Mechanisms of developmental regulation of affective behaviors

情感行为的发育调节机制

• 批准号: 8696228
• 负责人: Ipe Ninan
• 金额: $ 36.61万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-02 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696228
• 关键词: AMPA Receptors; ARHGEF5 gene; Adolescence; Adolescent; Adult; Affect; Affective; American; Anxiety; Anxiety Disorders; Back; Behavior; Behavior Therapy; Biological Models; Brain; Brain-Derived Neurotrophic Factor; Calcium; Child; DNA Sequence Rearrangement; Development; Diagnosis; Diagnostic; Disease; Emotional; Emotional Disturbance; Emotional disorder; Event; Excision; Excitatory Synapse; Exhibits; Extinction (Psychology); Fright; Human; Impairment; Individual; Interneurons; Isoxazoles; Life; Longevity; Medial; Mediating; Mental disorders; Molecular; Molecular Target; Mus; Myoepithelial cell; Neurobiology; Parvalbumins; Patients; Plant Roots; Prevalence; Prevention; Prevention approach; Prevention strategy; Propionic Acids; Proteinase 3; Regulation; Reporting; Research; Rodent; Role; Signal Transduction; Source; Staging; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Therapeutic Intervention; Time; Youth; base; conditioned fear; design; emerging adult; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; innovation; insight; learning extinction; meetings; multidisciplinary; public health relevance; receptor; research study; restoration; synaptic inhibition; transmission process

DESCRIPTION (provided by applicant): Adolescence is a developmental stage when the occurrence of anxiety disorders peaks in humans, and it is estimated that nearly 75 percent of adults with fear-related disorders met diagnostic criteria as children and adolescents. However, the neurobiological basis of increased vulnerability to emotional disturbances during this sensitive window of development is largely unknown. Given the critical role of fear extinction in the regulation of anxiety behaviors and its suppression during adolescence, this study is designed to investigate the mechanism underlying developmental regulation of fear extinction in mice. We have recently demonstrated that the diminished fear extinction during adolescence involves specific deficits in medial prefrontal cortical (mPFC) plasticity. Since the cortical gamma-aminobutyric acid (GABA)ergic system undergoes a protracted development, we hypothesize that an increased synaptic inhibition during adolescence causes this plasticity deficit. Utilizing our highly successful multidisciplinary collaborative approach, we will test thi hypothesis by: 1) investigating GABAergic synaptic transmission from parvalbumin-positive basket cells, the major source of inhibition in the cortex, in the mPFC pyramidal neurons of pre-adolescent, adolescent and adult mice, 2) establishing the intrinsic and synaptic mechanisms in the mPFC that are involved in the developmental regulation of fear extinction, and 3) studying whether and how an enhancement of brain-derived neurotrophic factor (BDNF) signaling in the mPFC restores fear extinction during adolescence. By undertaking this study, we expect to obtain significant insights into synaptic, molecular and intrinsic mechanisms that make the adolescent brain highly vulnerable to emotional challenges. Furthermore, our study might provide directions for innovative treatments and preventive strategies for anxiety disorders.

描述（由申请人提供）：青春期是一个发育阶段，当时人类焦虑症的发生峰值，据估计，与恐惧相关疾病的成年人中有将近75％符合儿童和青少年的诊断标准。但是，在这种敏感的发展窗口中，增加了情绪障碍脆弱性的神经生物学基础是未知的。鉴于恐惧灭绝在焦虑行为的调节及其在青春期的抑制中的关键作用，该研究旨在研究小鼠恐惧灭绝的发育发育调控的基础机制。我们最近证明，青春期恐惧灭绝的减少涉及内侧前额叶皮质（MPFC）可塑性的特定缺陷。由于皮质γ-氨基丁酸（GABA）ERGIC系统经历了持久的发育，因此我们假设青春期突触抑制增加会导致这种可塑性不足。利用我们非常成功的多学科协作方法，我们将通过以下方式测试假设：1）调查来自Parvalbumin阳性阳性篮细胞的GABA能突触传播，这是皮层抑制的主要来源，在皮层中，MPFC的MPFC Pyramidal Neuron在恐惧灭绝的发展调节中，以及3）研究MPFC中脑衍生的神经营养因子（BDNF）信号的增强是否以及如何增强青少年期间的恐惧灭绝。通过进行这项研究，我们希望获得对突触，分子和内在机制的重大见解，这些机制使青少年大脑高度容易受到情感挑战的影响。此外，我们的研究可能为创新治疗和焦虑症的预防策略提供指导。