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

神经科学的一个核心原则是，感觉刺激被表现为最终导致行为的神经元活动模式。有趣的是，即使刺激是固定的，比如食物来源的气味，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。这些因素共同决定了在许多可能的行为中选择哪一种。在气味的例子中，接近食物来源的决定可能受到以下因素的影响：饱腹程度与饥饿程度、气味的效价（这些气味在最后一次遇到时是否“好”？）、动物可能对潜伏的捕食者的任何记忆（对风险与回报的计算），或者动物已经学会的有效搜索策略。这些都是为了在一个复杂的世界中生存而选择“正确”行为的一系列信息的例子。最近的证据表明，行为灵活性的控制点可能早在感觉信息第一次被处理的阶段就出现了。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了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主要感觉区域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推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实施一门计算神经科学课程，以及一个虚拟现实项目，使学生（包括K-12和当地社区大学生）能够可视化神经网络的动态。本项目研究外围感觉处理的中枢调节作为影响行为终点的机制。要研究这个问题，需要两样东西：大脑中的反馈回路，1)编码包括记忆、恐惧和焦虑在内的复杂表征，2)以主要感觉区域为目标。最近的研究已经确定了从海马体的腹侧CA1 （vCA1）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，在小鼠中，嗅球1突触是第一次检测到气味的地方。这种联系提供了一个紧凑的实验系统，用来询问内部状态和/或学习和记忆如何在早期阶段影响感觉刺激的神经元表征。通过使用这个电路，这个项目：(1)检查vCA1、嗅球和其他已知目标区域之间的连接模式，以确定参与这种反馈控制的网络；(2)确定vCA1反馈如何重塑主嗅球神经元对气味的反应活动。第一个目标是使用新开发的逆行示踪剂标记从vCA1到灯泡的连接，同时使用自动化全脑重建方法来识别反馈电路的结构逻辑。第二个目标是利用光遗传学技术控制vCA1的活性，同时记录主嗅球中大量神经元的活动，从而确定反馈投射的生理效应以及反馈在编码气味识别和浓度信息中的作用。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。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.