Mechanisms for 5-HTT control of PPI and perseverative behavior using mouse models

使用小鼠模型研究 5-HTT 控制 PPI 和持续行为的机制

基本信息

批准号：
8038444
负责人：
STEPHANIE C DULAWA
金额：
$ 37.56万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-22 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8038444
关键词：
Acute Agonist Alleles Animal Model Antidepressive Agents Autistic Disorder Behavior Behavioral Behavioral Genetics Behavioral Model Binding Brain region Chronic Clomipramine Code Cognitive Coupling Desipramine Disease Exhibits Fluoxetine GTP gamma S Genes Genetic Genetic Models Human Hypersensitivity Infusion procedures Knock-out Knockout Mice Lead Link Measures Missense Mutation Moclobemide Modeling Monoamine Oxidase Inhibitors Motor Mouse Strains Mus Mutation Norepinephrine Obsessive-Compulsive Disorder Population Psyche structure Receptor Activation Reflex action Regulation Research Personnel Selective Serotonin Reuptake Inhibitor Sensory Serotonin Serotonin Receptor 5-HT1B Specificity Stimulus Techniques Testing Transgenic Mice Work effective therapy gain of function gain of function mutation inhibitor/antagonist insight mouse model mutant neuromechanism novel overexpression prepulse inhibition presynaptic prevent promoter receptor receptor binding receptor expression response reuptake serotonin transporter uptake

项目摘要

DESCRIPTION (provided by applicant): We propose to use behavioral and genetic mouse models to identify the neural mechanisms by which serotonin transporter (5-HTT) function modulates sensorimotor gating deficits and perseverative behaviors. Sensorimotor gating is a neural mechanism that filters excessive sensory, cognitive, and motor information, permitting mental and behavioral integration. Prepulse inhibition (PPI) is a form of startle plasticity that provides an operational measure of sensorimotor gating. Recent findings have implicated gain-of-function mutations in 5-HTT, and hypersensitivity of 5-HT1DP (homologous to mouse 5-HT1B) receptors, in two disorders characterized by deficient PPI and perseverative behaviors: obsessive-compulsive disorder (OCD) and autistic disorders. Only antidepressant drugs that potently block the reuptake of serotonin provide effective treatment for these disorders. Our recent findings in mice have identified a functional interaction between 5-HTT and 5-HT1B receptors in modulating PPI and perseverative behaviors. We found that the PPI deficits and perseverative behaviors induced by acute 5-HT1B agonist challenge are absent in 5-HTT knockout mice. We also found that the behavioral deficits induced by 5-HT1B agonists are absent in mice treated chronically, but not subchronically, with the selective serotonin reuptake inhibitor fluoxetine. Thus, we hypothesize that reducing 5-HTT function, genetically or pharmacologically, prevents the PPI deficits and perseverative behaviors induced by 5-HT1B receptor activation by desensitizing these receptors. We also hypothesize that increasing 5-HTT function, genetically or pharmacologically, will exacerbate the behavioral deficits induced by 5-HT1B receptor activation by sensitizing these receptors. Here, we propose to identify the mechanisms by which 5-HTT and 5-HT1B receptors interact to modulate these behaviors. First, we will test the hypothesis that potent blockade of 5-HTT is required to prevent 5-HT1B agonist-induced behavioral deficits by comparing the ability of different classes of antidepressants to reverse these effects. Second, we will assess 5-HT1B receptor expression and functional coupling to localize the brain regions in which 5-HT1B receptors are desensitized by antidepressant treatments. Third, we will generate two inducible transgenic mouse strains with increased 5-HTT function. One strain will overexpress mouse 5-HTT to evaluate the effects of increased 5-HTT availability, which may model the consequences of specific 5-HTT gene-linked polymorphic region (5-HTTLPR) alleles recently linked to OCD. The other strain will express human 5-HTT containing an uncommon mutation, Ne425Val, which renders 5-HTT constitutively active and was recently linked to OCD and autism. We hypothesize that both mouse strains will exhibit PPI deficits and perseverative behaviors, and increased behavioral responses to 5-HT1B agonists. Our unique approach could lead to novel animal models of the sensorimotor gating deficits and perseverative behaviors in OCD and autism.

描述（由申请人提供）：我们建议使用行为和遗传小鼠模型来识别血清素转运蛋白（5-HTT）功能调节感觉运动门控缺陷和持续行为的神经机制。感觉运动门控是一种神经机制，可以过滤过多的感觉、认知和运动信息，从而实现心理和行为的整合。前脉冲抑制（PPI）是惊吓可塑性的一种形式，提供感觉运动门控的操作测量。最近的研究结果表明，5-HTT 的功能获得性突变和 5-HT1DP（与小鼠 5-HT1B 同源）受体的超敏性与两种以 PPI 缺陷和持续行为为特征的疾病有关：强迫症 (OCD) 和自闭症。只有有效阻止血清素再摄取的抗抑郁药物才能有效治疗这些疾病。我们最近在小鼠身上的研究发现，5-HTT 和 5-HT1B 受体之间在调节 PPI 和持久行为方面存在功能性相互作用。我们发现 5-HTT 敲除小鼠中不存在由急性 5-HT1B 激动剂激发引起的 PPI 缺陷和持续行为。我们还发现，在使用选择性血清素再摄取抑制剂氟西汀进行长期而非亚慢性治疗的小鼠中，不存在由 5-HT1B 激动剂引起的行为缺陷。因此，我们假设从遗传或药理学角度降低 5-HTT 功能，可以通过使 5-HT1B 受体脱敏来预防 PPI 缺陷和由 5-HT1B 受体激活引起的持续行为。我们还假设，从遗传或药理学角度增加 5-HTT 功能将通过使 5-HT1B 受体敏感而加剧由这些受体激活引起的行为缺陷。在这里，我们建议确定 5-HTT 和 5-HT1B 受体相互作用以调节这些行为的机制。首先，我们将通过比较不同类别的抗抑郁药逆转这些影响的能力来检验以下假设：需要有效阻断 5-HTT 来预防 5-HT1B 激动剂诱导的行为缺陷。其次，我们将评估 5-HT1B 受体的表达和功能耦合，以定位 5-HT1B 受体因抗抑郁治疗而脱敏的大脑区域。第三，我们将产生两种具有增强的 5-HTT 功能的诱导型转基因小鼠品系。一种品系会过度表达小鼠 5-HTT，以评估 5-HTT 可用性增加的影响，这可能会模拟最近与 OCD 相关的特定 5-HTT 基因连锁多态性区域 (5-HTTLPR) 等位基因的后果。另一种菌株将表达含有罕见突变 Ne425Val 的人类 5-HTT，该突变使 5-HTT 具有组成型活性，最近被认为与强迫症和自闭症有关。我们假设这两种小鼠品系都会表现出 PPI 缺陷和持续行为，以及对 5-HT1B 激动剂的行为反应增加。我们独特的方法可能会产生关于强迫症和自闭症的感觉运动门控缺陷和持续行为的新型动物模型。