Systematic Evaluation of Sensory Processing in Distinct Interneuron Types

不同中间神经元类型的感觉处理的系统评估

• 批准号: 8220853
• 负责人: Christopher I Moore
• 金额: $ 34.73万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220853
• 关键词: Action Potentials; Air; Anatomy; Animals; Area; Attention; Behavior; Brain; Calcium; Data; Dependence; Disease; Dyes; Electrophysiology (science); Ensure; Environment; Epilepsy; Evaluation; Frequencies; Funding; Goals; Gold; Head; Health; Human; Image; Imagery; In Vitro; Interneuron function; Interneurons; Label; Laboratories; Literature; Maintenance; Maps; Measures; Mental disorders; Monitor; Motion; Mouse Strains; Mus; Neocortex; Neurons; Parvalbumins; Perception; Performance; Photons; Play; Preparation; Process; Property; Rattus; Resolution; Rodent; Role; Schizophrenia; Sensory; Sensory Process; Series; Somatostatin; Speed; Staining method; Stains; Stimulus; Surface; System; Techniques; Testing; Time; Variant; Vibrissae; Work; awake; barrel cortex; cell type; excitatory neuron; extracellular; flexibility; genetic manipulation; in vivo; information processing; innovation; insight; neocortical; receptive field; relating to nervous system; remediation; research study; response; sensory stimulus; sensory system; theories

DESCRIPTION (provided by applicant): Mammalian perception is a dynamic process. Animals and humans can exist in a variety of environments, and can optimize performance for distinct sensory tasks. This perceptual adaptability is believed to depend on the flexibility of neocortical circuits, and specifically on the sensory tuning of excitatory neurons. Several theories have proposed that diversity in the sensory tuning of inhibitory interneurons (IN) is key to neocortical dynamics. In support of this idea, in vitro studies have distinguished 2 IN classes by their responses to excitatory input. One IN type is sensitive, responding robustly to weak initial stimuli and subsequently adapting if a high-frequency stimulus is maintained. This IN type typically demonstrates fast- spiking action potentials and parvalbumin expressing. A second type of IN is initially insensitive, but subsequently facilitates if stimuli persist. This type is typically regular-spiking and somatostatin expressing. Despite the theoretical importance of this prediction, and in vitro support for it, these IN types have not been distinguished in vivo. We will test the hypothesis that different IN types show distinct sensitivity to the strength of sensory stimuli, and distinct dynamic adjustments to sustained high-frequency input. We will test this hypothesis by measuring IN receptive fields in layers II/III of the vibrissa barrel cortex with 3 complementary techniques: Extracellular recording, intracellular recording, and 2-photon imaging. Tetrode recording will provide a high neural yield, and allow distinction between regular- and fast-spiking neurons. Intracellular recording will provide conclusive cell type identification and unique access to subthreshold responses. 2-photon imaging will provide direct visualization of IN sub-types in mice with fluorescently labeled neurons, and the ability to track their activation using calcium imaging. We will test this hypothesis by parametric variation of the velocity and frequency of vibrissa motion, and with increasingly naturalistic stimuli, including whisking in air and across a surface. Accessibility of active sensing (whisking) in a preparation amenable to stable recording is a key advantage of this system. The barrel cortex has distinct benefits for testing our hypothesis. Barrel cortex is a high-resolution sensory area in a rodent, where unique techniques (e.g., imaging fluorescently labeled IN) are possible. Further, our laboratory has substantial expertise in this system. Testing IN receptive fields follows directly from our prior studies, and from our working theory of sensory-driven neocortical dynamics. These IN are hypothesized to contribute not only to normal function, but also to disease. For example, maladaptive changes in parvalbumin staining IN are predicted to be causal in schizophrenia. While systematic probes of IN function are more complicated in higher areas, sensory input to primary areas is an ideal initial preparation to test this hypothesis, and should provide insight into IN function across cortical areas. PUBLIC HEALTH RELEVANCE: These studies have direct relevance to understanding basic mechanisms underlying human mental illness. The key hypothesis tested is that distinct types of neocortical interneurons have distinct functions in the in vivo cortex. Maladaptive changes in the exact types we will examine are thought to be causal in Epilepsy and Schizophrenia: Understanding their potentially crucial role in information processing should have direct implications for interpretation of deficits in these maladies, and may potentially suggest avenues for remediation.

描述(申请人提供)：哺乳动物的感知是一个动态的过程。动物和人类可以在不同的环境中生存，并可以优化不同感官任务的性能。这种知觉适应性被认为依赖于新皮质回路的灵活性，特别是兴奋性神经元的感觉调节。一些理论认为，抑制性中间神经元(IN)感觉调谐的多样性是新皮质动力学的关键。为了支持这一观点，体外研究通过对兴奋性输入的反应来区分2个IN类。其中一种IN类型是敏感的，对微弱的初始刺激反应强烈，如果维持高频刺激，则随后进行适应。典型的IN型表现为动作电位快峰和小白蛋白表达。第二种类型的IN最初是不敏感的，但如果刺激持续存在，随后就会变得容易。这种类型典型的是有规律的尖峰和生长抑素的表达。尽管这一预测在理论上很重要，在体外也得到了支持，但这些IN类型还没有在体内得到区分。我们将检验这一假设，即不同的IN类型对感觉刺激的强度表现出不同的敏感性，并对持续的高频输入表现出不同的动态调整。我们将通过测量触觉桶皮质II/III层的IN感受野来验证这一假设，并使用3种互补技术：细胞外记录、细胞内记录和双光子成像。四极管记录将提供高神经产量，并允许区分规则和快速放电的神经元。细胞内记录将提供确凿的细胞类型识别和亚阈值反应的独特途径。双光子成像将提供带有荧光标记神经元的小鼠IN亚型的直接可视化，并能够使用钙成像跟踪其激活。我们将通过触觉运动速度和频率的参数变化，以及越来越自然的刺激，包括在空气中和表面上的搅拌来检验这一假设。在易于稳定记录的制剂中进行主动传感(搅拌)的可访问性是该系统的主要优点。桶状皮质对于检验我们的假说有明显的好处。桶皮质是啮齿类动物的一个高分辨率感觉区域，在那里可以使用独特的技术(例如，荧光标记的IN成像)。此外，我们的实验室在这一系统方面拥有丰富的专业知识。感受野的测试直接来自我们之前的研究，以及我们关于感觉驱动的新皮质动力学的工作理论。这些IN被认为不仅对正常功能有贡献，而且对疾病也有贡献。例如，小白蛋白染色IN的不适应变化被预测为精神分裂症的原因。虽然对IN功能的系统探测在较高的区域更加复杂，但对初级区域的感觉输入是检验这一假说的理想的初始准备，并且应该提供对跨皮质区域的IN功能的洞察。公共卫生相关性：这些研究与理解人类精神疾病的基本机制有直接关系。测试的关键假设是，不同类型的新皮质中间神经元在活体皮质中具有不同的功能。我们将研究的确切类型的适应不良变化被认为是癫痫和精神分裂症的原因：了解它们在信息处理中的潜在关键作用应该对解释这些疾病中的缺陷有直接影响，并可能提出补救的途径。