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

虽然感觉知觉和认知加工是神经科学中经常研究的主题，但很少有人对它们进行协同研究。当考虑到它们的个体发育时，这一点尤其正确。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，在开发过程中管理与内存相关电路的布线的一些复杂的相互作用已经得到解决。例如，我们最近在一项合作努力中证明，复杂的GABA-谷氨酸相互作用产生海马theta带驱动力，使前额叶皮质局部电路能够启动。对感觉和认知个体发育的很大程度上分开的研究源于这样一个事实，即大多数感觉系统在生命早期都不发达，因此，它们对支持认知加工的神经网络的形成的影响被认为是微不足道的。作为一个明显的例外，嗅觉系统在宫内生活中达到完全成熟，控制着母子之间的相互作用和生存。然而，尚不清楚早期的嗅觉输入是否会驱动边缘网络的发展。本研究的目的是了解嗅球(OB)和外侧内嗅皮层(LEC)之间的连接和通讯的结构和功能原理。外侧内嗅皮层是新生儿和青少年发育过程中边缘回路的守门人。通过阐明OB-LEC的连接性(目标1)，我们旨在为随后的嗅觉-边缘活动模式的生理学分析(目标2)提供一个解剖学框架。随后，我们将研究嗅觉刺激对边缘环路发育和相应认知行为的急性和长期影响(目标3)。为了实现这些目标，该项目以申请者的互补专业知识为中心，既在概念层面将嗅觉系统生理学(Spehr)与边缘电路的功能发展(Hanganu-Opatz)联系起来，又通过开发新颖的高度跨学科的实验策略，将跨突触追踪、光遗传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有助于下游内嗅觉-前额叶-海马网的携带和细化。从长远来看，我们的研究旨在提供对将感觉和认知神经生物学的基本方面联系起来的生理原理的详细洞察。

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.