Circuit versus stress hormonal influences in consolidation of fear memory strength and precision.

电路与压力荷尔蒙对巩固恐惧记忆强度和精确度的影响。

• 批准号: 10753860
• 负责人: RYAN T LALUMIERE
• 金额: $ 48.7万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753860
• 关键词: Address; Adrenalectomy; Amygdaloid structure; Animals; Area; Avoidance Learning; Binding; Brain; Corticosterone; Data; Dependence; Development; Discrimination; Elements; Event; Fright; Future; Glucocorticoid Receptor; Glucocorticoids; Hormonal; Hormones; Human; Intervention; Learning; Medial; Mediating; Memory; Mental disorders; Neural Pathways; Neurobiology; Neurons; Organism; Output; Pathway interactions; Play; Prefrontal Cortex; Process; Prosencephalon; Rat Transgene; Receptor Activation; Research; Role; Site; Stress; Structure of terminal stria nuclei of preoptic region; System; Testing; Training; Work; expectation; experience; experimental study; fear memory; improved; insight; knock-down; maladaptive behavior; memory consolidation; neural; neural circuit; neurobiological mechanism; neuromechanism; novel; optogenetics; response; stressor

Project Summary Discrimination between threatening and non-threatening contexts is an adaptive neurobiological process, whereas traumatic stressors may shift responses toward generalization. From a translational perspective, the loss of discrimination, or over-generalization, from a stressful to neutral context is one of the core features of stress-related psychiatric diseases. To date, many studies have made inroads in understanding memory consolidation processes in terms of overall memory strength, yet the post-learning processes that underlie discrimination vs. generalization remain poorly understood. New data from our research team suggests that limbic forebrain influences over the anteroventral bed nuclei of the stria terminalis (avBST) are poised to differentially regulate memory strength and discrimination following an aversive learning paradigm. Interestingly, these data further suggest a role for the basomedial amygdala (BMA) and rostral prelimbic (rPL) subdivision of the medial prefrontal cortex in modulating memory strength and generalization, respectively, via direct influences through avBST. Notably, activation of limbic cortical inputs to avBST supports different aspects of memory modulation, whereas the disengagement of each input may exaggerate fear memory and generalization via diminished activation over distinct circuits within avBST. This proposed work will address the hypothesis that activity in BMA/rPL–avBST circuits play distinct roles over memory strength and discrimination with both glucocorticoid-dependent and independent components. Aim 1 will address the roles of the rPL–avBST and BMA–avBST pathways and the avBST itself in modulating precision and memory strength following inhibitory avoidance learning. Aim 2 will assess whether the effects of avBST and BMA-avBST inhibition on memory consolidation depends on their effects on circulating glucocorticoids in the posttraining period. Aim 3 will focus on the sites of action within specific circuits in which glucocorticoids are having their effects on memory strength and/or precision. These findings will be instrumental for improving our understanding of how these circuits influence memory strength vs. precision in the period following an aversive learning experience and determine the degree to which these effects depend on alterations in glucocorticoids vs. direct influences on neuronal processes within the brain.

项目摘要 区分威胁性和非威胁性环境是一种适应性神经生物学过程， 而创伤性应激源可能会使反应转向泛化。从翻译的角度来看， 从紧张到中性的语境中丧失辨别力或过度概括是 与压力有关的精神疾病。迄今为止，许多研究在理解记忆方面取得了进展， 巩固过程的整体记忆强度，但学习后的过程， 对歧视与普遍化的认识仍然很少。我们研究小组的新数据表明， 边缘前脑对终纹前腹床核（avBST）的影响， 差异调节记忆强度和歧视以下厌恶学习范式。有趣的是， 这些数据进一步表明，杏仁核基底内侧（BMA）和吻侧边缘前核（rPL）亚群的作用， 内侧前额叶皮层通过直接影响分别调节记忆强度和概括 通过avBST。值得注意的是，对avBST的边缘皮层输入的激活支持记忆的不同方面 调制，而每一个输入的分离可能会夸大恐惧记忆和概括， avBST内不同回路的激活减弱。这项拟议的工作将解决的假设， BMA/rPL-avBST回路中的活动在记忆强度和辨别力方面发挥不同的作用， 糖皮质激素依赖性和非依赖性成分。目标1将阐述rPL-avBST的作用， BMA-avBST通路和avBST本身在抑制后调节精度和记忆强度中的作用 回避学习目的2将评估avBST和BMA-avBST抑制对记忆的影响 巩固取决于它们对训练后循环糖皮质激素的影响。目标3将重点 糖皮质激素对记忆强度产生影响的特定回路中的作用部位 和/或精度。这些发现将有助于我们更好地理解这些电路是如何 在一段令人厌恶的学习经历之后， 这些作用的程度取决于糖皮质激素的改变与对神经元的直接影响， 大脑内的过程。