CAREER:Investigating how internal states, learning, and memory shape olfactory coding

职业：研究内部状态、学习和记忆如何塑造嗅觉编码

• 批准号: 1749772
• 负责人: Krishnan Padmanabhan
• 金额: $ 66万
• 依托单位: University of Rochester
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1749772&HistoricalAwards=false
• 关键词: CAREER; Investigating; how; internal; states

A central principle of neuroscience is that sensory stimuli are represented as patterns of neuronal activity that ultimately give rise to behaviors. Interestingly, even when a stimulus is fixed, such as the odor from a food source, behavioral responses can be diverse, almost necessarily influenced by an assortment of factors ranging from the animal's internal state to memory. These collectively determine which one of many possible behaviors will be selected. In the odor example, the decision to approach the food source may be influenced by the degree of satiety vs. hunger, the valence of the odor (were these odors "good" the last time they were encountered?), any memory the animal might have about lurking predators (a calculation of risk versus reward), or an efficient strategy for search the animal has learned. These are examples of the array of information that gets integrated to select "the correct" behavior for survival in a complex world. Recent evidence suggests that control points for behavioral flexibility can happen as early as the level at which sensory information is first processed. In this model, feedback or top-down projections from higher processing areas directly alter patterns of neuronal firing in primary sensory regions. As a result, these feedback projections affect behavior by manipulating how stimuli are encoded in primary sensory regions. Thus, animals respond differently because they encode the world differently. This project uses an array of experimental and computational tools to advance understanding of this top-down modulation of sensory information. The project also includes the implementation of a computational neuroscience course for senior undergraduate and graduate students, and of a Virtual Reality program that enables students, including K-12 and local community college students, to visualize dynamics of neural networks.This project investigates central modulation of peripheral sensory processing as a mechanism of influencing behavioral endpoints. To study this question, two things are required: A feedback circuit in the brain that 1) encodes for complex representations including memory, fear, and anxiety for instance, and 2) targets primary sensory regions. Recent studies have identified a direct feedback connection from the ventral CA1 (vCA1) region of the hippocampus (that encodes fear, internal state, social information, and learning) to the main olfactory bulb 1 synapse from where odors are first detected in the mouse. This connection provides a compact experimental system with which to interrogate how internal states and/or learning and memory influence the neuronal representations of sensory stimuli at the earliest stages. By using this circuit, this project: (1) examines the patterns of connectivity between vCA1, the olfactory bulb and other known target regions to identify the networks involved in this feedback control; and (2) determines how vCA1 feedback reshapes the activity of neurons in the main olfactory bulb in response to odors. For the first aim, newly developed retrograde tracers are used to label connections from vCA1 to the bulb in tandem with automated whole brain reconstruction methods to identifying the structural logic of feedback circuits. For the second aim, optogenetic technology is used to control vCA1 activity while recording the activity of large populations of neurons in the main olfactory bulb, and thus to identify the physiological effects of feedback projections and the role feedback plays in encoding information about odor identity and concentration. This project is co-funded by the Mathematical Biology program in the Division of Mathematical Sciences and the Physics of Living Systems program in the Division of Physics of the Directorate for Mathematical and Physical Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

