Context-dependent plasticity of adult-born neurons

嗅觉信息首先由嗅球中的神经回路处理。现在人们普遍认为 嗅球回路是以经验依赖的方式改变的。一个特别戏剧性的例子 嗅球回路可塑性的一个重要方面是成年神经发生，在这个过程中，成千上万的新生神经元 在整个成年期，这些神经元作为局部抑制神经元被纳入延髓回路。大多数 这些成人出生的神经元（ABN）成为颗粒细胞，通过脊髓提供抑制， 顶树突到主二尖瓣/簇状细胞上。在这个提议中，我们将描述突触的特征， 嗅球内ABNs的结构可塑性，并探讨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。我们 中心假设是：1）ABN在生长过程中增加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时， 和2）ABN可塑性的这种背景特异性是通过梨状核的反馈投射来保证的 在任务学习过程中增加ABN树突活动的嗅球皮层。这样的 ABN抑制的上下文特异性募集可以为刺激特异性抑制提供基础， 任务相关气味表征的模式分离。 我们将通过结合体内双光子结构成像、体内双光子成像和体内双光子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。我们一直 开创性地使用这些技术研究嗅球回路的动力学（Kato et al. Neuron 2012，Kato等人Neuron 2013，Boyd等人Cell Reports 2015，Chu等人Neuron 2016，Chu等人eNeuro 2017）。 特别是，我们将利用我们最近的研究，表明ABN是学习的独特要求， 精细嗅觉辨别（Li等人eLife 2018）。在目标1中，我们将调查年龄和背景- 颗粒细胞突触可塑性在体内的特异性和测试的假设，年轻的ABNs独特地增加 他们的脊椎密度。在目标2中，我们将检查ABN的树枝状钙活性，作为一种 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 从梨状皮质到嗅球的投射作为一种潜在的电路机制，确保了 ABN可塑性的上下文特异性。这些目标代表了一种系统的方法来调查 行为环境如何影响嗅觉回路可塑性的机制。

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.