Short axon cells implement gain control in the mouse olfactory bulb

短轴突细胞在小鼠嗅球中实现增益控制

• 批准号: 8688984
• 负责人: Dinu Florentin ALBEANU
• 金额: $ 47.25万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688984
• 关键词: Anosmia; Auditory system; Axon; Brain; Brain Stem; Cell Communication; Cells; Chemicals; Dependence; Disease; Dopamine; Environment; Equilibrium; Feedback; Genetic; Health; Human; Image; Individual; Interneurons; Light; Lighting; Maps; Mediating; Mental disorders; Modality; Monitor; Mus; Neurons; Neurotransmitters; Odors; Olfaction Disorders; Olfactory Cortex; Optics; Output; Pattern; Perception; Problem Solving; Process; Property; Publishing; Quality of life; Reporting; Role; Sensory; Sensory Process; Signal Transduction; Source; Stimulus; Synapses; System; Testing; Variant; Visual system structure; autism spectrum disorder; gamma-Aminobutyric Acid; in vivo; light gated; light intensity; neuronal patterning; olfactory bulb; optogenetics; public health relevance; receptive field; response; sensory system; therapy design

DESCRIPTION (provided by applicant): The brain encodes sensory inputs as patterns of neuronal activity. While stimuli in the environment can vary over several orders of magnitude, neuronal responses cannot scale infinitely and span a limited range of outputs. Thus, a fundamental problem in sensory encoding lies in the trade-off between maintaining responsiveness to a wide range of intensities and resolving subtle variations in a stimulus. To overcome this challenge, sensory systems need to tune their output in order to match the average variation in input intensity. One way to achieve this is by proportionately changing the slope (gain) of the input-output function of individual neurons to increase or decrease the dynamic range of the outputs. This process is called gain control and has been shown to be implemented via normalization mechanisms in the auditory and visual systems. In the olfactory system, less is understood regarding how odors are reliably identified despite huge variations in their concentration. Several possible mechanisms have been suggested to contribute to olfactory gain control, ranging from local inhibition via interneurons that regulate the firing of he olfactory bulb's outputs, to feedback signals to the bulb from the olfactory cortex or the brainstem, or local processing in the cortex itself. In this proposal, we will study a particular class of neurons called short axon cells (SA cells) that are best suited anatomically and physiologically to implement gain control in this early olfactory circuit. We will test whether removing the contribution of these cells in the intact brain narrows the response spectrum of the output neurons of the bulb (mitral/tufted cells, M/T) across odors and concentrations. "To this end, we will first characterize responses of SA cells to a large set of odors and concentrations. We will use genetic targeting to express optical indicators of neuronal activity specifically in th SA cells and monitor odor triggered responses via wide-field and multiphoton imaging. "Then, using a similar approach, we will express light-gated (optogenetic) switches of neuronal activity in SA cells and use patterned optical illumination to suppress their activity in a controlled and reversible fashion. Simultaneously, we will present odor stimuli and monitor the response of M/T cells via electrophysiological recordings. We will compare M/T responses to increasing odor concentrations both in the presence and absence of SA inputs. Alterations in the concentration response curve of M/T cells upon light-induced inhibition of SA cells will directly reveal the contribution (if any) of SA cells. "Finally, we will begin to dissect the specific mechanisms by which SA cells modulate M/T activity. These cells are known to be the only source of the neurotransmitter dopamine in the bulb. We will determine the contribution of dopamine in mediating SA to M/T cell communication by using blockers of dopamine activity. We will determine whether blocking dopamine action can reverse the effects on M/T cell activity observed upon optogenetic manipulation of SA cells.

描述（由申请人提供）：大脑将感觉输入编码为神经元活动的模式。虽然环境中的刺激可以在几个数量级上变化，但神经元的反应不能无限地扩展，并跨越有限的输出范围。因此，感觉编码的一个基本问题在于保持对大范围强度的反应和解决刺激中的细微变化之间的权衡。为了克服这一挑战，感觉系统需要调整其输出，以匹配输入强度的平均变化。实现这一点的一种方法是通过成比例地改变单个神经元的输入-输出函数的斜率（增益）来增加或减小输出的动态范围。这个过程被称为增益控制，并已被证明是通过听觉和视觉系统中的标准化机制来实现的。在嗅觉系统中，尽管气味的浓度变化很大，但人们对气味如何可靠地识别知之甚少。已经提出了几种可能的机制来促进嗅觉增益控制，范围从通过调节嗅球输出的发射的中间神经元的局部抑制，到从嗅皮层或脑干反馈信号到嗅球，或者皮层本身的局部处理。在这个提议中，我们将研究一类特殊的神经元，称为短轴突细胞（SA细胞），它们在解剖学和生理学上最适合在早期嗅觉回路中实现增益控制。我们将测试在完整的大脑中去除这些细胞的贡献是否会缩小灯泡（二尖瓣/簇状细胞，M/T）的输出神经元在气味和浓度上的反应谱。“为此，我们将首先描述SA细胞对大量气味和浓度的反应。我们将使用遗传靶向表达神经元活动的光学指标，特别是在th SA细胞和监测气味触发的反应，通过宽场和多光子成像。“然后，使用类似的方法，我们将在SA细胞中表达神经元活动的光门控（光遗传学）开关，并使用图案化的光学照明以受控和可逆的方式抑制它们的活动。同时，我们将通过电生理记录呈现气味刺激并监测M/T细胞的反应。我们将比较M/T的反应，增加气味浓度的存在和不存在的SA输入。光诱导SA细胞抑制后M/T细胞浓度响应曲线的改变将直接揭示SA细胞的贡献（如果有的话）。“最后，我们将开始剖析SA细胞调节M/T活性的具体机制。这些细胞被认为是灯泡中神经递质多巴胺的唯一来源。我们将通过使用多巴胺活性的阻断剂来确定多巴胺在介导SA到M/T细胞通信中的贡献。我们将确定阻断多巴胺作用是否可以逆转在SA细胞的光遗传学操作后观察到的对M/T细胞活性的影响。