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）：请求重新支持 MH53484，“惊吓门控的皮质纹状体基质”。 MH 53484 的研究评估了大鼠惊吓反射感觉运动门控的神经控制，重点关注腹侧海马 (VH) 和内侧前额叶皮层 (MPFC)，以及它们与伏隔核 (NAC) 的相互作用。精神分裂症患者的感觉运动门控——通过惊吓前脉冲抑制（PPI）测量——显着减少；这些 PPI 缺陷与这种疾病的功能损伤和脆弱基因有关。在大鼠中，通过对 VH 和 MPFC（与精神分裂症的病理生理学密切相关的边缘皮质区域）的特定操作来降低 PPI。 MH53484的策略是利用动物研究来了解边缘皮层紊乱后PPI降低的神经回路基础。通过阐明 VH 和 MPFC 改变后 PPI 降低的基础，我们将拥有强大的工具来解释精神分裂症中 PPI 的缺失，开发新的疗法来减少与这种缺失相关的功能障碍，并预测基因的靶点使人容易患这种疾病。本申请的新研究重点关注 VH、MPFC 和基底外侧杏仁核 (BLA) 之间在调节大鼠 PPI 方面的神经相互作用。目标 1 的研究将使用神经解剖学追踪、穹窿病变和行为“断开”策略来绘制来自 VH、通过 MPFC 和/或 BLA 的串行信息流。目标 2 将采用类似的方法，重点关注 MPFC 及其潜在的串行信息流。与 NAC 和 BLA 的联系。目标 3 将重点关注 BLA 及其在 PPI 调节中与 MPFC 的潜在相互作用，并将确定 PPI 是否由 BLA 和 NAC 形成的串联电路调节。目标 4 将研究边缘皮质操作对腹侧苍白球 (VP) GABA 释放的影响，以及这些“下游”效应在 PPI 调节中的作用。目标 5 将通过评估因发育（隔离饲养）或遗传（应变相关）变异而变得“脆弱”的大鼠边缘皮质操作对 PPI 破坏效应的敏感性变化，将这些边缘皮质基质与更广泛的精神分裂症病理生理学模型联系起来。这些研究的新信息将为精神分裂症和其他遗传性神经精神疾病的病理生理学创新模型以及新药开发的前瞻性策略奠定基础。