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Central noradrenergic circuits regulating prepulse inhibition of the startle response.

机译：中央去甲肾上腺素能电路调节惊吓反应的预脉冲抑制。

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摘要

Prepulse inhibition (PPI) refers to the normal attenuation of the startle response when a weak prestimulus precedes the startling stimulus. PPI is an index of sensorimotor gating, or the ability to filter information from the internal and external environments, and is deficient in patients with certain psychiatric disorders, such as schizophrenia. Despite the large number of studies on the neurotransmitter and neuroanatomical substrates of PPI, relatively little is known about the role of the norepinephrine (NE) system in regulating sensorimotor gating. This is surprising, given the prominent role of NE in processes relevant to attention and cognitive functioning. Thus, the experiments in the present thesis were designed to systematically examine the role of NE in regulating PPI by exploring the neural circuitry through which NE modulates PPI. First, we found that stimulation of alpha1 NE receptors in the brain disrupts PPI, indicating that NE could be disrupting PPI through stimulation of central alpha1 receptors. Second, pharmacological stimulation of the locus coeruleus (LC), the primary source of NE to the forebrain, disrupts PPI, presumably through putative release of NE in LC terminal regions. Importantly, LC stimulation-induced deficits in PPI were blocked by atypical antipsychotics, but not by the traditional antipsychotics, indicating that the LC-NE system might be an important circuit in the efficacy of atypical antipsychotic treatment. Third, stimulation of alpha1 or beta NE receptors in the posterior region of the medial prefrontal cortex or the nucleus accumbens shell (terminal regions of the LC) disrupts PPI, indicating these might be regions through which NE from the LC is disrupting PPI. Fourth, blockade of alpha1 NE receptors prevents deficits in PPI induced by amphetamine administration, indicating that alpha1 receptors are necessary for this psychotomimetic drug to disrupt PPI. Taken together, these results overwhelmingly indicate that increasing central NE transmission disrupts PPI. Importantly, these studies constitute the first attempt to characterize the neural substrates underlying NE regulation of PPI, which is an important area of research because it furthers our understanding of NE regulation of cognition and also has potential clinical and therapeutic applications.
机译：前脉冲抑制（PPI）是指当在惊吓刺激之前先有弱刺激时惊吓反应的正常衰减。 PPI是感觉运动门控的指标，或者是从内部和外部环境中过滤信息的能力，并且在患有某些精神疾病（例如精神分裂症）的患者中缺乏。尽管对PPI的神经递质和神经解剖基质进行了大量研究，但对去甲肾上腺素（NE）系统在调节感觉运动门控方面的作用了解甚少。考虑到NE在与注意力和认知功能相关的过程中的重要作用，这令人惊讶。因此，本文的实验旨在通过探索神经元调节PPI的神经回路，系统地研究NE在调节PPI中的作用。首先，我们发现刺激大脑中的alpha1 NE受体会破坏PPI，这表明NE可能会通过刺激中央alpha1受体来破坏PPI。其次，药理学刺激蓝斑（LC）是前脑NE的主要来源，它可能是通过推定NE在LC末端区域释放来破坏PPI。重要的是，LC刺激引起的PPI缺陷被非典型抗精神病药阻止，但未被传统抗精神病药阻止，这表明LC-NE系统可能是非典型抗精神病药疗效的重要途径。第三，刺激内侧前额叶皮层或伏隔核壳后部区域（LC的末端区域）中的alpha1或βNE受体会破坏PPI，表明这些区域可能是LC的NE破坏PPI的区域。第四，α1NE受体的阻断可防止苯丙胺给药引起的PPI缺乏，这表明该拟精神病药物破坏PPI是必需的α1受体。综上所述，这些结果绝大多数表明，中央网元传输的增加破坏了PPI。重要的是，这些研究是表征PPI的NE调节基础的神经底物的首次尝试，这是一个重要的研究领域，因为它加深了我们对NE的认知调节的理解，并且具有潜在的临床和治疗应用。

著录项

  • 作者

    Alsene, Karen Marie.;

  • 作者单位

    The University of Wisconsin - Madison.;

  • 授予单位 The University of Wisconsin - Madison.;
  • 学科 Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 321 p.
  • 总页数 321
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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