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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：
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
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/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

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.

项目总结