Experience-driven plasticity of olfactory bulb odor representations

 描述(申请人提供)：通过重复的经验，可以更好地检测或辨别感官刺激。这种形式的学习被称为知觉学习，从根本上塑造了我们大脑处理感觉信息的方式。知觉学习背后的确切位置和机制仍然存在争议。我们讨论嗅觉感知学习的机制，重点放在嗅球，大脑的第一个嗅觉中心。在嗅球中，新生抑制性神经元在成年期持续整合，提供了显著的可塑性潜力。我们的中心假设是：1)嗅觉学习通过二尖瓣细胞的整体活动提高气味辨别能力，二尖瓣细胞是嗅球中的主要神经元，2)成年出生的抑制性神经元在学习过程中表现出特别的适应性可塑性和支持二尖瓣细胞的可塑性。为了解决这些想法，我们将在清醒的小鼠的嗅球中长期应用体内双光子钙成像，这些小鼠在几天内经历了各种嗅觉体验范例。这与小鼠遗传学相结合，专门标记二尖瓣细胞和成人出生的抑制性神经元并消融 成人神经发生。我们最近开发了一种系统来长期成像清醒小鼠嗅球中特定神经元群体的活动(Kato等人。神经元2012，加藤等人。神经元2013)。目前的建议扩展了这一方法，以表征在为期一周的经验范例期间嗅球中气味表征的动态。在目标1中，我们将表征二尖瓣细胞在被动暴露条件下长达一周的体验中对一对非常相似的气味的反应以及几个辨别学习任务。我们的初步结果表明，辨别学习通过二尖瓣细胞群活动增强了对经验气味的辨别能力。在目标2中，我们将测试成人神经发生是否对嗅觉学习和二尖瓣细胞可塑性是必要的。我们将使用 阻止成人神经发生的遗传策略，并检查其对辨别学习任务的影响。此外，神经生成消融将与二尖瓣细胞成像相结合，以测试二尖瓣细胞在嗅觉体验期间的可塑性是否会随着神经生成消融而改变。我的目标3，我们将评估这一假设，即年轻的成人出生的抑制性神经元在嗅觉体验过程中表现出特别显著的适应性可塑性。我们将通过在嗅觉体验范例中直接成像年龄定义的成人出生的颗粒细胞的活动来做到这一点。这些实验结合了尖端技术，包括慢性高分辨率双光子成像，头部固定小鼠的行为任务，以及小鼠遗传学，以标记或消融特定的神经元类型。他们将揭示感知学习背后的精细回路可塑性，并确定成人神经发生的功能意义。 相关性：感官信息的动态和灵活处理对于动物在不断变化的环境中的福祉是必不可少的，在精神分裂症等神经障碍中经常受到损害。我们研究嗅觉学习的神经机制，特别强调成人嗅球内的神经发生，嗅球是大脑的第一个嗅觉中心。这一结果不仅有助于我们理解成人神经发生的功能意义，而且对阿尔茨海默病和老年痴呆等学习障碍的未来治疗也有指导意义。

 DESCRIPTION (provided by applicant): Through repetitive experience, one can better detect or discriminate sensory stimuli. This form of learning, termed perceptual learning, fundamentally shapes the way our brains process sensory information. The precise loci and mechanisms underlying perceptual learning are still debated. We address mechanisms of olfactory perceptual learning, focusing on the olfactory bulb, the first olfactory center of the brain. In th olfactory bulb, newborn inhibitory neurons are continuously integrated throughout adulthood, providing a remarkable potential for plasticity. Our central hypotheses are that 1) olfactory perceptual learning improves odor discriminability by the ensemble activity of mitral cells, the principal neurons in the olfactory bulb, and that 2) adult-born inhibitory neurons show particularly adaptive plasticity and support mitral cell plasticity during learning. To address thee ideas, we will apply in vivo two-photon calcium imaging chronically in the olfactory bulb of awake mice undergoing various olfactory experience paradigms over days. This is combined with mouse genetics to specifically label mitral cells and adult-born inhibitory neurons and ablate adult neurogenesis. We recently developed a system to chronically image the activity of defined populations of neurons in the olfactory bulb of awake mice (Kato et al. Neuron 2012, Kato et al. Neuron 2013). The current proposal extends this approach to characterize the dynamics of odor representations in the olfactory bulb during one-week-long experience paradigms. In Aim 1, we will characterize mitral cell responses to a pair of very similar odors during one-week-long experience in a passive exposure condition as well as several discrimination learning tasks. Our preliminary results suggest that discrimination learning enhances the discriminability of experienced odors by mitral cell ensemble activity. In Aim 2, we will test whether adult neurogenesis is necessary for olfactory perceptual learning and mitral cell plasticity. We will use genetic strategies to block adult neurogenesis and examine the effect on discrimination learning tasks. Furthermore, neurogenesis ablation will be combined with mitral cell imaging to test whether mitral cell plasticity during olfactory experience is altered with neurogenesis ablation. I Aim 3, we will evaluate the hypothesis that young adult-born inhibitory neurons show particularly pronounced and adaptive plasticity during olfactory experience. We will do this by directly imaging the activity of age-defined adult-born granule cells throughout the olfactory experience paradigms. These experiments combine cutting-edge technologies including chronic high-resolution two-photon imaging, behavioral tasks by head-fixed mice, and mouse genetics to label or ablate specific neuron types. They will reveal fine-scale circuit plasticity underlying perceptual learning and identify functional significance of adult neurogenesis. RELEVANCE: Dynamic and flexible processing of sensory information is essential for the well-being of animals in a changing environment and often impaired in neural disorders such as schizophrenia. We study neural mechanisms underlying olfactory perceptual learning, with a particular emphasis on adult neurogenesis within the olfactory bulb, the first olfactory center of the brain. The results will not only help us understand the functional significance of adult neurogenesis but also have implications in future treatments of learning disorders such as Alzheimer's disease and aging-related dementia.