Piriform cortex: sequential developmental events

描述(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，气味的感知始于嗅觉上皮，每个分子受体仅表达1200个候选受体中的一个。当感觉神经元轴突离开上皮细胞时，它们穿过嗅球表面，所有来自表达相同气味感受器的神经元的轴突在嗅球内汇聚成2-3个肾小球。然而，至少在梨状皮质(PCX)中，嗅球的会聚和离散回路并不明显。梨状肌的传入投射呈分叉状，分布广泛。此外，与更广泛研究的新大脑皮层相比，三层梨状古大脑皮层并没有表现出明确的柱状结构，这就留下了一个悬而未决的问题，即从新大脑皮层学到的原理是否可以应用于理解梨形。我们所知道的梨状突触的神经元和突触组织的大部分来自对大鼠和负鼠的早期研究，尽管这些研究很重要，但并没有从当代的遗传和分子工具中受益。小鼠已经成为研究嗅觉上皮和嗅球的主要哺乳动物模型，它从这些新工具中获得了不可估量的好处。然而，将当代遗传学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，板层组织的时间表是什么？突触最早出现在小鼠PCX中是什么时候？它们什么时候实现板层分离？职能活动在PCX开发和最终组织的动态中扮演什么角色？PCX神经元/结构的命运和特异性背后的分子机制/转录因子是什么？为了开始解决我们知识中的这些显著差距，我们提出了3个具体目标：目标1-测试假设，即PCX中的神经元亚群具有不同的发育谱系，并且板层特异性的出现发生在协调的时间线上；目标2-测试气味体验、传入活动、影响PCX神经元命运和突触电路的假设；以及目标3-测试候选转录因子表达以顺序定义的方式发生并且是PCX神经元命运的基本决定因素的假设。

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.