Circuit and cellular mechanisms of adult neurogenesis in context encoding and discrimination

环境编码和辨别中成人神经发生的回路和细胞机制

• 批准号: 10197790
• 负责人: Mazen A Kheirbek
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197790
• 关键词: Ablation; Address; Adult; Age; Antidepressive Agents; Behavior; Behavioral; Brain; Calcium; Cell physiology; Cells; Chronic; Development; Discrimination; Emotional; Environment; Environmental Risk Factor; Exercise; Exhibits; Exposure to; Fire - disasters; Fright; Goals; Hippocampal Formation; Hippocampus (Brain); Human; Image; Imaging Techniques; Immediate-Early Genes; In Vitro; Intervention; Knowledge; Learning; Life; Measurement; Measures; Memory; Monitor; Moods; Mus; Nature; Neurons; Optics; Pattern; Phase; Play; Population; Process; Property; Role; Slice; Stress; Techniques; Testing; Therapeutic; Time; Work; adult neurogenesis; anxiety treatment; anxiety-related disorders; behavioral study; cell type; cognitive function; cohort; dentate gyrus; environmental enrichment for laboratory animals; fear memory; granule cell; in vivo; innovation; neurogenesis; novel; response; temporal measurement; tool

Project summary The dentate gyrus subfield of the adult hippocampal formation exhibits a unique form of plasticity, the ability to generate new neurons throughout life. These adult born granule cells (abGCs) integrate into existing circuitry and have distinct properties during specific phases of their development. This process of adult neurogenesis is dynamically regulated by environment and emotional state; interventions that have negative effects on mood, such as stress and isolation can reduce levels of neurogenesis, while interventions that increase mood, such as enrichment and exercise can increase levels of neurogenesis. Behaviorally, these abGCs have been implicated in cognitive functions such as learning and memory, as well as mood related functions such as responses to stress or antidepressant treatment. However, we lack a complete understanding of the firing patterns of abGCs in freely behaving mice, how their dynamic encoding patterns differ from mature GCs (mGCs) and how environment may alter these activity patterns in vivo. Here we will address these long- standing questions in the field. Using novel, cutting-edge tools for monitoring and manipulating the activity of age-matched cohorts of abGCs in vivo, we will ask how these neurons contribute to hippocampal function during their development. First, we will use cell-type specific optical techniques to silence specific cohorts of these neurons during phases of context encoding and discrimination. Then we will use functional calcium imaging in freely moving mice to determine how abGCs function during these tests of context encoding and differentiation. Finally, we will determine how environmental enrichment and exercise alter the firing patterns and encoding properties of abGCs and the DG- CA3 circuit in vivo. The goal of these studies is to understand the mechanisms by which these neurons encode contextual representations during fear memory formation. Understanding the role of abGCs in this process may allow us to harness this unique form of plasticity in the adult brain for the treatment of fear and anxiety- related disorders.

项目摘要 成年海马结构的齿状回亚区表现出一种独特的可塑性形式， 产生新的神经元。这些成人出生的颗粒细胞（abGC）整合到现有的电路中， 并且在其发育的特定阶段具有不同的特性。这个成年神经发生的过程 受环境和情绪状态的动态调节;对情绪有负面影响的干预， 例如压力和孤立可以降低神经发生水平，而增加情绪的干预措施， 因为丰富的营养和锻炼可以提高神经发生的水平。从行为上讲，这些abGC 涉及认知功能，如学习和记忆，以及情绪相关功能，如 对压力或抗抑郁治疗的反应。然而，我们对这次枪击事件 自由行为小鼠中abGCs的模式，它们的动态编码模式与成熟GCs有何不同 （mGCs）以及环境如何在体内改变这些活动模式。在这里，我们将讨论这些长期- 现场的常见问题使用新颖的尖端工具来监测和操纵 在体内年龄匹配的abGCs队列中，我们将询问这些神经元如何有助于海马功能 在他们的发展过程中。首先，我们将使用细胞类型特异性光学技术来沉默特定的细胞群。 这些神经元在上下文编码和辨别的阶段。那么我们就用功能钙 在自由移动的小鼠中成像，以确定abGC在这些上下文编码测试期间如何起作用， 分化最后，我们将确定环境丰富和运动如何改变放电模式 以及体内abGCs和DG-CA 3回路的编码特性。这些研究的目的是了解 这些神经元在恐惧记忆形成过程中编码情境表征的机制。 了解abGCs在这一过程中的作用可能使我们能够利用这种独特的可塑性形式， 用于治疗与恐惧和焦虑有关的疾病。