神经科学的一个中心原则是，感觉刺激被表示为最终引起行为的神经元活动的模式。有趣的是，即使刺激是固定的，例如来自食物来源的气味，行为反应也可能是多种多样的，几乎必然受到从动物内部状态到记忆的各种因素的影响。这些共同决定了将选择许多可能行为中的哪一个。在气味的例子中，接近食物源的决定可能受到饱腹感与饥饿感的程度、气味的效价（这些气味在最后一次遇到时是“好的”吗？）动物可能拥有的关于潜伏捕食者的任何记忆（风险与回报的计算），或者动物学到的有效搜索策略。 这些是信息阵列的例子，这些信息被整合以选择在复杂世界中生存的“正确”行为。 最近的证据表明，行为灵活性的控制点可以早在感官信息首次处理的水平上发生。 在这个模型中，来自高级处理区域的反馈或自上而下的投射直接改变初级感觉区域的神经元放电模式。 因此，这些反馈投射通过操纵刺激在初级感觉区域中的编码方式来影响行为。 因此，动物的反应不同，因为它们对世界的编码不同。该项目使用一系列实验和计算工具来促进对这种自上而下的感官信息调制的理解。 该项目还包括为高年级本科生和研究生开设计算神经科学课程，以及让学生（包括K-12和当地社区大学的学生）可视化神经网络动态的虚拟现实程序。该项目研究了外周感觉处理的中枢调制作为影响行为终点的机制。 为了研究这个问题，需要两件事：大脑中的反馈回路，1）编码复杂的表征，包括记忆，恐惧和焦虑，以及2）针对初级感觉区域。 最近的研究已经确定了从海马体腹侧CA 1（vCA 1）区域（编码恐惧，内部状态，社会信息和学习）到主要嗅球1突触的直接反馈连接，从那里首次检测到气味。这种联系提供了一个紧凑的实验系统，询问内部状态和/或学习和记忆如何影响神经元的感官刺激在最早阶段的表示。通过使用这个回路，该项目：（1）检查vCA 1，嗅球和其他已知目标区域之间的连接模式，以识别参与这种反馈控制的网络;（2）确定vCA 1反馈如何重塑主嗅球中神经元对气味的反应。 对于第一个目标，新开发的逆行示踪剂用于标记从vCA 1到灯泡的连接，并与自动全脑重建方法相结合，以识别反馈回路的结构逻辑。对于第二个目标，光遗传学技术用于控制vCA 1活性，同时记录主嗅球中大量神经元的活性，从而识别反馈投射的生理效应以及反馈在编码有关气味的信息中所发挥的作用身份和浓度。 该项目由数学科学部的数学生物学项目和数学与物理科学理事会物理部的生命系统物理学项目共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Centrifugal Inputs to the Main Olfactory Bulb Revealed Through Whole Brain Circuit-Mapping

通过全脑回路映射揭示主嗅球的离心输入

• DOI: 10.3389/fnana.2018.00115
• 发表时间: 2019
• 期刊: Frontiers in Neuroanatomy
• 影响因子: 2.9
• 作者: Padmanabhan, Krishnan;Osakada, Fumitaka;Tarabrina, Anna;Kizer, Erin;Callaway, Edward M.;Gage, Fred H.;Sejnowski, Terrence J.
• 通讯作者: Sejnowski, Terrence J.

Sex differences in head‐fixed voluntary running behavior in C57BL/6J mice

C57BL/6J 小鼠头部的性别差异固定自愿跑步行为

• DOI: 10.1111/ejn.14654
• 发表时间: 2019
• 期刊: European Journal of Neuroscience
• 影响因子: 3.4
• 作者: Warner, Emily J.;Padmanabhan, Krishnan
• 通讯作者: Padmanabhan, Krishnan

Top-down feedback enables flexible coding strategies in the olfactory cortex

自上而下的反馈可以在嗅觉皮层中实现灵活的编码策略

• DOI: 10.1016/j.celrep.2022.110545
• 发表时间: 2022
• 期刊: Cell Reports
• 影响因子: 8.8
• 作者: Chen, Zhen;Padmanabhan, Krishnan
• 通讯作者: Padmanabhan, Krishnan

Changes in pairwise correlations during running reshape global network state in the main olfactory bulb

• DOI: 10.1152/jn.00464.2020
• 发表时间: 2021-05-01
• 期刊: JOURNAL OF NEUROPHYSIOLOGY
• 影响因子: 2.5
• 作者: Chockanathan, Udaysankar;Crosier, Emily J. W.;Padmanabhan, Krishnan
• 通讯作者: Padmanabhan, Krishnan