Representing the identity of a smell We still don't know how odors retain their identities over a range of concentrations. Working in mice, Bolding and Franks simultaneously recorded spiking activity from neurons in the olfactory bulb and piriform cortex, two important brain regions for olfaction. Odor information was transformed from a representation that was highly concentration dependent in the olfactory bulb to a representation that was largely concentration invariant in the piriform cortex. The underlying mechanism involves a “winner-takes-all” lateral inhibition. In the collateral network of the piriform cortex, the principal cells responded promptly to output from the olfactory bulb, and recurrent inhibition curtailed the intensity dependence of the signal. Science, this issue p. eaat6904 Feedback inhibition mediates the suppression of concentration-dependent sustained activity in the olfactory cortex. INTRODUCTION Objects can appear remarkably stable despite the often fickle cues they provide to our senses. For instance, a foraging mouse can identify and locate a piece of cheese several meters away entirely by smell, even though the concentration of airborne “cheese” molecules varies steeply over this distance. How the brain maintains perceptual stability across such widely ranging stimulus intensities remains a fundamental, unanswered question. The response properties of olfactory sensory neurons in the mouse’s nose may provide part of the answer. With each sniff, inhaled odorant molecules activate subsets of sensory neurons that each express a single type of odorant receptor. At low concentrations, when only a few odorant molecules are present, only those cells that express the most sensitive receptors for that particular odorant will be activated. However, many cells that express lower-affinity receptors will also be activated at higher concentrations, potentially degrading the odor representation. Crucially, the sensory neurons that express high-affinity receptors will always be activated earliest in the sniff, regardless of concentration. Could the mouse’s brain exploit this temporal structure to maintain stable odor representations despite changing odorant concentrations? RATIONALE To test this idea, we simultaneously recorded spiking activity from olfactory bulb (OB) mitral cells, which receive input from the olfactory sensory neurons, and from their cortical targets, principal neurons (PNs) in the piriform cortex (PCx), where odor identity is encoded. PNs form extensive, long-range “recurrent” excitatory synapses with each other in addition to forming excitatory synapses on PCx inhibitory interneurons. We hypothesized that this architecture enables the earliest activated—and therefore most selective—PCx PNs to rapidly inhibit less selective PCx PNs, helping to maintain stimulus specificity across odorant concentrations. We directly tested this idea by selectively expressing tetanus toxin in PCx PNs, blocking their ability to excite other PCx neurons but leaving them responsive to OB inputs. RESULTS In control mice, OB responses to different odors were more correlated and were more sensitive to differences in odor concentration than responses in PCx. Individual OB neurons fired bursts of action potentials, with odor-specific latencies and prolonged responses that were strongly concentration-dependent. By contrast, PCx PNs were briefly excited immediately after inhalation and then rapidly truncated by strong and sustained suppression. To identify the source of this suppression, we recorded from feedforward and feedback inhibitory interneurons in PCx. Feedforward interneurons, which are excited exclusively by OB inputs, exhibited little odor-evoked activity. By contrast, feedback interneurons, which are excited by PCx PNs but not by OB, showed robust and sustained spiking that mirrored PN suppression, indicating that PCx itself controls the timing and strength of its own suppression. We eliminated this intracortical communication by silencing recurrent excitatory synapses in PCx with tetanus toxin. This amplified and prolonged PCx PN responses, rendered their responses steeply concentration-dependent, and abolished the ability to stably predict odor identity across concentrations from PCx spiking activity. DISCUSSION The PCx cells that respond earliest after inhalation represent the most odorant-specific and concentration-invariant features of the odor. The extensive, long-range recurrent circuitry broadcasts their activation across PCx, recruiting strong, sustained global inhibition that then suppresses subsequent cortical activity. Recurrent circuitry therefore effectively amplifies the impact of the earliest arriving OB inputs and discounts the impact of less-selective inputs that arrive later. Thus, the recurrent circuitry in the PCx acts as a precisely timed gate to ensure that only the most salient information is relayed further into the brain to guide the mouse’s behavior. Whenever a mouse inhales, volatile molecules activate odorant receptors in the nose, evoking sequences of activity in the olfactory bulb. Bulb cells driven by the most specific receptors, which therefore best represent the odor stimulus (cheese), will always respond earliest. When this information is relayed to piriform cortex, activated principal neurons (red cells) recruit inhibitory neurons (green cells) that then suppress cortical responses to subsequent, less-specific olfactory bulb input (such as garlic, shoe, or flower), preserving the identity of the stimulus. ILLUSTRATION BY JULIA KUHL Animals rely on olfaction to find food, attract mates, and avoid predators. To support these behaviors, they must be able to identify odors across different odorant concentrations. The neural circuit operations that implement this concentration invariance remain unclear. We found that despite concentration-dependence in the olfactory bulb (OB), representations of odor identity were preserved downstream, in the piriform cortex (PCx). The OB cells responding earliest after inhalation drove robust responses in sparse subsets of PCx neurons. Recurrent collateral connections broadcast their activation across the PCx, recruiting global feedback inhibition that rapidly truncated and suppressed cortical activity for the remainder of the sniff, discounting the impact of slower, concentration-dependent OB inputs. Eliminating recurrent collateral output amplified PCx odor responses rendered the cortex steeply concentration-dependent and abolished concentration-invariant identity decoding.

