Context-dependent plasticity of adult-born neurons

成年神经元的上下文依赖性可塑性

基本信息

批准号：
10653490
负责人：
Takaki Komiyama
金额：
$ 7.25万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

项目摘要

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.

嗅觉信息首先由嗅球中的神经回路处理，现在已得到广泛认可。嗅球电路以依赖于经验的方式进行修改，这是一个特别引人注目的例子。嗅球回路的可塑性是成体神经发生，其中数千个新生神经元在整个成年期每天都作为局部抑制神经元融入延髓回路。这些成年神经元 (ABN) 变成颗粒细胞，通过其处的棘提供抑制作用在本提案中，我们将描述突触的特征。嗅球中 ABN 的结构可塑性并研究其环境特异性和机制。了解特定环境可塑性的详细机制将对临床疾病，如阿尔茨海默病、年龄相关性痴呆和创伤后应激障碍。中心假设是 1) ABN 增加了其顶端树突棘的密度学习嗅觉辨别任务，但不是在被动体验相同气味的过程中， 2) ABN 可塑性的这种上下文特异性是由梨状体的反馈投影确保的皮层到嗅球，这会在任务学习过程中增加 ABN 的树突活动。 ABN 抑制的特定环境募集可以为刺激特异性抑制提供基础，以促进与任务相关的气味的表示的模式分离。我们将通过结合体内双光子结构成像、体内双光子结构成像来解决这些假设光子钙成像、头部固定小鼠的行为任务以及通路特异性光遗传学。开创性地使用这些技术来研究嗅球回路的动力学（Kato 等人，Neuron） 2012 年，Kato 等人 2013 年，Boyd 等人 2015 年，Chu 等人 2016 年，Chu 等人 2017 年。特别是，我们将利用我们最近的研究，该研究表明 ABN 是学习所必需的。精细嗅觉辨别（Li et al. eLife 2018）在目标 1 中，我们将调查年龄和背景。体内颗粒细胞突触可塑性的特异性并检验年轻 ABN 独特增加的假设在目标 2 中，我们将检查 ABN 的树突钙活性。调节 ABN 树突可塑性的潜在细胞机制在目标 3 中，我们将讨论反馈的作用。从梨状皮层到嗅球的投射作为一种潜在的电路机制，确保 ABN 可塑性的背景特殊性。这些目标代表了研究 ABN 可塑性的系统方法。行为环境如何影响嗅觉回路可塑性的机制。