Piriform cortex: sequential developmental events

描述（由申请人提供）：当气味配体与嗅觉感觉神经元纤毛上表达的分子受体结合时，气味的感知开始于嗅觉上皮，每个分子受体仅表达1200个候选受体中的1个。当感觉神经元轴突离开上皮时，它们沿着嗅球表面前进，所有来自表达相同气味受体的神经元的轴突汇聚到嗅球内仅2-3个肾小球。然而，嗅球的汇聚和离散电路在梨状皮质（PCX）中并不明显，至少粗略地看是这样。梨状的传入突起呈发散状，分布广泛。此外，与被广泛研究的新皮层相比，三层梨状古皮层并没有明确的柱状结构，这就留下了一个问题，即从新皮层中学到的原理是否可以应用于理解梨状。我们对梨状体神经元和突触组织的了解大多来自于对大鼠和负鼠的早期研究，尽管这些研究很重要，但并没有受益于当代的遗传和分子工具。小鼠已经成为研究嗅上皮和嗅球的主要哺乳动物模型，从这些新工具中获益良多。然而，当代遗传和分子方法应用于小鼠梨状皮质研究的例子很少。可悲的是，我们仍然对小鼠梨状皮质最基本的特征一无所知：PCX神经元是什么时候出生的，层流组织的时间是什么时候？小鼠PCX中突触何时首次出现，何时实现层流分离？在PCX开发和最终组织的动态过程中，功能活动的作用是什么？PCX神经元/结构的命运和特异性的分子机制/转录因子是什么？为了开始解决这些知识上的重大空白，我们提出了3个具体目标：目标1 -验证PCX神经元亚群具有不同的发育谱系的假设，以及层流特异性的出现沿着协调的时间线发生；目的2 -验证气味体验、传入活动影响PCX神经元命运和突触回路的假设；目的3 -验证候选转录因子表达以顺序定义的方式发生的假设，并且是PCX神经元命运的基本决定因素。

DESCRIPTION (provided by applicant): The perception of odors begins in the olfactory epithelium when odorant ligands bind to molecular receptors expressed on the cilia of the olfactory sensory neurons, each of which expresses only 1 of 1200 candidate receptors. As the sensory neuron axons exit the epithelium they progress over the surface of the olfactory bulb and all of the axons coming from neurons expressing the same odorant receptor converge into only 2-3 glomeruli in the olfactory bulb. However, the convergence and discrete circuitry of the olfactory bulb is not apparent in piriform cortex (PCX), at least grossly. Afferent projections to piriform appear divergent and broadly distributed. Moreover, in contrast to the more widely studied neocortex, the 3 layer piriform paleocortex does not exhibit a definitive columnar structure, leaving open the question of whether principles learned from neocortex can be applied to understanding piriform. Most of what we know of the neuronal and synaptic organization of piriform has come from early studies of rat and opossum that while important did not benefit from contemporary genetic and molecular tools. The mouse, which has emerged as the dominant mammalian model for studies of the olfactory epithelium and bulb, has benefited immeasurably from these new tools. However, there are few examples of the application of contemporary genetic and molecular methods to studies of mouse piriform cortex. We remain woefully ignorant of the most fundamental features of mouse piriform cortex: When are the PCX neurons born and what is the timeline for the laminar organization? When do synapses first appear in mouse PCX and when do they achieve laminar segregation? What is the role of functional activity in the dynamics of PCX development and final organization? What are the molecular mechanisms/transcription factors underlying the fate and specificity of PCX neurons/structure? To begin addressing these significant gaps in our knowledge we are proposing 3 specific aims: Aim 1 - Test the hypothesis that the subpopulations of neurons in PCX have distinct developmental lineages and that the emergence of laminar specificity occurs along a coordinated timeline; Aim 2 - Test the hypothesis that odor experience, afferent activity, influences PCX neuron fate and synaptic circuitry; and Aim 3 - Test the hypothesis that candidate transcription factor expression occurs in a sequentially defined manner and is an essential determinant of PCX neuronal fate.