The role of immature neurons in hypothalamic plasticity from small to large brain mammals

我的中心研究项目考察了下丘脑发育的细胞和分子机制，重点是神经发生：新神经元的诞生。到目前为止，我们所有的研究都集中在胚胎神经发生上，最近的数据使我们在这里测试了一种新的成人下丘脑可塑性机制。基于我们意外地观察到成人下丘脑富含未成熟神经元，我们认为这些细胞已经为功能整合做好了必要的准备。在经典的观点中，成年神经发生经历了明确的阶段，在这些阶段，这些利基中的神经干细胞被重新唤醒，然后增殖和分化成成熟的神经元，然后再迁移到适当的位置，整合到功能回路中。然而，新生神经元在成年大脑中的整合仅限于这些干细胞利基区域，大脑的大片区域没有受到影响，特别是在大型脑哺乳动物中。相比之下，成人神经可塑性是将新神经元整合到现有连接中，这可以发生在整个大脑实质中，可能具有进化优势。在成人中，我们有了一个令人惊讶的发现，即下丘脑实质中富含双皮质素(DCX+)未成熟神经元，这些神经元是BrdU-(例如，在成人神经发生期间不是新生的)。这一出人意料的发现是这一提议的基础，并导致了我们的假设，即下丘脑实质中填充着在胚胎发育过程中出生的未成熟神经元，这些神经元仍然准备好诱导进入神经元回路，以适应成人的环境挑战。我们从两个方面验证了这一假说：目的1.描述不同物种和年龄的下丘脑中DCX+未成熟神经元的特征。2.为了全面确定DCX+未成熟神经元在高脂饮食挑战下对成年小鼠下丘脑的功能命运和功能需求，本研究将提供对这些未成熟神经元在驱动成人下丘脑可塑性中的作用的机制理解，并提供一个进化背景，以了解大脑中未被成人神经源性利基提供服务的区域如何维持可塑性。我们的HQP将学习一系列尖端的分子、细胞和行为技术，这将使他们成为加拿大自然科学部门的领导者。

My central research program examines the cellular and molecular mechanisms underlying hypothalamic development, with an emphasis on neurogenesis: the birth of new neurons. To date, all our studies have focused on embryonic neurogenesis, with recent data now leading us to test herein a novel mechanism for hypothalamic plasticity in the adult. Based on our unexpected observation that the adult hypothalamus is enriched with immature neurons, we propose these cells are primed for functional integration as needed. In the classic view, adult neurogenesis occurs across well-defined stages, whereby neural stem cells in these niches become re-awakened, then proliferate and differentiate into mature neurons that then migrate to the proper location to be integrated into functional circuits. However, the integration of newly born neurons in the adult brain is restricted to regions serviceable by these stem cell niches, leaving vast regions of the brain untouched, especially in large brain mammals. Adult neural plasticity, in contrast, is the integration of new neurons into existing connections, which can occur throughout the brain parenchyma and might have evolutionary advantages. In the adult, we made the surprising discovery that the hypothalamic parenchyma is enriched with doublecortin (DCX+) immature neurons that were BrdU- (e.g., not newly born during adult neurogenesis). This unexpected finding is the backbone for this proposal and led to our hypothesis that the hypothalamic parenchyma is populated with immature neurons born during embryogenesis that remain primed for induction into neuronal circuits as needed to adapt to environmental challenges in the adult. We test this hypothesis across two aims: Aim 1. To characterize DCX+ immature neurons in the hypothalamus across species and ages Aim 2. To determine the functional fate and requirement of DCX+ immature neurons in the murine adult hypothalamus in response to a high-fat diet challenge Overall, this study will provide a mechanistic understanding into the role of these immature neurons in driving plasticity in the adult hypothalamus, as well as provide an evolutionary context as to how brain regions not served by adult neurogenic niches might maintain plasticity. Our HQP will learn a range of cutting-edge molecular, cellular, and behavioral techniques, which will position them as leaders in Canada's natural sciences sector.