Mechanisms of developmental regulation of affective behaviors

描述（由申请人提供）：青春期是人类焦虑症发生高峰的发育阶段，据估计，近75%患有恐惧相关疾病的成年人符合儿童和青少年的诊断标准。然而，在这个敏感的发展窗口期，情绪障碍的脆弱性增加的神经生物学基础在很大程度上是未知的。鉴于恐惧消退在青少年期焦虑行为的调节和抑制中的重要作用，本研究旨在探讨小鼠恐惧消退的发育调节机制。我们最近已经证明，在青春期减少的恐惧灭绝涉及特定的赤字内侧前额叶皮层（mPFC）的可塑性。由于皮质γ-氨基丁酸（GABA）能系统经历了一个漫长的发展，我们假设，在青春期增加突触抑制导致这种可塑性缺陷。利用我们非常成功的多学科合作方法，我们将通过以下方式测试这一假设：1）在青春期前、青春期和成年小鼠的mPFC锥体神经元中研究来自小清蛋白阳性篮状细胞（皮质中抑制的主要来源）的GABA能突触传递，2）在mPFC中建立参与恐惧消退的发育调节的内在和突触机制，研究mPFC中脑源性神经营养因子（BDNF）信号的增强是否以及如何恢复青春期的恐惧消退。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要见解，这些机制使青少年的大脑非常容易受到情感挑战的影响。此外，我们的研究可能为焦虑症的创新治疗和预防策略提供指导。

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.