Context-dependent plasticity of adult-born neurons

嗅觉信息首先由嗅球中的神经回路处理。现在它得到了广泛的赞赏 嗅球回路是以一种经验依赖的方式改变的。一个特别戏剧性的例子 嗅球回路的可塑性是成人神经发生，其中数千个新生神经元是 整个成年期每天都作为局部抑制神经元被合并到球部回路中。大多数人 这些成年出生的神经元(ABN)中的一部分成为颗粒细胞，通过它们的脊椎提供抑制 顶端树突生长到主二尖瓣/簇状细胞上。在这个提案中，我们将描述突触的特征 ABN在嗅球内的结构可塑性，并探讨其上下文特异性和机制。 理解特定于背景的可塑性的详细机制将对 临床疾病，如阿尔茨海默病、老年痴呆症和创伤后应激障碍。我们的 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，但不是在对相同气味的被动体验期间， 2)梨状核的反馈投射确保了ABN可塑性的这种语境特异性 大脑皮质到嗅球，在任务学习过程中增加了ABN的树突活动。这样的一个 语境特异性的ABN抑制可以为刺激特异性抑制促进ABN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、体内双光子结构成像来解决这些假说。 光子钙成像，头部固定小鼠的行为任务，以及特定路径的光遗传学。我们一直在 率先使用这些技术来研究嗅球回路的动力学(Kato等人)。神经元 2012年，Kato et al.神经元2013，博伊德等人。《细胞报告2015》，朱等人。神经元2016，朱等人。ENeuro 2017)。 特别是，我们将利用我们最近的研究，该研究表明ABN是学习所唯一需要的 嗅觉歧视(Li等人)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及幼年ABN唯一增加假说的检验 它们在学习过程中的脊椎密度。在目标2中，我们将检测ABN的树突状钙活性作为 调控ABN树突状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回路机制，确保 ABN可塑性的语境特异性。这些目标代表了一种系统的方法来调查 行为背景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.