中文翻译：

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循环皮质回路实现浓度不变的气味编码

代表气味的特性 我们仍然不知道气味是如何在一定浓度范围内保持其特性的。Bolding 和 Franks 在小鼠身上同时记录了嗅球和梨状皮层神经元的尖峰活动，这两个重要的嗅觉大脑区域。气味信息从在嗅球中高度依赖于浓度的表示转换为在梨状皮层中很大程度上浓度不变的表示。潜在的机制涉及“赢家通吃”的横向抑制。在梨状皮层的侧支网络中，主要细胞对嗅球的输出反应迅速，反复抑制减少了信号的强度依赖性。科学，这个问题 p。eaat6904 反馈抑制介导嗅觉皮层中浓度依赖性持续活动的抑制。简介 尽管物体向我们的感官提供了经常变化无常的线索，但它们看起来非常稳定。例如，一只觅食的老鼠可以完全通过气味识别和定位几米外的一块奶酪，即使空气中“奶酪”分子的浓度在这个距离内变化很大。大脑如何在如此广泛的刺激强度下保持知觉稳定性仍然是一个基本的、悬而未决的问题。小鼠鼻子中嗅觉感觉神经元的反应特性可能会提供部分答案。每次嗅闻时，吸入的气味分子都会激活感觉神经元的子集，每个子​​集都表达一种气味受体。在低浓度下，当只有少数气味分子存在时，只有那些表达该特定气味的最敏感受体的细胞才会被激活。然而，许多表达较低亲和力受体的细胞也会在较高浓度下被激活，这可能会降低气味表现。至关重要的是，无论浓度如何，表达高亲和力受体的感觉神经元总是在嗅觉中最早被激活。尽管气味浓度发生变化，老鼠的大脑能否利用这种时间结构来保持稳定的气味表征？基本原理为了测试这个想法，我们同时记录了来自嗅球 (OB) 二尖瓣细胞的尖峰活动，这些细胞接收来自嗅觉感觉神经元的输入，以及它们的皮层目标，梨状皮层 (PCx) 中的主要神经元 (PN)，其中气味身份被编码。除了在 PCx 抑制性中间神经元上形成兴奋性突触外，PNs 还相互形成广泛的、长距离的“循环”兴奋性突触。我们假设这种架构使最早激活的（因此也是最具选择性的）PCx PN 能够快速抑制选择性较低的 PCx PN，从而有助于保持跨气味浓度的刺激特异性。我们通过在 PCx PNs 中选择性表达破伤风毒素来直接测试这个想法，阻止它们激发其他 PCx 神经元的能力，但让它们对 OB 输入有反应。结果在对照小鼠中，OB 对不同气味的反应比 PCx 中的反应更相关，对气味浓度差异更敏感。单个 OB 神经元发出动作电位的爆发，具有气味特定的潜伏期和强烈依赖浓度的长时间反应。相比之下，PCx PNs 在吸入后立即短暂兴奋，然后被强烈和持续的抑制迅速截断。为了确定这种抑制的来源，我们记录了 PCx 中的前馈和反馈抑制中间神经元。前馈中间神经元完全由 OB 输入激发，表现出很少的气味诱发活动。相比之下，由 PCx PN 而不是由 OB 激发的反馈中间神经元表现出稳健和持续的尖峰，反映了 PN 抑制，表明 PCx 本身控制着自身抑制的时间和强度。我们通过用破伤风毒素使 PCx 中的复发性兴奋性突触沉默来消除这种皮层内交流。这种放大和延长的 PCx PN 响应，使他们的反应急剧地依赖于浓度，并消除了从 PCx 尖峰活动的浓度中稳定预测气味特性的能力。讨论 吸入后反应最早的 PCx 细胞代表了气味中最具气味特异性和浓度不变的特征。广泛的、远程的循环回路在 PCx 上广播它们的激活，招募强大的、持续的全局抑制，然后抑制随后的皮质活动。