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。动物和人类可以生存在各种各样的环境中，并且可以为不同的感官任务优化表现。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节。一些理论提出，抑制性中间神经元（in）感觉调节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区分了两类In。一种IN类型是敏感的，对微弱的初始刺激有强烈的反应，如果保持高频刺激，随后就会适应。这种IN类型典型地表现为快速的动作电位和小蛋白表达。第二种类型的IN最初是不敏感的，但如果刺激持续存在，随后就会促进。这种类型是典型的有规律的尖峰和生长抑素表达。尽管这一预测在理论上具有重要意义，并且在体外得到了支持，但这些in类型尚未在体内得到区分。我们将检验不同IN类型对感官刺激强度的不同敏感性以及对持续高频输入的不同动态调整的假设。我们将通过三种互补技术（细胞外记录、细胞内记录和双光子成像）测量振动桶皮层II/III层的IN感受野来验证这一假设。四极管记录将提供高神经产出，并允许区分正常和快速尖峰神经元。细胞内记录将提供结论性的细胞类型鉴定和独特的阈下反应途径。双光子成像将提供具有荧光标记神经元的小鼠IN亚型的直接可视化，以及使用钙成像跟踪其激活的能力。我们将通过振动速度和频率的参数变化，以及越来越自然的刺激，包括在空气中和在表面上摇动，来检验这一假设。在适于稳定记录的制备中，可获得主动传感（搅拌）是该系统的一个关键优势。桶状皮层对于验证我们的假设有明显的好处。桶状皮质是啮齿动物的高分辨率感觉区域，在这里可以使用独特的技术（例如，荧光标记成像）。此外，我们的实验室在该系统方面拥有丰富的专业知识。接受区的测试直接遵循我们之前的研究，以及我们的感觉驱动的新皮层动力学的工作理论。据推测，这些IN不仅与正常功能有关，而且与疾病有关。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。虽然对高级区域的神经网络功能的系统探测更为复杂，但对初级区域的感觉输入是测试这一假设的理想初始准备，并应提供对皮质区域神经网络功能的深入了解。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。实验的关键假设是，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意义，并可能提供潜在的补救途径。

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.