Influence of the locus coeruleus on fear learning and threat processing in the ventral hippocampus

蓝斑对腹侧海马恐惧学习和威胁处理的影响

• 批准号: 10391884
• 负责人: Brian J Wiltgen
• 金额: $ 23.2万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-20 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391884
• 关键词: Acute; American; Amygdaloid structure; Anxiety; Anxiety Disorders; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Bipolar Disorder; Brain region; Catecholamines; Cells; Cognitive; Disease; Environment; Fiber; Follow-Up Studies; Fright; Goals; Hippocampus (Brain); Hormones; Human; Hypothalamic structure; Image; Lateral; Learning; Lesion; Mediating; Memory; Memory impairment; Mental disorders; Monitor; Neurons; Output; Pathway interactions; Phase; Photometry; Physiological; Play; Process; Production; Research; Role; Schizophrenia; Shock; Signal Transduction; Stimulus; Stress; Structure; System; Testing; Training; United States; United States National Institutes of Health; anxiety-related behavior; cell type; comorbidity; conditioned fear; experience; experimental study; follow-up; in vivo; in vivo calcium imaging; interdisciplinary approach; locus ceruleus structure; neuromechanism; neuroregulation; novel; optogenetics; prevent; relating to nervous system; response

Abstract The locus coeruleus (LC) and ventral hippocampus (vHPC) both influence our response to threatening stimuli. Research to date has focused primarily on the contribution each of these structures makes to fear learning and anxiety. However, few studies have examined the interactions that occur between the LC and vHPC during threat processing. The LC is typically thought to provide a salience signal to the HPC and other brain regions, that enhances plasticity and facilitates memory formation. However, the LC and vHPC have also been shown to drive innate anxiety-related behaviors in stressful situations. To resolve this apparent discrepancy, we will test the novel idea that fear learning and innate anxiety are both controlled by distinct oscillations in the LC (phasic vs tonic firing) that are transmitted to the vHPC when a threat is encountered. Acute, fear-inducing stimuli have been shown to produce large, transient responses in the LC and the vHPC. For example, aversive footshock produces phasic activity in both structures that can persist for up to several seconds after the stimulus has terminated. As phasic LC responses are typically associated with focused attention and the encoding of salient stimuli, we hypothesize that phasic activity in the LC promotes fear learning by enhancing shock processing in the vHPC. In contrast, situations that induce anxiety, such as open, unsheltered environments, produce smaller, but longer lasting increases in tonic activity in the LC. Consequently, we hypothesize that the LC elicits anxiety-related behaviors when a potential threat is encountered by inducing tonic firing in the vHPC. To test these ideas, we will use a multidisciplinary approach that combines in vivo fiber photometry with cell-type specific optogenetics to simultaneously monitor vHPC activity while manipulating LC neurons during fear conditioning and situations that provoke anxiety. Follow-up studies will build on these results by using in vivo calcium imaging to determine the effects of tonic and phasic LC firing on the activity of shock-responsive and anxiety-responsive cells in the vHPC.

摘要 蓝斑（LC）和腹侧海马（vHPC）都影响我们对威胁性刺激的反应。 到目前为止，研究主要集中在这些结构中的每一个对恐惧学习的贡献上， 焦虑然而，很少有研究检查LC和vHPC之间发生的相互作用， 威胁处理LC通常被认为向HPC和其他大脑区域提供显著信号， 增强可塑性和促进记忆形成的物质。然而，LC和vHPC也显示出 在紧张的情况下驱动与焦虑相关的行为。为了解决这一明显的矛盾，我们将 测试新的想法，即恐惧学习和先天焦虑都是由LC的不同振荡控制的 （相位与紧张性放电），当遇到威胁时，这些信号被传输到vHPC。急性，引起恐惧 已经表明，刺激在LC和vHPC中产生大的瞬态响应。例如，厌恶 足电击在两个结构中产生阶段性活动，在电击后可以持续长达几秒钟。 刺激已经结束。由于阶段性LC反应通常与集中注意力相关， 我们假设LC中的阶段性活动通过增强显著刺激的编码来促进恐惧学习， vHPC中的冲击处理。相反，诱发焦虑的情况，如开放，无遮蔽， 环境中，产生较小的，但更持久的增加紧张活动的LC。因此我们 假设当遇到潜在威胁时，LC通过诱导 vHPC中的紧张性放电。为了测试这些想法，我们将使用多学科的方法， 使用细胞类型特异性光遗传学的光度测定法在操作LC的同时监测vHPC活性 神经元在恐惧条件反射和引发焦虑的情况下。后续研究将建立在这些基础上 结果通过使用体内钙成像来确定紧张性和相位性LC放电对 vHPC中的休克反应细胞和焦虑反应细胞。