Neurobiology of Self-Injurious Behavior

自残行为的神经生物学

• 批准号: 6623974
• 负责人: HYDER A JINNAH
• 金额: $ 29.71万
• 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/6623974
• 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.

自残行为是多种神经发育和精神疾病中的常见问题。目前针对这种行为的安全可靠的治疗方法很少，部分原因是我们对其神经生物学基础的了解有限。 最近，我们证明给予 L 型钙通道激动剂 Bay K 8644 可以严重引发断奶小鼠的自伤，这提供了一种新的动物模型，可用于研究这种异常行为的神经生物学。 具体目标 1 通过两种功能性组织化学图谱方法（诱导编码即早期基因 c-fos 的 mRNA 和 2-脱氧葡萄糖放射自显影法）解决了 Bay K 8644 引发的自伤行为的神经解剖学基础。 我们对此的假设是 Bay K 8644 通过影响尾壳核的功能而导致自残行为，在其他研究中尾壳核是最常涉及自残行为表达的区域。 具体目标 2-3 阐述了 Bay K 8644 引发的自残行为的神经药理学基础，特别是多巴胺能和血清素能系统的参与，这两种神经递质系统在先前的研究中最常被认为是行为的中介。 我们对这些目标的假设是 Bay K 8644 通过激活特定的多巴胺能和血清素能受体亚型而引起自残行为。 具体目标 4 解决了 L 型钙通道在另一个充分表征的自伤行为模型中的作用，即对新生儿期接受 6-羟基多巴胺损伤的大鼠施用多巴胺能或血清素能激动剂。 我们将测试钙通道拮抗剂在该模型中阻止自伤行为表达的能力。 我们对此目标的假设是，L 型钙通道可能为自伤的表达提供“最终共同途径”。 这些研究对于理解自伤行为的神经解剖学和神经化学基础具有直接相关性，并对潜在的新型治疗策略具有直接影响。