Olfactory control of long-range coupling in developing prefrontal-hippocampal-entorhinal networks

虽然感官知觉和认知处理代表了神经科学中的恒定研究主题，但它们很少被协同研究。在考虑它们的个体发育时尤其如此。几十年来，通过强调分子线索、自发电活动和经验的相关性，大量的努力阐明了感觉系统的成熟原则。最近，一些复杂的相互作用，在发展过程中管理的内存相关电路布线已经解决。例如，我们最近在一次合作中证明，复杂的GABA -谷氨酸相互作用产生海马θ-带驱动力，使前额叶皮层的局部回路启动。对感觉和认知个体发育的研究在很大程度上是分开的，这是因为大多数感觉系统在生命早期都不发达，因此，它们对认知过程中神经元网络形成的影响被认为是微不足道的。作为一个明显的例外，嗅觉系统在子宫内的生命达到完全成熟，控制母亲与后代的互动和生存。然而，早期嗅觉输入是否驱动边缘系统网络的发展仍然是未知的。本研究的目的是了解嗅球（OB）和外侧内嗅皮层（LEC）之间的连接和通信的结构和功能原则，新生儿和青少年发育过程中的边缘系统电路的看门人。通过阐明OB - LEC连接（目的1），我们旨在为随后的嗅觉-边缘系统活动模式的生理分析（目的2）提供解剖学框架。随后，我们将研究嗅觉刺激对边缘回路发育和相应认知行为的急性和长期影响（目的3）。为了实现这些目标，该项目集中于申请人在概念层面的互补专业知识，通过将嗅觉系统生理学（Spehr）与边缘电路（Hanganu-Opatz）的功能发展联系起来，以及方法层面，通过利用新颖的和高度跨学科的实验策略，将联合收割机跨突触追踪，光学和药物遗传学操作与体外和体内生理学相结合。鉴于早期嗅觉输入的独特重要性，我们假设，在新生儿发育过程中OB活动的特定时空组织促进了下游内鼻-前额-海马网络的夹带和细化。从长远来看，我们的研究旨在提供有关感觉和认知神经生物学基本方面的生理学原理的详细见解。

While sensory perception and cognitive processing represent constant research topics in Neuroscience, they have seldom been investigated synergistically. This is especially true when considering their ontogeny. Over decades, substantial efforts elucidated the maturation principles of sensory systems by highlighting the relevance of molecular cues, spontaneous electrical activity and experience. More recently, some complex interactions governing the wiring of memory-relevant circuitry during development have been resolved. For example, we recently demonstrated in a collaborative effort that a complex GABA - glutamate interplay generates the hippocampal theta-band driving force that enables the initiation of local circuits in the prefrontal cortex. The largely separate investigation of sensory and cognitive ontogeny stems from the fact that most sensory systems are underdeveloped during early life and, thus, their impact on the formation of neuronal networks underlying cognitive processing has been deemed negligible. As a notable exception, the olfactory system reaches full maturity during intrauterine life, controlling mother-offspring interactions and survival. It is, however, still unknown whether early olfactory inputs drive the development of limbic networks. The goal of the present research proposal is to understand the structural and functional principles underlying the connectivity and communication between the olfactory bulb (OB) and lateral entorhinal cortex (LEC), the gatekeeper of limbic circuitry during neonatal and juvenile development. By elucidating OB - LEC connectivity (aim 1) we aim to provide an anatomical framework for subsequent physiological analysis of olfactory - limbic activity patterns (aim 2). Subsequently, we will investigate the acute and long-term effects of olfactory stimulation on the development of limbic circuits and corresponding cognitive behavior (aim 3). To reach these goals, the project is centered on complementary expertise of the applicants both at a conceptual level, by linking olfactory system physiology (Spehr) with functional development of limbic circuitry (Hanganu-Opatz), and a methodological level, by exploiting novel and highly interdisciplinary experimental strategies that combine trans-synaptic tracing, opto- and pharmacogenetic manipulations with in vitro and in vivo physiology. Given the unique importance of early olfactory input, we hypothesize that a specific spatiotemporal organization of OB activity during neonatal development facilitates the entrainment and refinement of downstream entorhinal-prefrontal-hippocampal networks. On the long-term, our study is designed to provide detailed insight into the physiological principles that link fundamental aspects of sensory and cognitive neurobiology.