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

我的主要研究项目是研究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，最近的数据现在引导我们在这里测试成人下丘脑可塑性的新机制。根据我们意想不到的观察，成年下丘脑富含未成熟的神经元，我们提出这些细胞为必要的功能整合做好了准备。在经典的观点中，成人神经发生发生在明确的阶段，在这些小生境中的神经干细胞被重新唤醒，然后增殖并分化成成熟的神经元，然后迁移到适当的位置，整合到功能回路中。然而，成年大脑中新生神经元的整合仅限于这些干细胞龛可用的区域，导致大脑的大片区域未受影响，尤其是在大型脑部哺乳动物中。相比之下，成人神经的可塑性是指新神经元与现有连接的整合，这种整合可能发生在整个脑实质中，并且可能具有进化优势。在成人中，我们令人惊讶地发现下丘脑实质富含双皮质素（DCX+）未成熟的BrdU-神经元（例如，在成人神经发生期间不是新生的）。这一意想不到的发现是这一建议的基础，并导致了我们的假设，即下丘脑实质中充满了胚胎发育过程中出生的未成熟神经元，这些神经元在成年后仍然准备诱导进入神经元回路，以适应环境挑战。我们通过两个目标来检验这一假设：不同物种和年龄下丘脑DCX+未成熟神经元的特征研究[2]。为了确定小鼠成年下丘脑中DCX+未成熟神经元在应对高脂肪饮食挑战时的功能命运和需求，本研究将为这些未成熟神经元在驱动成年下丘脑可塑性中的作用提供机制理解，并为未被成年神经源性生态位服务的大脑区域如何维持可塑性提供进化背景。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领域的领导者。

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.