Short axon cells implement gain control in the mouse olfactory bulb

描述(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能会在几个数量级上有所不同，但神经元的反应不可能无限扩大，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，感觉系统需要调整它们的输出，以便与输入强度的平均变化相匹配。实现这一点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)，以增加或减小输出的动态范围。这一过程被称为增益控制，已被证明是通过听觉和视觉系统中的归一化机制实现的。在嗅觉系统中，人们对气味如何可靠地识别知之甚少，尽管气味的浓度变化很大。已经提出了几种可能的机制来促进嗅觉获得控制，从局部抑制到调节嗅球输出的中间神经元的发射，到从嗅皮层或脑干向球的反馈信号，或者皮质本身的局部处理。在这个方案中，我们将研究一类特殊的神经元，称为短轴突细胞(SA细胞)，在解剖学和生理学上最适合在这个早期的嗅觉回路中实现获得控制。我们将测试移除这些细胞在完整大脑中的作用是否会缩小球茎输出神经元(二尖瓣/簇状细胞，M/T)在不同气味和浓度下的反应频谱。为此，我们将首先描述SA细胞对大量气味和浓度的反应。我们将使用基因打靶来表达神经元活动的光学指示器，特别是在TH SA细胞中，并通过广域和多光子成像监测气味触发的反应。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(光遗传)开关，并使用图案化光学照明以受控和可逆的方式抑制其活动。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。我们将比较在存在和不存在SA输入的情况下M/T对气味浓度增加的响应。光抑制SA细胞后M/T细胞浓度反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细胞活动的具体机制。众所周知，这些细胞是鳞茎中神经递质多巴胺的唯一来源。我们将通过使用多巴胺活动的阻断剂来确定多巴胺在介导SA对M/T细胞通讯的作用中的作用。我们将确定阻断多巴胺作用是否可以逆转在SA细胞光遗传操作中观察到的对M/T细胞活动的影响。

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.