Short axon cells implement gain control in the mouse olfactory bulb

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变化几个数量级，但神经元的反应不能无限扩展，也不能跨越有限的输出范围。因此，感觉编码的一个基本问题在于在维持对大范围强度的反应性和解决刺激的细微变化之间的权衡。为了克服这一挑战，感官系统需要调整它们的输出，以匹配输入强度的平均变化。实现这一目标的一种方法是按比例改变单个神经元的输入输出函数的斜率（增益），以增加或减少输出的动态范围。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的归一化机制实现的。在嗅觉系统中，尽管气味的浓度存在巨大差异，但人们对如何可靠地识别气味知之甚少。人们提出了几种可能的机制来促进嗅觉增益控制，包括通过调节嗅球输出的中间神经元进行局部抑制，从嗅皮层或脑干向嗅球反馈信号，或者在皮层本身进行局部处理。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这种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球茎输出神经元（二尖瓣/簇状细胞，M/T）对气味和浓度的反应谱。“为此，我们将首先表征SA细胞对大量气味和浓度的反应。我们将使用基因靶向来表达SA细胞中神经元活动的光学指标，并通过宽视场和多光子成像来监测气味触发的反应。“然后，使用类似的方法，我们将表达SA细胞中神经元活动的光门控（光遗传）开关，并使用图案光学照明以可控和可逆的方式抑制其活动。同时，我们将呈现气味刺激，并通过电生理记录监测M/T细胞的反应。我们将比较在存在和不存在SA输入的情况下，M/T对增加气味浓度的反应。光诱导SA细胞抑制后M/T细胞浓度响应曲线的变化将直接揭示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。这些细胞是已知的唯一来源的神经递质多巴胺的球茎。我们将通过使用多巴胺活性阻滞剂来确定多巴胺在介导SA对M/T细胞通信中的作用。我们将确定阻断多巴胺的作用是否可以逆转光遗传学操作对SA细胞观察到的M/T细胞活性的影响。

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.