Olfactory information is first processed by the neural circuits in the olfactory bulb. It is now widely appreciated that the olfactory bulb circuit is modified in an experience-dependent manner. An especially dramatic example of plasticity in olfactory bulb circuits is adult neurogenesis, in which thousands of newly born neurons are incorporated into the bulbar circuitry as local inhibitory neurons every day throughout adulthood. The majority of these adult-born neurons (ABNs) become granule cells that provide inhibition through the spines at their apical dendrites onto the principal mitral/tufted cells. In this proposal, we will characterize the synaptic structural plasticity of ABNs in the olfactory bulb and investigate its context-specificity and mechanisms. Understanding the detailed mechanisms of context-specific plasticity would have an important impact on clinical disorders such as Alzheimer's disease, age-related dementia, and post-traumatic stress disorders. Our central hypotheses are that 1) ABNs increase the density of their apical dendritic spines during learning of an olfactory discrimination task but not during passive experience of the same odorants, and 2) this context-specificity of ABN plasticity is ensured by feedback projections from the piriform cortex to the olfactory bulb which increases dendritic activity of ABNs during task learning. Such a context-specific recruitment of ABN inhibition could provide the basis for stimulus-specific inhibition to promote the pattern separation of representations of task-relevant odorants. We will address these hypotheses by combining in vivo two-photon structural imaging, in vivo two- photon calcium imaging, behavioral task in head-fixed mice, and pathway-specific optogenetics. We have been pioneering the use of these techniques in studying the dynamics of olfactory bulb circuits (Kato et al. Neuron 2012, Kato et al. Neuron 2013, Boyd et al. Cell Reports 2015, Chu et al. Neuron 2016, Chu et al. eNeuro 2017). In particular, we will leverage on our recent study that showed that ABNs are uniquely required for the learning of fine olfactory discrimination (Li et al. eLife 2018).
In Aim 1, we will investigate the age- and context- specificity of granule cell synaptic plasticity in vivo and test the hypothesis that young ABNs uniquely increase their spine density during learning.
In Aim 2, we will examine the dendritic calcium activity of ABNs as a potential cellular mechanism regulating ABN dendritic plasticity.
In Aim 3, we will address the role of feedback projections from the piriform cortex to the olfactory bulb as a potential circuit mechanism that ensures the context specificity of ABN plasticity.
These aims represent a systematic approach to investigate the mechanisms of how behavioral context can affect the plasticity of an olfactory circuit.

Public Health Relevance

Mechanisms of learning and memory and their dependence on behavioral contexts have important implications in memory disorders such as Alzheimer's disease and age-related dementia, as well as post-traumatic stress disorders. The olfactory bulb adult neurogenesis presents an excellent model for studying experience- dependent plasticity. We propose to study the cellular and circuit mechanisms for the context specificity of synaptic structural plasticity of adult-born neurons in the olfactory bulb.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Sullivan, Susan L
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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