Cortico-Striatal Substrates of Deficient Startle Gating

惊吓门控缺陷的皮质纹状体基底

• 批准号: 7196306
• 负责人: NEAL R SWERDLOW
• 金额: $ 20.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196306
• 关键词: Acoustics; Agonist; Amprenavir; Amygdaloid structure; Animal Model; Animals; Behavioral; Brain; Brain Diseases; Brain Stem; Classification; Cognitive; Contralateral; Corpus striatum structure; Development; Disease; Disruption; Dopamine; Elements; Exhibits; Feasibility Studies; Figs - dietary; Foundations; Functional disorder; Future; GABA Agonists; Gene Targeting; Genes; Genetic Predisposition to Disease; Globus Pallidus; Hippocampus (Brain); Human; Hypothalamic structure; Individual; Infusion procedures; Inherited; Lead; Lesion; Link; Maps; Measures; Medial; Mediating; Mental disorders; Metabolism; Methods; Microdialysis; Modeling; Muscimol; N-Methylaspartate; Neurobiology; Norway; Nucleus Accumbens; Pathogenesis; Pathology; Patients; Pattern; Peer Review; Physiologic pulse; Physiological Processes; Prefrontal Cortex; Process; Progress Reports; Prosencephalon; Publications; Pulse taking; Rattus; Reflex action; Regulation; Reporting; Research Design; Response to stimulus physiology; Role; Schizophrenia; Sensory; Sprague-Dawley Rats; Stimulus; Structure; System; Testing; Thalamic structure; Time; Variant; Ventral Striatum; Work; abstracting; base; behavior measurement; drug development; functional disability; gamma-Aminobutyric Acid; genetic strain; in vivo; innovation; loss of function; male; millisecond; nerve supply; neural circuit; neuropsychiatry; neuroregulation; novel strategies; prepulse inhibition; prevent; programs; prospective; relating to nervous system; research study; social; tool

DESCRIPTION (provided by applicant): Renewed support is requested for MH53484, "Cortico-striatal substrates of startle gating". Studies in MH 53484 have assessed the neural control of sensorimotor gating of the startle reflex in rats, focusing on the ventral hippocampus (VH) and medial prefrontal cortex (MPFC), and their interactions with the nucleus accumbens (NAC). Sensorimotor gating - measured by prepulse inhibition of startle (PPI) - is significantly reduced in schizophrenia patients; these PPI deficits are linked to both functional impairment and vulnerability genes in this disorder. In rats, PPI is reduced by specific manipulations of the VH and MPFC - limbic cortical regions strongly implicated in the pathophysiology of schizophrenia. The strategy of MH53484 is to use animal studies to understand the neural circuit basis for reduced PPI after disturbances within limbic cortex. By clarifying the basis for reduced PPI after alterations of the VH and MPFC, we will have powerful tools to explain the loss of PPI in schizophrenia, to develop new therapies to reduce functional impairment associated with this loss, and to predict the targets of genes that confer vulnerability to this disorder. New studies in this application focus on the neural interactions among the VH, MPFC and basolateral amygdala (BLA) in the regulation of PPI in rats. Studies in Aim 1 will use neuroanatomical tracing, fornix lesions and behavioral "disconnection" strategies to map the serial flow of information from VH, through the MPFC and/or BLA Aim 2 will take a similar approach, focusing on the MPFC and its potential serial connections with the NAC and BLA. Aim 3 will focus on the BLA and its potential interactions with the MPFC in the regulation of PPI, and will determine whether PPI is regulated by a serial circuit formed by the BLA and NAC. Aim 4 will examine the impact of limbic cortical manipulations on ventral pallidal (VP) GABA release, and the role of these "downstream" effects in the regulation of PPI. Aim 5 will relate these limbic cortical substrates to broader models for schizophrenia pathophysiology, by assessing changes in sensitivity to the PPI-disruptive effects of limbic cortical manipulations in rats made "vulnerable" via developmental (isolation rearing) or genetic (strain-related) variations. New information from these studies will be a foundation for innovative models of the pathophysiology of schizophrenia and other inherited neuropsychiatric disorders, and for prospective strategies for novel drug development.

描述（由申请人提供）：对MH53484要求更新支持，“惊吓门的Cortico-Striatal基板”。在MH 53484中的研究评估了大鼠惊吓反射的感觉运动门控的神经控制，重点是腹侧海马（VH）和内侧前额叶皮层（MPFC），以及它们与Nucleus accumbens（NAC）的相互作用。精神分裂症患者的感觉运动门控 - 通过抑制惊吓（PPI）测量 - 显着降低；这些PPI缺陷与该疾病的功能障碍和脆弱性基因有关。在大鼠中，通过对精神分裂症病理生理的VH和MPFC-边缘皮质区域的特定操纵来减少PPI。 MH53484的策略是使用动物研究来了解边缘皮层障碍后PPI减少的神经回路基础。通过阐明VH和MPFC改变后PPI减少的基础，我们将拥有强大的工具来解释精神分裂症中PPI的丧失，开发新的疗法以减少与此损失相关的功能障碍，并预测赋予该疾病脆弱性的基因靶标。该应用中的新研究集中于在大鼠调节PPI中VH，MPFC和基底外侧杏仁核（BLA）之间的神经相互作用。 AIM 1中的研究将使用神经解剖学示意图，近原状病变和行为“断开连接”策略来绘制通过MPFC和/或BLA AIM 2的信息流的串行流动，将采用类似的方法，重点是MPFC及其与NAC和BLA的潜在串行连接。 AIM 3将集中在PPI调节中的BLA及其与MPFC的潜在相互作用上，并将确定PPI是否由BLA和NAC形成的串行电路调节。 AIM 4将检查边缘皮质操纵对腹侧苍白球（VP）GABA释放的影响，以及这些“下游”效应在PPI调节中的作用。 AIM 5将通过评估通过发育（隔离饲养）或遗传学（应变）变化的大鼠的边缘皮质操纵的敏感性，将这些边缘皮质底物与精神分裂症病理生理学的更广泛模型与更广泛的病理生理学模型联系起来。这些研究的新信息将是精神分裂症和其他遗传神经精神疾病的病理生理学创新模型的基础，并为新型药物开发的前瞻性策略提供了基础。