Neurobiology of Self-Injurious Behavior

自残行为的神经生物学

• 批准号: 6737559
• 负责人: HYDER A JINNAH
• 金额: $ 29.43万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6737559
• 关键词: 6 hydroxydopamine; autoradiography; behavior test; behavioral /social science research tag; behavioral genetics; brain mapping; calcium channel; calcium channel blockers; disease /disorder model; dopamine receptor; gene targeting; genetically modified animals; histochemistry /cytochemistry; in situ hybridization; laboratory mouse; laboratory rat; neural transmission; neurobiology; neurochemistry; neuropharmacology; psychobiology; psychopharmacology; self destructive behavior; serotonin receptor; stimulant /agonist

Self-injurious behavior is a common problem among several neurodevelopmental and psychiatric disorders. There are currently few safe and reliable treatments for the behavior, in part because of our limited understanding of its neurobiological basis. Recently, we demonstrated that administration of the L-type calcium channel agonist Bay K 8644 can acutely provoke self-injury in weanling mice, providing a new animal model that can be exploited to study the neurobiology of this unusual behavior. Specific Aim 1 addresses the neuroanatomical substrates for self-injurious behavior provoked by Bay K 8644 with two functional histochemical mapping methods, induction of the mRNA encoding the immediate-early gene c-fos and 2-deoxyglucose autoradiography. Our hypothesis for this aim is that Bay K 8644 causes self-injurious behavior by influencing the functions of the caudoputamen, the region most often implicated in the expression of self-injurious behavior in other studies. Specific Aims 2-3 address the neuropharmacological basis for self-injurious behavior provoked by Bay K 8644, and in particular the involvement of dopaminergic and serotonergic systems, the two neurotransmitter systems most often implicated as mediators of the behavior in prior studies. Our hypothesis for these aims is that Bay K 8644 causes self-injurious behavior by activating specific dopaminergic and serotonergic receptor subtypes. Specific Aim 4 addresses the role of L-type calcium channels in another well-characterized model for self-injurious behavior, the administration of dopaminergic or serotonergic agonists to rats that had received 6-hydroxydopamine lesions during the neonatal period. We will test the ability of calcium channel antagonists to prevent the expression of self-injurious behavior in this model. Our hypothesis for this aim is that the L-type calcium channels may provide a "final common pathway" for the expression of self-injury. These studies have direct relevance for understanding the neuroanatomical and neurochemical basis for self-injurious behavior and direct implications for a potential novel treatment strategy.

自我伤害行为是几种神经发育和精神病障碍中的一个普遍问题。目前，对这种行为的安全和可靠的治疗很少，部分原因是我们对神经生物学基础的理解有限。 最近，我们证明了L型钙通道激动剂湾K 8644可以在断奶小鼠中急剧促进自伤，提供了一种新的动物模型，可以利用该模型来研究这种异常行为的神经生物学。 特定的目标1解决了Bay K 8644引起的自我伤害行为的神经解剖底物，采用两种功能性组织化学映射方法，诱导了编码即时的基因C-FOS和2-脱氧葡萄糖体增生的mRNA。 我们针对此目标的假设是，Bay K 8644通过影响尾audoputamen的功能而导致自治行为，该地区通常与其他研究中的自我伤害行为表达有关。 具体目的2-3解决了Bay K 8644引起的自我伤害行为的神经药理基础，尤其是多巴胺能和血清素能系统的参与，这是两种神经递质系统，通常在先前的研究中最常见于该行为的介体。 我们针对这些目的的假设是，Bay K 8644通过激活特定的多巴胺能和血清素能受体亚型来引起自我伤害行为。 特定的目标4解决了L型钙通道在另一种良好特征的自我伤害行为的模型中的作用，在新生儿期间接受了6-羟基多巴胺病变的大鼠多巴胺能或血清素能激动剂。 我们将测试钙通道拮抗剂在此模型中防止自我伤害行为表达的能力。 我们针对此目标的假设是L型钙通道可能为自我伤害表达提供“最终共同途径”。 这些研究具有直接相关性，以理解自治行为的神经解剖学和神经化学基础，以及对潜在的新型治疗策略的直接影响。