Neurobiology of pain and behavior changes associated with rare diseases and developmental disabilities

与罕见疾病和发育障碍相关的疼痛和行为变化的神经生物学

• 批准号: 10022068
• 负责人: Zenaide Quezado
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10022068
• 关键词: Adolescent; Animal Model; BTBR Mouse; Behavior; Behavior Therapy; Brain; Caring; Child; Chronic; Complex; Detection; Developmental Disabilities; Dose; Drug Targeting; Evaluation; FDA approved; FMR1; Family member; Fragile X Syndrome; Functional disorder; Gene Mutation; Genetic; Goals; Human; Individual; Inflammatory; Intelligence quotient; Methyl-CpG-Binding Protein 2; Modeling; Modification; Mus; Neurobiology; Nicotine; Nicotinic Receptors; Nociception; Pain; Pain Threshold; Pattern; Phelan-McDermid syndrome; Plasma; Process; Questionnaires; Rare Diseases; Reporting; Research Personnel; Rett Syndrome; Risk; Role; Safety; Sensory; Signal Transduction; Social Behavior; Standardization; Stimulus; Study models; Supplementation; Symptoms; Synaptic Transmission; System; Tactile; Therapeutic Agents; Time; Touch sensation; Visceral pain; autism spectrum disorder; autistic; behavior change; behavioral impairment; behavioral response; cholinergic; desensitization; improved; interest; mouse model; neuropsychiatric disorder; nicotine patch; null mutation; pain behavior; pain processing; pain sensitivity; preclinical evaluation; pressure; repetitive behavior; response; sensory stimulus; social; social deficits; targeted treatment

While researchers have reported on qualitative patterns of altered sensory processing in autism spectrum disorders (ASD), the neurobiological underpinnings of these alterations remain poorly understood. It remains unknown whether the associations between social deficits, repetitive behaviors, and sensory dysfunctions are causally related or are due to shared underlying pathobiology. The overall goal of this project is to elucidate the mechanism of altered nociception in animal models that recapitulate the core symptoms of ASD. We will conduct mechanistic studies in well characterized autistic-like mouse models that harbor gene mutations known to be associated with increased risk for ASD. We will also conduct preclinical evaluation of therapeutic agents that might improve sociability, repetitive behaviors, and at the same time possibly correct the altered nocifensive response. The evidence that individuals with ASD have altered nociception, pain processing, and pain response is inconclusive. In humans, others have shown that high-functioning adolescent with ASD have decreased thermal sensitivity (increased warmth and cold detection threshold) and that their thermal detection thresholds and heat pain thresholds correlates with their intelligence quotients. In another study, high functioning ASD children were shown to have increased pain (lower pressure pain thresholds) and touch sensitivities (Von Frey monofilaments) compared to healthy children. Using standardized questionnaires for the evaluation of behavioral responses to sensory stimuli, family members and care-takers answers indicate that in individuals with ASD, higher levels of tactile hypo-responsiveness and increased tactile seeking behaviors significantly correlates with increased social impairment and repetitive behaviors. Studies in animal models that recapitulate the social deficits and repetitive behaviors of ASD have increased our understanding of altered behavior and pain sensitivity in ASD. Mice harboring gene mutations, known to be associated with increased risk for ASD, such as Mecp2 (a model of Rett syndrome), Shank2, Shank3 (a model for Phelan-Mcdermid syndrome), Fmr1 (a model for Fragile-X syndrome), offer a powerful combination of genetics, a mammalian brain, and the ability to quantify simple and complex behaviors like sociability and nocifensive response. We are particularly interested in understanding the role of the nicotinic cholinergic system on the alterations of social behaviors and nocifensive response to noxious stimuli. Multiple lines of evidence implicate the nicotinic cholinergic system on the pathobiology of behavior deficits in ASD. Our recent findings in BTBR T+Itpr3tf/J (BTBR) mice, a well-studied model of ASD, further support this hypothesis and suggest that drugs targeting nicotinic acetylcholine receptors (nAChRs) may have a role in the treatment of behavior deficits in ASD. We showed that nicotine, which activates and up-regulates nAChR subtypes particularly 42* and 7, has two distinct effects in BTBR. Nicotine improves social deficits, at lower but not higher doses, and reduces repetitive behavior, at higher but not lower doses. These effects were observed with chronic nicotine administration and plasma levels within ranges achieved with nicotine supplementation therapies (nicotine patch). Together, these results implicate nAChRs in the pathobiology of behavior deficits in ASD and suggest that activation and/or desensitization of different nAChR subtypes and consequent modifications in cholinergic signaling and synaptic transmission were associated with the beneficial effects of nicotine on behavior deficits in BTBR. Our findings also support using BTBR mice to screen therapies targeting nAChRs to modulate core ASD deficits. We have also conducted studies to evaluate the role of the nicotinic cholinergic system on the nocifensive response on the BTBR mouse and on mice harboring Fmr1 null mutation (a model for Fragile-X syndrome). By integrating the results from our two recent studies we are now evaluating the use of several drugs targeting nAChRs, which have a track record of safety and efficacy and are FDA-approved to treat neuropsychiatric disorders

