Long non-coding enhancer RNA controls stress-induced changes in reward-related behaviors

长非编码增强子RNA控制应激引起的奖励相关行为的变化

基本信息

批准号：
10659424
负责人：
Makoto Taniguchi
金额：
$ 37.75万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659424
关键词：
3-Dimensional Address Behavior Biological Assay Brain Chromatin Loop Chronic Chronic stress Clustered Regularly Interspaced Short Palindromic Repeats Code DNA Data Dendritic Spines Dependovirus Enhancers Epigenetic Process Female Functional disorder Gene Expression Gene Expression Process Gene Expression Regulation Gene Mutation Genes Genetic Transcription Goals Human Genome Hybrids Image In Vitro Individual Knowledge Link Measures Medial Mediating Messenger RNA Minor Modeling Molecular Morphology Mus NPAS4 gene Neurons Nucleus Accumbens Pathologic Physiological Prefrontal Cortex Proteins Psychiatry Psychosocial Stress RNA Regulation Research Rewards Role Self Administration Stress Structure Sucrose Synapses Synaptic Transmission Synaptic plasticity Transcription Initiation Site Untranslated RNA behavioral plasticity chromatin immunoprecipitation chromosome conformation capture density excitatory neuron experience experimental study expression vector hippocampal pyramidal neuron innovation insight knock-down male mammalian genome neural circuit neuropsychiatry neurotransmission novel overexpression patch clamp preference psychological stressor psychosocial stressors recruit response rodent genome small hairpin RNA social defeat transcription factor transmission process vector

项目摘要

Project Summary/Abstract Chronic stress alters reward-related behavior and this is accompanied by changes in neural circuit function, especially that involving the medial prefrontal cortex (mPFC). However, the molecular mechanisms controlling circuit dysfunction and its effect on associated behaviors remain poorly understood. The Npas4 gene encodes the Neuronal PAS domain protein 4 (NPAS4) transcription factor that functions as a homeostatic regulator of excitatory and inhibitory synaptic connections in response to changes in synaptic activity. Our preliminary findings in mice show that aversive stress experience trigger the transient induction of NPAS4 expression in mPFC and that this is required for chronic social defeat stress (CSDS)-induced reward-related behavior deficit. Furthermore, these studies show that NPAS4 is required for CSDS-induced reduction of mPFC pyramidal neuron excitatory transmission and dendritic spine density. Interestingly, while protein-coding genes (mRNA) are obviously important for functional regulation of brain activity, human and rodent genomes encode a much larger number of long non-coding RNAs (lncRNAs). Emerging evidence demonstrates significant roles for lncRNAs in gene expression, but the physiological and pathological functions of individual lncRNAs are only beginning to be explored. To address this knowledge gap, we will study a novel, non-annotated, lnc-enhancer RNA (lnc-eRNA) transcribed from the enhancer region of Npas4 (Npas4eRNA). We found that Npas4eRNA is required for Npas4mRNA expression and for CSDS-induced deficits in sucrose preference. Npas4eRNA forms an DNA:RNA hybrid R-loop structure that is required for Npas4mRNA expression. We hypothesize that the Npas4eRNA and its R-loop structure directly link the enhancer-associated transcriptional machinery with the Npas4 transcription start site via 3D chromatin loop structure. In this proposal, we will combine innovative molecular and cellular approaches with ethologically relevant models of psychosocial and psychological stressors in both male and female mice and examine the function of Npas4eRNA and R-loop in the PFC for the stress-induced epigenetic gene regulation, functional and morphological synaptic plasticity, and alterations in reward-related behaviors.

项目概要/摘要慢性压力会改变与奖励相关的行为，并且伴随着神经的变化电路功能，特别是涉及内侧前额叶皮层（mPFC）的电路功能。然而，控制回路功能障碍的分子机制及其对相关行为的影响仍然知之甚少。 Npas4 基因编码神经元 PAS 结构域蛋白 4 (NPAS4) 转录因子作为兴奋性和抑制性突触连接的稳态调节器对突触活动变化的反应。我们对小鼠的初步研究结果表明，厌恶压力经历触发 mPFC 中 NPAS4 表达的短暂诱导，这是慢性社会失败压力（CSDS）引起的奖励相关行为缺陷所需的。此外，这些研究表明 NPAS4 是 CSDS 诱导的 mPFC 减少所必需的锥体神经元兴奋性传递和树突棘密度。有趣的是，虽然蛋白质编码基因（mRNA）对于功能性显然很重要大脑活动的调节，人类和啮齿动物基因组编码大量长链非编码 RNA (lncRNA)。新的证据表明 lncRNA 在基因表达，但单个lncRNA的生理和病理功能仅开始被探索。为了解决这一知识差距，我们将研究一种新颖的、无注释的、 lnc-增强子 RNA (lnc-eRNA) 从 Npas4 (Npas4eRNA) 增强子区域转录而来。我们发现 Npas4eRNA 是 Npas4mRNA 表达和 CSDS 诱导的缺陷所必需的蔗糖偏好。 Npas4eRNA 形成 DNA:RNA 混合 R 环结构，这是 Npas4mRNA 表达。我们假设 Npas4eRNA 及其 R 环结构直接连接通过 3D 观察增强子相关转录机制与 Npas4 转录起始位点染色质环结构。在这项提案中，我们将结合创新的分子和细胞方法男性和女性心理社会和心理应激源的行为学相关模型雌性小鼠并检查 Npas4eRNA 和 R 环在 PFC 中对应激诱导的功能表观遗传基因调控、功能和形态突触可塑性以及突触的改变与奖励相关的行为。