Longitudinal Imaging of Frontal Cortex Afferents in a Mouse Model of Anxiety

描述（由申请人提供）：改变活动依赖性回路形成的遗传变异可能导致回路发育中的经验依赖性失衡。脑源性神经营养因子（BDNF）是一种参与神经过程发育成熟和细胞存活的神经营养因子。20-30%的高加索人携带BDNF基因的多态性，其中密码子66从缬氨酸改变为甲硫氨酸（Shimizu et al.，2004），这是一种改变BDNF活性调节释放的变化（Chen et al.，2006年）。BDNF val 66 met多态性与焦虑和抑郁有关（尽管并非没有争议），在具有最大量的早期生活压力的人中具有更强的相关性（Gatt等人，2009年）的报告。我们假设，个人拥有脑源性神经营养因子的met 66等位基因有削弱海马旁扣带回的输入和早期生活压力增强杏仁核的输入扣带回。我们假设额叶皮质投射的不平衡会影响情绪体验和行为。在我们的动物模型的这个过程中，（parahippocampal）perirhinal（PRH）扣带传入的发育不足，使增强，竞争性发展的基底外侧杏仁核（BLA）扣带传入导致异常的优势，在额叶回路中的动作选择和认知控制的伤害回避信息。我们提出了一个PRH：BLA扣带回投影不平衡，与不同的原因，可能是一系列的焦虑和新奇寻求频谱的障碍。我们将检验这样的假设，即表现出增强焦虑的BDNF met 66变体小鼠（Chen等，2006）也表现出向扣带皮层的PRH和BLA输入的不平衡发展。为了追求焦虑的这种推定的内表型，我们将使用突触形成的现有技术水平的纵向体内成像（Aim 1）和光遗传学工具（Aim 2）来探测BDNF val 66 met敲除小鼠中从PRH和BLA到扣带皮层的长距离传入的青少年发育（Chen等人，2006年）。具体措施将包括在体内扣带棘和PRH和BLA扣带转换和密度（目标1），由BLA和PRH传入驱动的兴奋性和抑制性电流的比率扣带，和平均PRH和BLA扣带AMPA：NMDA比率（目标2）。我们还将研究青少年压力和认知训练对PRH和BLA传入的可塑性（目的1）和连接性（目的2）的影响。我们预测，在任务中进行PRH和扣带的认知训练将防止PRH：BLA不平衡的发展，并减少焦虑行为。我们的实验将告知焦虑和伤害回避障碍的发展病因学的理解，提供一个可以转移到人类研究的内在表型，并测试认知疗法的形式，以重新平衡电路的发展。7.过度焦虑或其相反，低伤害避免，可以深刻地破坏人类的生活。在我们的模型中，异常的青少年发展导致输入缺乏平衡，将有关安全和危险的信息传递给额叶皮层，对决策产生不利影响。我们将测试这个模型，以阐明焦虑和伤害回避障碍的发展原因，提供一种可以转移到人类研究的生物学措施，并测试认知疗法的形式，以修复这些回路中的不平衡。

DESCRIPTION (provided by applicant): Genetic variation that alters activity-dependent circuit formation may contribute to an experience-dependent imbalance in circuit development. Brain derived neurotrophic factor (BDNF) is a neurotrophic factor involved in developmental maturation of neural processes and cell survival. 20-30% of Caucasians carry a polymorphism in the BDNF gene, where codon 66 is altered from a valine to methionine (Shimizu et al., 2004), a change which has been shown to alter activity regulated release of BDNF (Chen et al., 2006). The BDNF val66met polymorphism has been linked to anxiety and depression (although not without controversy), with stronger correlation in persons who have had the greatest amount of early life stress (Gatt et al., 2009). We hypothesize that individuals possessing the met66 allele of BDNF have weakened parahippocampal inputs to the cingulated and that early life stress enhances amygdala inputs to the cingulated. We hypothesize an imbalance in projections to the frontal cortex biases emotional experience and behaviors. In our animal model of this process, underdevelopment of the (parahippocampal) perirhinal (PRH) cingulated afferents enable enhanced, competitive development of the basolateral amygdala (BLA) cingulated afferents leading to abnormal dominance of harm avoidance information in frontal circuits involved in action selection and cognitive control. We propose a PRH:BLA cingulated projection imbalance, with diverse causes, may underlie a range of disorders in the spectrum of anxiety and novelty seeking. We will test the hypothesis that BDNF met66 variant mice which show enhance anxiety (Chen et al. 2006) also show unbalanced development of PRH and BLA inputs to the cingulated cortex. To pursue this putative endophenotype of anxiety, we will use state of the art longitudinal in vivo imaging of synapse formation (Aim 1) and optogenetic tools (Aim 2) to probe the adolescent development of long range afferents from the PRH and BLA to the cingulated cortex in BDNF val66met knocking mice (Chen et al., 2006). Specific measures will include in vivo cingulated spine and PRH and BLA bouton turnover and density (Aim 1), the ratio of excitatory and inhibitory currents driven by the BLA and PRH afferents in the cingulated, and the average PRH- and BLA-cingulated AMPA:NMDA ratio (Aim 2). We will also investigate the effects adolescent stress and cognitive training on plasticity (Aim 1) and connectivity (Aim 2) of PRH and BLA afferents. We predict that cognitive training in tasks that engage the PRH and the cingulated together will protect against the development of PRH:BLA imbalance and reduce anxiety behavior. Our experiments will inform understanding of the developmental etiology of disorders of anxiety and harm avoidance, provide an endophenotype that may be transferred to human studies, and test forms of cognitive therapy to rebalance circuit development. 7. Project Narrative Excess anxiety or its opposite, low harm avoidance, can profoundly disrupt human lives. In our model, abnormal juvenile development leads to a lack of balance in inputs that relay information about safety and danger to the frontal cortex adversely affecting decision making. We will test this model to illuminate the developmental causes of disorders of anxiety and harm avoidance, provide a biological measure that can be transferred to human studies, and test forms of cognitive therapy to repair an imbalance in these circuits.