The role of immature olfactory sensory neurons in olfactory processing and plasticity

 描述(申请人提供)：嗅觉系统在一生中保持高度可塑性方面是不同寻常的，使嗅觉回路在受损后能够再生。OU的长期目标是确定成人嗅觉回路如何平衡这种高水平的可塑性和功能稳定性。嗅觉系统再生能力的一个主要因素是由鼻子中的干细胞形成的嗅觉感觉神经元(OSNs)终生神经发生。OSN将感觉输入传递到嗅球中的神经元，在那里气味信息在被发送到嗅皮质区之前被处理。然而，新的OSNs功能整合到成人嗅球回路的过程还不清楚。了解这一过程对于设计有效的基于干细胞的治疗策略至关重要，以修复神经退行性疾病、中风和创伤性脑损伤等条件下受损的神经回路。我们将使用转基因策略来标记和操纵未成熟OSN的活动，以确定它们在嗅球功能和可塑性中的作用。首先，利用嗅球切片的光发生光激活和电生理记录，我们将识别未成熟嗅球神经元与之形成突触联系的嗅球神经元。接下来，使用体内双光子钙成像结合气味刺激和光遗传激活和沉默，我们将确定未成熟的OSN通过二尖瓣和簇状细胞对嗅球输出的贡献。最后，利用体内突触的双光子成像，我们将确定气味输入恢复后未成熟和成熟OSN突触的恢复速度。这项拟议的研究的成功完成将揭示将内源性干细胞来源的神经元群体纳入成年神经回路的功能影响。

 DESCRIPTION (provided by applicant): The olfactory system is unusual in retaining a high level of plasticity throughout life, enabling olfactory circuits to regenerate following damage. Ou long-term goal is to determine how adult olfactory circuits balance this high level of plasticity with functional stability. One major contributor to the regenerative capacity of the olfactory system is lifelong neurogenesis of olfactory sensory neurons (OSNs) from stem cells in the nose. OSNs transmit sensory input to neurons in the olfactory bulb, where odor information is processed before being sent to olfactory cortical areas. However, the process by which new OSNs functionally incorporate into adult olfactory bulb circuits has been unclear. Understanding this process will be crucial in designing effective stem cell-based therapeutic strategies to repai damaged neural circuits in conditions such as neurodegenerative disease, stroke and traumatic brain injury. We will use a transgenic strategy to label and manipulate the activity of immature OSNs, in order to determine their role in olfactory bulb function and plasticity. First, using optogenetic photoactivation and electrophysiological recording in olfactory bulb slices, we will identify the olfactory bulb neurons with which immature OSNs form synaptic connections. Next, using in vivo 2-photon calcium imaging in combination with odor stimulation and optogenetic activation and silencing, we will determine the contribution made by immature OSNs to olfactory bulb output via mitral and tufted cells. Finally, using in vivo 2-photon imaging of synapses, we will determine the rate of recovery of immature and mature OSN synapse turnover following restoration of odor input. Successful completion of the proposed research will reveal the functional impact of incorporation of an endogeneous population of stem cell-derived neurons into adult neural circuits.