Fkbp5 modulation of prefrontal function.

Fkbp5 调节前额叶功能。

• 批准号: 9513781
• 负责人: James T. Porter
• 金额: $ 47.04万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513781
• 关键词: AMPA Receptors; Affect; Amygdaloid structure; Animal Model; Anxiety; Behavioral; Brain; Catecholamines; Cell Nucleus; Clinical Data; Data; Depressed mood; Development; Emotional; Extinction (Psychology); FK506 binding protein 5; FOS gene; Female; Frequencies; Fright; Glucocorticoid Receptor; Glucocorticoids; Halorhodopsins; Human; Hypothalamic structure; Individual; Infusion procedures; Label; Lateral; Lead; Learning; Medial; Mediating; Memory; Mental disorders; Modeling; N-Methyl-D-Aspartate Receptors; Neurons; Plasmids; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Rattus; Receptor Signaling; Rodent; Role; Signal Transduction; Slice; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Synapses; Testing; Trauma; Viral; Viral Vector; base; beta-adrenergic receptor; conditioned fear; excitatory neuron; follow-up; inhibitory neuron; knock-down; male; novel; optogenetics; overexpression; patch clamp; promoter; selective expression; small hairpin RNA

Project Summary/Abstract: The widely accepted model proposes that the infralimbic cortex (IL) is a key structure for fear extinction that plays no role in fear conditioning. Surprisingly, we found that selectively decreasing expression of FK506 binding protein 5 (FKBP5) in IL reduced acquisition and recall of conditioned fear. Although clinical data suggest that FKBP5 plays a role in PTSD, it is unclear whether differences in FKBP5 expression alone could predispose or protect individuals from the development of PTSD. Our data suggests that higher expression of FKBP5 in the ventral medial prefrontal cortex (equivalent of IL in humans) could predispose people to the development of PTSD following trauma. Since direct stimulation of IL inputs in the amygdala do not reduce fear acquisition, the reduced fear acquisition after knocking down IL FKBP5 is likely to be mediated by IL projections to other subcortical structures. The acquisition of conditioned fear requires glucocorticoid and beta adrenergic receptor stimulation in the basolateral amygdala. Therefore, IL could modulate fear learning by modulating glucocorticoid or catecholamine release via inputs to the lateral hypothalamus (LHA), bed nucleus of the stria terminalis (BNST), or nucleus tractus solitarius (NTS). In this project, we will test the novel hypothesis that signaling via Fkpb5 modulates fear learning and memory by modulating the excitability of IL projections to the BNST, LHA, or NTS. To test this hypothesis, we will first evaluate whether reducing or overexpressing FKBP5 selectively in IL projection neurons modulates acquisition or recall of conditioned fear. Next, we will evaluate whether FKBP5 modulates the intrinsic or synaptic excitability of IL neurons projecting to the BNST, LHA, or NTS using patch-clamp recordings of retrogradely labeled IL projections in brain slices. Finally we will use optogenetics to evaluate whether IL inputs to the BNST, LHA, or NTS modulate fear learning and memory.

项目摘要/摘要： 广泛接受的模型提出边缘下皮层（IL）是恐惧的关键结构 消退在恐惧调节中不起任何作用。令人惊讶的是，我们发现选择性地 IL 中 FK506 结合蛋白 5 (FKBP5) 表达的减少减少了获取和回忆 条件性恐惧。尽管临床数据表明 FKBP5 在 PTSD 中发挥作用，但 尚不清楚仅 FKBP5 表达差异是否会导致个体易感或保护个体 从 PTSD 的发展来看。我们的数据表明 FKBP5 在 腹侧内侧前额叶皮层（相当于人类的白介素）可能使人倾向于 创伤后创伤后应激障碍（PTSD）的发展。由于直接刺激杏仁核中的 IL 输入会 不减少恐惧获得，敲除 IL FKBP5 后恐惧获得减少很可能 通过 IL 投射到其他皮层下结构来介导。条件收购 恐惧需要糖皮质激素和基底外侧β肾上腺素能受体刺激 杏仁核。因此，IL可以通过调节糖皮质激素或 儿茶酚胺通过输入到外侧下丘脑 (LHA)、纹状体床核释放 终末肌 (BNST) 或孤束核 (NTS)。在这个项目中，我们将测试小说 假设通过 Fkpb5 发出的信号通过调节恐惧学习和记忆 IL 对 BNST、LHA 或 NTS 的预测的兴奋性。为了检验这个假设，我们首先 评估是否在 IL 投射神经元中选择性减少或过度表达 FKBP5 调节条件性恐惧的获得或回忆。接下来我们来评估一下FKBP5是否 调节投射到 BNST、LHA 或 的 IL 神经元的内在或突触兴奋性 NTS 使用膜片钳记录脑切片中逆行标记的 IL 投影。最后 我们将使用光遗传学来评估 IL 输入到 BNST、LHA 或 NTS 是否可以调节恐惧 学习和记忆。