尽管研究人员报告了自闭症谱系障碍（ASD）感觉改变的定性模式（ASD），但这些改变的神经生物学基础知识仍然很少。 尚不清楚社会缺陷，重复行为和感觉功能障碍之间的关联是因果关系相关的还是由于共享的基础病理生物学而引起的。 该项目的总体目标是阐明动物模型中伤害感受的机制，以概括ASD的核心症状。 我们将在具有良好表征的自闭症小鼠模型中进行机械研究，这些模型具有与ASD风险增加有关的基因突变。 我们还将对可能改善社交性，重复行为的治疗剂进行临床前评估，同时可能会纠正改变的单化反应。 ASD患者改变了伤害感，疼痛处理和疼痛反应的证据尚无定论。 在人类中，其他人表明，与ASD的高功能青少年具有降低的热敏感性（增强的温暖和冷检测阈值），并且其热检测阈值和热疼痛阈值与其智力相关。 在另一项研究中，与健康儿童相比，在另一项研究中，表现出高功能的ASD儿童的疼痛增加（较低的压力疼痛阈值）和触摸敏感性（von Frey单丝）。 使用标准化的问卷来评估对感觉刺激的行为反应，家庭成员和护理人员答案表明，在ASD的个体中，触觉性低响应性和增加的触觉行为的较高水平与社会障碍和重复性行为的增加显着相关。概括ASD的社会缺陷和重复行为的动物模型中的研究增加了我们对ASD行为改变和疼痛敏感性的理解。 具有基因突变的小鼠，已知与ASD风险增加有关，例如MECP2（RETT综合征模型），Shank2，Shank2，Shank3（用于Phelan-Mcdermid综合征的模型），FMR1（一种模型）（脆弱综合征的模型），提供了遗传学和SOCIFIF SOCIFINID和SOCIFIF SOCIFIF和SOCIFIF SOCIFIF和SOCIFIF SOCIFIF and SOCIFIF and SOCIFIF and SOCIFIF and SOCIFIF and SOCIFIF and SOCIFIF and SOCIFIF and SOCIF。 我们特别有兴趣了解烟碱胆碱能系统对社会行为改变以及对有害刺激的单化反应的作用。 多种证据线暗示了烟碱胆碱能系统在ASD中行为缺陷的病理学上。 我们最近在BTBR T+ITPR3TF/J（BTBR）小鼠（ASD良好模型）中进一步支持该假设的发现，并表明针对烟碱乙酰胆碱受体（NACHRS）的药物可能在ASD中行为缺陷的治疗中起作用。 我们表明，尼古丁激活并上调了NACHR亚型，尤其是42*和7，在BTBR中具有两个不同的作用。 尼古丁以较低但不降低剂量的重复行为来改善社会缺陷，并减少较低剂量的重复行为。通过补充尼古丁补充疗法（尼古丁斑块）在范围内的慢性尼古丁给药和血浆水平中观察到了这些作用。总之，这些结果表明NACHR在ASD中行为缺陷的病理生物学中，并表明不同NACHR亚型的激活和/或脱敏，以及随之而来的胆碱能信号传导和突触传播的修饰与Nicotine对BTBR行为缺陷的有益作用有关。 我们的发现还支持使用BTBR小鼠来筛选靶向NACHR的疗法以调节核心ASD缺陷。 我们还进行了研究，以评估烟碱胆碱能系统在BTBR小鼠和具有FMR1 NULL突变的小鼠（脆弱-X综合征模型）上的单化反应中的作用。 通过整合我们最近的两项研究的结果，我们现在正在评估使用几种针对NACHR的药物的使用，这些药物具有安全性和功效的记录，并经过FDA批准以治疗神经精神疾病