Basal Forebrain Modulation of Olfactory Bulb Function

项目摘要 包括嗅觉在内的感觉系统在很大程度上依赖于来自高级大脑区域的信号， 调节警觉和注意力的行为状态。这些调节性输入的主要中心是基底核 前脑基底前脑（BF）在整个大脑中发送轴突投射，并涉及 行为过程中皮层和感觉回路的动态调节。BF通常被认为是 胆碱能投射中枢：整个大脑中胆碱能投射的中心，其主要功能是调节注意力 信息处理的调制。然而，最近出现的新的工具，探测神经回路， vivo使我们能够更深入和更细致地了解基底前脑的组织和作用， 认知. BF投射到新皮层实际上是神经化学上多样的，并且是精确组织的， 投射目标。此外，不同的BF亚群与行为的不同方面有关， 涉及多种认知功能，包括奖励信号，对感官线索的行为反应， 任务学习然而，尽管取得了这些进展，我们仍然对高炉对初始加工的影响知之甚少 感觉输入到大脑皮层。 嗅球（OB）是研究基底前脑功能的有利部位，因为它是基底前脑中唯一的主要结构。 （前皮质）感觉处理区接收BF输入，因为嗅觉是一个主要的形式驱动 啮齿动物的行为BF向OB发送大量投影，并在所有OB层中终止。许多这些 投射是胆碱能的然而，对于新皮层，BF到OB的投射在神经化学上是多样的， 大量的GABA能神经元。这种多样性的重要性直到最近才开始受到重视。 这一点在皮质中得到了赞赏，但在OB电路方面几乎完全没有得到检查。最近的一项研究表明， GABA能基底前脑向嗅球的投射靶向不同的神经元亚群， 独立于胆碱能投射，调节OB回路以影响气味感知。但我们的 理解BF胆碱能和GABA能在调节OB回路中各自发挥的作用， 气味感知仍然是基本的。基本的未回答的问题包括是否胆碱能和 GABA能基底前脑投射靶向嗅球回路的不同组成部分，无论它们是否具有 在嗅球输出水平上对气味表征的互补或相反作用， 胆碱能和GABA能基底前脑神经元在行为过程中的活动模式，以及它们在行为中的作用 投射在气味感知或气味引导行为中起作用？ 本研究的总体目标是研究基底前脑神经调节输入如何影响 嗅球功能在一项多学科研究中跨越了单神经元水平的调查， 利用电生理学、光遗传学/药物遗传学和高分辨率活动的进展来研究动物行为 成像和显微内窥镜检查。

PROJECT SUMMARY Sensory systems, including olfaction, are heavily dependent on signals from higher brain regions that regulate behavioral states of alertness and attention. A major center for these modulatory inputs is the basal forebrain. The basal forebrain (BF) sends axonal projections throughout the brain and has been implicated in dynamic modulation of cortical as well as sensory circuits during behavior. BF is classically thought of as a center for cholinergic projections throughout the brain, whose chief functional role is to mediate attentional modulation of information processing. However, the recent advent of novel tools for probing neural circuits in vivo has enabled a deeper and more nuanced understanding of basal forebrain organization and role in cognition. BF projections to neocortex are in fact neurochemically diverse and precisely organized with respect to projection target. Further, different BF subpopulations are linked to distinct aspects of behavior and are implicated in diverse cognitive functions including reward signaling, behavioral responding to sensory cues and task learning. Despite these advances, however, we still know little about BF impact on the initial processing of sensory inputs on their way to cortex. The olfactory bulb (OB) is advantageous for investigating basal forebrain function, as it is the only primary (pre-cortical) sensory processing area receiving BF inputs and because olfaction is a primary modality driving behavior in rodents. BF sends massive projections to the OB, with terminations in all OB layers. Many of these projections are cholinergic. However, as for neocortex, BF projections to OB are neurochemically diverse with substantial numbers of GABAergic neurons. The importance of this diversity has only recently begun to be appreciated for cortex, but almost entirely unexamined with respect to OB circuitry. A recent study showed that GABAergic basal forebrain projections to the olfactory bulb target distinct neuronal subpopulations and can, independent of cholinergic projections, modulate OB circuits to affect odor perception. However, our understanding of the respective roles played by BF cholinergic and GABAergic in modulating OB circuits and odor perception remains rudimentary. Fundamental unanswered questions include whether cholinergic and GABAergic basal forebrain projections target distinct components of olfactory bulb circuits, whether they have complementary or opposing effects on odor representations at the level of olfactory bulb output, what are the activity patterns of cholinergic and GABAergic basal forebrain neurons during behavior, and what role these projections play in odor perception or odor-guided behaviors? The overall goal of this proposal is to investigate how the basal forebrain neuromodulatory inputs affect olfactory bulb function in a multi-disciplinary study spanning investigation at the level of single neurons through to animal behavior utilizing advances in electrophysiology, opto-/pharmacogenetics, and high resolution activity imaging and microendcosopy in behaving animals.