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.