Sex as a Factor in Normal Retinal Function and Schizophrenia

项目摘要 研究使用视网膜电信号(ERG)作为一种非侵入性方法来检查视网膜功能，这种方法具有 在疾病中反映大脑功能障碍的可能性。视网膜与大脑由相同的组织发育而来， 可以提供一扇了解大脑功能异常的“窗口”。因此，视网膜功能的非侵入性测量具有 由于它们有可能诊断和预测有患神经精神疾病风险的人，因此引起了人们的兴趣。 然而，对性别差异如何在正常和疾病的视网膜功能中发挥作用的理解一直是 未得到充分研究。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 性别差异已经确立的状况。我们研究了闪光ERG(FERG)在小鼠模型中的表现 丝氨酸消旋酶(SRKO)突变导致N-甲基-D-天冬氨酸功能低下的精神分裂症 受体(NMDAR)。基于男性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分析了我们的数据。令我们惊讶的是，世界上几乎所有的差异 这些基因型之间的FERG是由于雄性SRKO小鼠所致。雄鼠的波幅降低。 A波和b波的潜伏期延长，而SRKO女性基本不受影响。这位男性- 考虑到SRKO小鼠发病和死亡的已知差异，控制降低SRKO小鼠的FERG反应是很重要的 男性精神分裂症患者的严重程度与女性相比。当我们观察到SRKO的性别差异时 我们还观察了雄性和雌性野生型(WT)小鼠在FERG上的性别差异。这些结果 提示性激素在正常视网膜功能中起作用，但性腺激素如何改变尚不清楚。 驱动弗罗格的场势。有趣的是，在老鼠研究中只观察到了性别差异 在中间视光适应期间，而不是传统的暗视和明视适应。这表明 视网膜网络中的性别差异由视杆细胞和视锥细胞共同决定，而不是仅由一种类型的 光感受器。视网膜水平上的性别差异的基础尚不清楚，但如果已知，可能是 用于在根据性别不同的疾病情况下使用FERG。我们将确定是否 卵巢切除或去势将消除生殖器内的性别差异。也有可能是因为 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。 性别分化的结果。为了验证这一假设，我们将用氟他胺(一种抗病毒药物)治疗新生雄性小鼠。 雄激素)或新生的雌性小鼠注射睾酮，并确定FERG中的性别差异是否 被这种防止性别分化的早期治疗所废除，性别分化反过来改变大脑发育。我们的 工作假说是性腺激素在视网膜功能的性别差异中起着关键作用。

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.