。这些性别差异在视网膜级别的基础是未知的，但如果已知，可能是用于利用Ferg在疾病条件下的使用，这些疾病条件因性别而异。我们将确定是否卵巢术或cast割将消除Ferg的性别差异。也可能存在在正常时期，从出生开始的性腺恐怖措施可能使视网膜和大脑女性化性别差异。为了检验这一假设，我们将用氟他胺治疗新生儿小鼠具有睾丸激素的雄激素）或新生儿小鼠，并确定Ferg的性别差异是否为这种早期治疗可以防止性别差异化，从而改变了大脑发育。我们的工作假设是，性腺恐怖在永久功能中的性别差异中起着至关重要的作用。