A sex-specific circuit for emotional memory

项目摘要 恐惧情绪是记忆储存的强大触发因素，帮助我们避免与厌恶相关的线索 结果。然而，恐惧记忆变得适应不良，并引发不适当的情绪反应， 常见的精神疾病，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， 更严重的症状导致患有这些疾病的妇女的生活质量更差。可惜 支持这种易感性性别差异的神经生物学机制仍然知之甚少， 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 与男性不同的记忆，我们将查明性别特异性机制和恐惧的治疗策略- 基于精神疾病。这个项目的目的是确定分子，细胞和电路为基础的 女性易患基于恐惧的精神疾病的潜在机制。根据初步实验， 这项工作将集中在侧隔（LS）上，这是边缘系统的一个两性异形枢纽， 适应不良的情绪行为我们表明，LS是鲁棒激活期间线索的威胁（也称为 恐惧）记忆形成的女性，而不是男性，这种性别特异性激活是因果关系联系在一起， 威胁记忆的强度，并且女性LS威胁记忆集合体的神经元直接投射到 驱动线索诱发的情绪反应的区域。本申请中提出的实验将扩展 根据这些初步研究结果来检验中心假设，即女性特定的参与和随后的 迄今未被认识的LS回路的突触强化增强了女性与男性的线索威胁记忆。 男性。在目标1中，我们将检验以下假设：选择性募集与威胁相关的LS神经元增强了 威胁记忆编码和表达在女性与男性通过解除抑制的投射神经元 下丘脑腹侧海马体和导水管周围灰质在目标2中，我们将检验以下假设： 内侧前额叶皮层的兴奋性投射是LS记忆集合的必要和充分条件 招募和增强的记忆编码。最后，在目标3中，我们将测试 LS神经元分子结构的性别差异驱动性别特异性记忆的假说 配置中这些实验有可能改变我们对基本大脑回路的理解， 恐惧记忆的储存和表达在性别之间存在差异。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性别特异性治疗靶点。

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.