Neurobiology of Aggression Co-morbidity in Mouse Model of Idic15 Autism

Idic15 自闭症小鼠模型中攻击性共病的神经生物学

基本信息

批准号：
8529976
负责人：
MATTHEW P ANDERSON
金额：
$ 26.1万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8529976
关键词：
Adult Affect Age Aggressive behavior Amygdaloid structure Anabolic steroids Androgen Receptor Androgens Animal Model Animals Aromatase Autistic Disorder Axon Behavior Behavioral Biological Birth Brain Brain region Cell Nucleus Child Chromosomes, Human, Pair 15 Communication Comorbidity Complement Cytogenetic Analysis Development Diagnosis Disease Distress Engineering Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Estradiol Estrogen Receptors Estrogens Event Exhibits Exons Female Gene Dosage Gene Expression Gene Expression Regulation Gene Proteins Genes Genetic Goals Gonadal Steroid Hormones Grant Hormonal Hormones Human Human Genetics Hypothalamic structure Incidence Individual Inherited Injection of therapeutic agent Isodicentric Chromosome Knowledge Life Masculine Medial Molecular Mus Neonatal Neurobiology Neurons Nuclear Nuclear Hormone Receptors Nuclear Receptors Pattern Perinatal Phenotype Receptor Signaling Reporting Role Signal Pathway Signal Transduction Social Interaction Structure of terminal stria nuclei of preoptic region Supplementation System Tamoxifen Testing Testosterone Time Transcript Transgenes Transgenic Animals Transgenic Mice Transgenic Model Ultrasonics Weaning arm autism spectrum disorder critical period density dosage early childhood in utero male mouse model novel overexpression postnatal preference prenatal prevent protein function public health relevance receptor recombinase reconstitution social theories tool trait ubiquitin-protein ligase vocalization

项目摘要

DESCRIPTION (provided by applicant): Individuals diagnosed with autism spectrum disorders (ASDs) are, in addition to signature traits, often burdened by excess aggression (~70% incidence), but knowledge on how this co-morbidity develops and current treatment options are limited. Brain masculinization, the organization of sexually dimorphic regions, is thought to occur during a critical period of brain development during perinatal life. In males this period is identified by a testosterone surge that declines rapidly soon after birth. This testosterone is mostly converted to estradiol locally in the brain by neurons that synthesize the enzyme aromatase (cyp19). Estrogen then activates its cognate receptors in these neurons, where the nuclear hormone transcriptional factor induces changes in gene expression that underlie functional and structural changes in the neuronal circuits. These critical hormonal events orchestrate masculinization of these aromatase-expressing brain circuits, making a canvas for the expression of male specific behaviors later in life. Indeed it will be mostly androgen receptors and secondary testosterone surges that ultimately determine the activity of these brain regions and the extent of male-specific behaviors, such as aggression in adulthood. Recently we described a mouse model of human isodicentric chromosome 15 (idic15) that in addition to the core autism-related traits reported in Smith et al. 2011 also exhibits increased aggressive behavior. This represents the first known animal model of a human genetic autism displaying the co-morbidity of increased aggression. As in human idic15, the mice have a tripled gene and protein dosage of Ube3a, a known co- activator at nuclear hormone receptors, including those for estrogen and androgens. In the light of these findings, we propose to test the novel idea (appropriate for an exploratory R21 grant) that excess Ube3a in idic15 individuals and in our mouse model of the disorder causes abnormally strong estrogen receptors signaling during the key period of brain development to hypermasculinize the brain generating excess aggression in adulthood. The idea is congruent with existing "hypermale" theory of autism (Baron-Cohen), but provides a concrete biological explanation. To verify this new biological idea, we will perform the following studies: 1) Use our newly created conditional Ube3a ON transgenic mice for temporally-induced over- expression of the idic15 gene dosage of Ube3a to determine the developmental time period when excess Ube3a generates the exaggerated aggression behaviors and predicted hyper-male transcriptional and neuroanatomical (aromatase expressing neuron) brain phenotypes. 2) Use our second newly created conditional Ube3a OFF transgenic mice for induced rescue of the hyper-masculine behavioral and brain phenotypes. Pharmacological agents that inhibit the testosterone-aromatase-estrogen signaling pathway will also be tested for their ability to rescue these phenotypes. These studies provide a biological example and molecular mechanism for the hypermale brain in autism and explain increased aggression in idic15 autism.

描述（由申请人提供）：被诊断患有自闭症谱系障碍 (ASD) 的个体，除了标志性特征外，还常常承受过度攻击性的负担（发病率约 70%），但关于这种共病如何发展以及当前治疗方案的了解并不多。有限的。大脑男性化，即性别二态性区域的组织，被认为是发生的在围产期大脑发育的关键时期。对于男性来说，这一时期的标志是睾丸激素激增，但在出生后不久就会迅速下降。这种睾酮大部分在大脑中通过合成芳香酶 (cyp19) 的神经元转化为雌二醇。然后雌激素激活这些神经元中的同源受体，其中核激素转录因子诱导基因表达的变化，这是神经元回路功能和结构变化的基础。这些关键的荷尔蒙事件协调了这些表达芳香酶的大脑回路的男性化，为以后生活中男性特定行为的表达奠定了基础。事实上，最终决定这些大脑区域的活动以及男性特有行为（例如成年期的攻击性）程度的主要是雄激素受体和继发性睾酮激增。最近，我们描述了人类等双着丝粒染色体 15 (idic15) 的小鼠模型，除了 Smith 等人报道的核心自闭症相关特征之外，该模型还具有其他特征。 2011 年攻击行为也有所增加。这是第一个已知的人类遗传自闭症动物模型，显示出攻击性增加的共病。与人类 idic15 一样，小鼠体内的 Ube3a 基因和蛋白质剂量增加了三倍，Ube3a 是核激素受体（包括雌激素和雄激素受体）的已知共激活剂。根据这些发现，我们建议测试这个新想法（适合探索性 R21 资助），即 idic15 个体和我们的小鼠模型中过量的 Ube3a 会在大脑发育的关键时期导致异常强烈的雌激素受体信号传导，从而使大脑过度男性化，在成年后产生过度的攻击性。这个想法与现有的自闭症“超男性”理论（Baron-Cohen）一致，但提供了具体的生物学解释。为了验证这一新的生物学想法，我们将进行以下研究：1）使用我们新创建的条件性Ube3a ON转基因小鼠暂时诱导Ube3a的idic15基因剂量的过度表达，以确定过量的Ube3a产生的发育时间段。夸大攻击行为并预测超男性转录和神经解剖学（表达芳香酶的神经元）大脑表型。 2) 使用我们第二只新创建的条件性 Ube3a OFF 转基因小鼠来诱导拯救超男性行为和大脑表型。抑制睾酮-芳香酶-雌激素信号通路的药物也将被测试其拯救这些表型的能力。这些研究为自闭症患者的超男性大脑提供了生物学实例和分子机制，并解释了 idic15 自闭症患者攻击性的增加。