因此，循环电路有效地放大了最早到达的 OB 输入的影响，并降低了稍后到达的选择性较少的输入的影响。因此，PCx 中的循环电路充当了一个精确定时的门，以确保只有最重要的信息才能进一步传递到大脑中以指导鼠标的行为。每当老鼠吸气时，挥发性分子就会激活鼻子中的气味受体，从而激发嗅球中的一系列活动。由最具体的受体驱动的球细胞，因此最能代表气味刺激（奶酪），总是最早做出反应。当这些信息传递到梨状皮层时，激活的主要神经元（红细胞）会招募抑制性神经元（绿色细胞），然后抑制皮层对随后的、特异性较低的嗅球输入（如大蒜、鞋或花）的反应，从而保护刺激的身份。JULIA KUHL 的插图 动物依靠嗅觉来寻找食物、吸引配偶和躲避捕食者。为了支持这些行为，他们必须能够识别不同气味浓度的气味。实现这种浓度不变性的神经回路操作仍不清楚。我们发现，尽管嗅球 (OB) 具有浓度依赖性，但在梨状皮层 (PCx) 的下游保留了气味特性的表征。吸入后最早响应的 OB 细胞在 PCx 神经元的稀疏子集中驱动了强烈的响应。反复的侧支连接在 PCx 上广播它们的激活，招募全局反馈抑制，迅速截断和抑制嗅觉剩余部分的皮质活动，忽略较慢的、浓度依赖的 OB 输入的影响。消除经常性侧支输出放大的 PCx 气味反应使皮层高度依赖于浓度，并消除了浓度不变的身份解码。我们发现，尽管嗅球 (OB) 具有浓度依赖性，但在梨状皮层 (PCx) 的下游保留了气味特性的表征。吸入后最早响应的 OB 细胞在 PCx 神经元的稀疏子集中驱动了强烈的响应。反复的侧支连接在 PCx 上广播它们的激活，招募全局反馈抑制，迅速截断和抑制嗅觉剩余部分的皮质活动，忽略较慢的、浓度依赖的 OB 输入的影响。消除经常性侧支输出放大的 PCx 气味反应使皮层高度依赖于浓度，并消除了浓度不变的身份解码。我们发现，尽管嗅球 (OB) 具有浓度依赖性，但在梨状皮层 (PCx) 的下游保留了气味特性的表征。吸入后最早响应的 OB 细胞在 PCx 神经元的稀疏子集中驱动了强烈的响应。反复的侧支连接在 PCx 上广播它们的激活，招募全局反馈抑制，迅速截断和抑制嗅觉剩余部分的皮质活动，忽略较慢的、浓度依赖的 OB 输入的影响。消除经常性侧支输出放大的 PCx 气味反应使皮层高度依赖于浓度，并消除了浓度不变的身份解码。吸入后最早响应的 OB 细胞在 PCx 神经元的稀疏子集中驱动了强烈的响应。反复的侧支连接在 PCx 上广播它们的激活，招募全局反馈抑制，迅速截断和抑制嗅觉剩余部分的皮质活动，忽略较慢的、浓度依赖的 OB 输入的影响。消除经常性侧支输出放大的 PCx 气味反应使皮层高度依赖于浓度，并消除了浓度不变的身份解码。吸入后最早响应的 OB 细胞在 PCx 神经元的稀疏子集中驱动了强烈的响应。反复的侧支连接在 PCx 上广播它们的激活，招募全局反馈抑制，快速截断和抑制嗅觉剩余部分的皮质活动，忽略较慢的、浓度依赖性 OB 输入的影响。消除经常性侧支输出放大的 PCx 气味反应使皮层高度依赖于浓度，并消除了浓度不变的身份解码。不考虑较慢的、依赖于浓度的 OB 输入的影响。消除经常性侧支输出放大的 PCx 气味反应使皮层高度依赖于浓度，并消除了浓度不变的身份解码。打折较慢的、依赖于浓度的 OB 输入的影响。消除经常性侧支输出放大的 PCx 气味反应使皮层高度依赖于浓度，并消除了浓度不变的身份解码。