Systematic Evaluation of Sensory Processing in Distinct Interneuron Types

描述（由申请人提供）：哺乳动物的感知是一个动态过程。动物和人类可以存在于各种环境中，并且可以优化不同感官任务的性能。这种感知适应性被认为取决于新皮层回路的灵活性，特别是兴奋性神经元的感觉调谐。一些理论认为，抑制性中间神经元（IN）的感觉调谐的多样性是新皮层动力学的关键。为了支持这一观点，体外研究已经通过对兴奋性输入的反应区分了2种IN类。一种IN类型是敏感的，对弱的初始刺激做出强烈反应，如果维持高频刺激，则随后进行适应。典型的IN类型表现为快速尖峰动作电位和小白蛋白表达。第二种类型的IN最初是不敏感的，但如果刺激持续，则随后促进。这种类型是典型的规则尖峰和生长抑素表达。尽管这一预测的理论重要性，并在体外支持它，这些IN类型还没有在体内区分。我们将测试的假设，不同类型的IN表现出不同的敏感性的强度的感官刺激，和不同的动态调整持续的高频输入。我们将测试这一假设，通过测量在第二/第三层的触须桶皮质的感受野与3个互补的技术：细胞外记录，细胞内记录，和2-光子成像。四极记录将提供高神经产率，并允许区分常规和快速尖峰神经元。细胞内记录将提供决定性的细胞类型鉴定和对亚阈值反应的独特访问。2-光子成像将提供在具有荧光标记的神经元的小鼠中IN亚型的直接可视化，以及使用钙成像追踪其激活的能力。我们将测试这一假设的参数变化的速度和频率的触须运动，并与越来越自然的刺激，包括在空气中搅拌和整个表面。在适合稳定记录的制备中的主动感测（搅拌）的可访问性是该系统的关键优势。桶状皮层对于验证我们的假设有明显的好处。桶皮层是啮齿动物中的高分辨率感觉区域，其中独特的技术（例如，成像荧光标记的IN）是可能的。此外，我们的实验室在该系统中具有丰富的专业知识。感受野测试直接来自我们先前的研究，以及我们的感觉驱动的新皮层动力学工作理论。据推测，这些IN不仅有助于正常功能，而且有助于疾病。例如，小清蛋白染色IN的适应不良变化被预测为精神分裂症的病因。虽然在较高的领域的IN功能的系统探针是更复杂的，感觉输入的主要领域是一个理想的初始准备，以测试这一假设，并应提供深入了解跨皮层区域的IN功能。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直接相关。测试的关键假设是不同类型的新皮层中间神经元在体内皮层中具有不同的功能。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因果关系：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的缺陷有直接的影响，并可能提出补救的途径。

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.