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.
Anxiety disorders are one of the most prevalent psychiatric disorders affecting the youth today. An in-depth analysis of the developmental regulation of fear behaviors will be undertaken to identify appropriate time windows and molecular targets that will facilitate innovative approaches for the prevention and treatment of anxiety disorders.