A sex-specific circuit for emotional memory

情绪记忆的性别特异性回路

• 批准号: 10408159
• 负责人: Elizabeth Kathleen Lucas
• 金额: --
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408159
• 关键词: Anxiety Disorders; Architecture; Auditory; Brain; Cells; Chemosensitization; Cues; Data; Disease; Disinhibition; Electrophysiology (science); Emotional; Emotions; Event; Female; Fright; Gender; Generalized Anxiety Disorder; Genetic Identity; Hippocampus (Brain); Hypothalamic structure; Impairment; In Vitro; Individual; Knowledge; Lateral; Lateral Hypothalamic Area; Learning; Libido; Limbic System; Link; Maps; Medial; Mediator of activation protein; Memory; Mental disorders; Methods; Modeling; Molecular; Molecular Profiling; Neurons; Outcome; Panic Disorder; Patients; Pharmacology; Phobias; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Process; Quality of life; Regulation; Role; Severities; Sex Differences; Slice; Structure; Symptoms; Synapses; Testing; Therapeutic Intervention; Translations; Woman; Work; base; biological sex; conditioning; effective therapy; emotion dysregulation; emotional behavior; experience; experimental study; fear memory; in vivo; male; memory encoding; memory process; men; midbrain central gray substance; neural circuit; neurobiological mechanism; novel; optogenetics; postsynaptic; pre-clinical; pre-clinical research; recruit; resilience; response; sex; sexual dimorphism; showing emotion; therapeutic target; transcriptome; treatment strategy

PROJECT SUMMARY The emotion of fear is a powerful trigger for memory storage, helping us avoid cues associated with aversive outcomes. However, fear memories become maladaptive and trigger inappropriate emotional responses in common psychiatric diseases such as post-traumatic stress disorder (PTSD), generalized anxiety disorder, and panic disorder. Women are twice as likely as men to experience fear-based psychiatric conditions, and greater symptom severity leads to poorer quality of life in women with these illnesses. Unfortunately, the neurobiological mechanisms underpinning this sex difference in susceptibility remain poorly understood due to a lack of female subjects in preclinical research. By understanding how females encode and express fear memories differently than males, we will pinpoint sex-specific mechanisms and treatment strategies for fear- based psychiatric disease. The purpose of this project is to identify the molecular-, cellular-, and circuit-based mechanisms underlying female susceptibility to fear-based mental illness. Based on preliminary experiments, this work will focus on the lateral septum (LS), a sexually dimorphic hub of the limbic system known to gate maladaptive emotional behaviors. We show that the LS is robustly activated during cued threat (also known as fear) memory formation in females but not males, that this sex-specific activation is causally linked to the strength of the threat memory, and that neurons of the female LS threat memory ensemble directly project to regions that drive cue-evoked emotional responses. The experiments proposed in this application will expand upon these initial findings to test the central hypothesis that female-specific engagement and subsequent synaptic strengthening of a hitherto unrecognized LS circuit enhances cued threat memory in females versus males. In Aim 1, we will test the hypothesis that selective recruitment of threat-related LS neurons enhance threat memory encoding and expression in females versus males through disinhibition of projection neurons of the hypothalamus, ventral hippocampus, and periaqueductal gray. In Aim 2, we will test the hypothesis that excitatory projections from the medial prefrontal cortex are necessary and sufficient for LS memory ensemble recruitment and enhanced memory encoding in females versus males. Finally, in Aim 3, we will test the hypothesis that sex differences in the molecular architecture of LS neurons drive sex-specific memory allocation. These experiments have the potential to transform our understanding of how basic brain circuits for fear memory storage and expression differ between the sexes. Our long-term objective of this work is to help clinicians uncover novel gender-specific therapeutic targets for fear-based psychiatric disease.

项目总结 恐惧的情绪是记忆存储的强大触发器，帮助我们避免与厌恶有关的线索 结果。然而，恐惧记忆会变得不适应，并引发不适当的情绪反应 常见精神疾病，如创伤后应激障碍(PTSD)、广泛性焦虑症、 和恐慌症。女性经历基于恐惧的精神疾病的可能性是男性的两倍，而且 症状越严重，患有这些疾病的妇女的生活质量就越差。不幸的是， 这种性别易感性差异的神经生物学机制仍然知之甚少，因为 在临床前研究中缺乏女性受试者。通过了解女性如何编码和表达恐惧 不同于男性的记忆，我们将精确定位针对性别的恐惧机制和治疗策略-- 以精神疾病为基础。本项目的目的是确定基于分子、细胞和电路的 女性对基于恐惧的精神疾病易感性的潜在机制。根据初步实验， 这项工作将集中在外侧隔(LS)，一个边缘系统的性二态枢纽，已知为GATE 不适应的情绪行为。我们发现，LS在提示威胁(也称为 恐惧)女性而不是男性的记忆形成，这种性别特异性的激活与 威胁记忆的强度，以及女性LS威胁记忆集合的神经元直接投射到 驱动线索引发情绪反应的区域。本申请中提出的实验将扩展 在这些初步发现的基础上，测试女性特有的参与和随后的 突触强化迄今未被识别的LS环路增强女性的线索威胁记忆 男性。在目标1中，我们将检验选择性招募威胁相关LS神经元增强 雌性与雄性威胁记忆的编码和表达通过去抑制投射神经元 下丘脑、腹侧海马体和中脑导水管周围灰质。在目标2中，我们将检验假设 内侧前额叶皮质的兴奋性投射是LS记忆的必要条件和充分条件 女性对男性的招募和增强的记忆编码。最后，在目标3中，我们将测试 假设LS神经元分子结构中的性别差异驱动性别特异性记忆 分配。这些实验有可能改变我们对基本大脑回路如何 恐惧记忆的储存和表达在性别上存在差异。我们这项工作的长期目标是帮助 临床医生为基于恐惧的精神疾病发现了新的针对性别的治疗目标。