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）：除了签名特征外，被诊断出患有自闭症谱系障碍的人（ASDS）通常会受到过度侵略的负担（〜70％的发病率），但是了解这种合并症如何发展和当前治疗方案的知识受到限制。脑男性化是性二态性区域的组织，被认为发生在围产期生活期间大脑发育的关键时期。在男性中，这一时期是由睾丸激素激增在出生后不久迅速下降的。该睾丸激素主要通过合成酶芳香酶（CYP19）的神经元在大脑中局部转化为雌激素。然后，雌激素在这些神经元中激活其同源受体，在这些神经元中，核激素转录因子诱导基因表达的变化，而神经元回路的功能和结构变化是基因表达的变化。这些关键的荷尔蒙事件策划了表达芳香酶的脑回路的男性化，这使得在以后的生活中表达男性特定行为的画布。实际上，主要是雄激素受体和二次睾丸激素激增最终决定了这些大脑区域的活性以及男性特异性行为的程度，例如成年后的攻击性。最近，我们描述了人类杂质染色体15（IDIC15）的小鼠模型，除了在Smith等人中报道的核心自闭症相关性状外。 2011年还表现出侵略性行为。这代表了人类遗传自闭症的第一个已知动物模型，该模型表现出增加攻击性的合并症。与人IDIC15一样，小鼠的基因和蛋白质剂量是Ube3a（核激素受体，包括雌激素和雄激素）的ube3a的三倍和蛋白质剂量。鉴于这些发现，我们建议测试新颖的想法（适用于探索性R21赠款），IDIC15个个体中的UBE3A和我们的小鼠模型中的ube3a在大脑发育的关键时期内异常强烈的雌激素受体信号传导，超出大脑的关键时期，使大脑促进大脑的过度侵袭，从而在掺假型中产生了过多的攻击。这个想法与现有的自闭症理论（男爵）是一致的，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，我们将执行以下研究：1）使用我们新创建的转基因小鼠上有条件的Ube3a进行时间诱导的UBE3A的IDIC15基因剂量的过度表达来确定多余的UBE3A的发育时间，而UBE3A过多的UBE3A产生了夸张的攻击行为，并产生了表达的超中型和神经术语（预测的超中型和预测）。 2）使用我们的第二个新创建的有条件的Ube3a从转基因小鼠中诱导了超男性行为和脑表型。抑制睾丸激素 - 芳香蛋白酶 - 雌激素信号传导途径的药理学剂也将测试其营救这些表型的能力。这些研究提供了自闭症中高性分子大脑的生物学示例和分子机制，并解释了IDIC15自闭症的侵略性增加。