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

描述(由申请人提供)：改变依赖活动的回路形成的遗传变异可能会导致依赖经验的回路发育不平衡。脑源性神经营养因子(BDNF)是一种神经营养因子，参与神经突起发育成熟和细胞存活。20%-30%的高加索人携带BDNF基因的多态，其中密码子66从缬氨酸改变为蛋氨酸(Shimizu等人，2004年)，这一变化已被证明改变了BDNF的活性调节释放(Chen等人，2006年)。BDNF Val66Met基因多态与焦虑和抑郁有关(尽管并非没有争议)，在早期生活压力最大的人中相关性更强(Gatt等人，2009年)。我们假设，拥有脑源性神经营养因子Met66等位基因的个体减弱了对扣带回的副海马区的输入，而早期的生活应激增强了对扣带区的杏仁核的输入。我们假设额叶皮质的投射不平衡会偏向情绪体验和行为。在我们的这一过程的动物模型中，(海马旁)周围扣带(PRH)扣带传入的不发达使基底外侧杏仁核(BLA)扣带传入的竞争发展增强，导致伤害回避信息在参与动作选择和认知控制的额叶回路中异常占优势。我们提出了一种PRH：BLA扣带投影失衡，原因多样，可能是焦虑和寻求新奇的一系列障碍的基础。我们将检验BDNF Met66变异小鼠表现出增强焦虑的假设(Chen等人。2006)也显示了PRH和BLA传入扣带皮质的不平衡发展。为了探索焦虑的这种假定的内在表型，我们将使用最先进的突触形成体内纵向成像(AIM 1)和光遗传学工具(AIM 2)来探索BDNF Val66 Met敲击小鼠从PRH和BLA到扣带皮质的远程传入的青少年发育(Chen等，2006)。具体措施将包括体内扣带回和PRH和BLA的周转和密度(目标1)，被扣带区BLA和PRH传入所驱动的兴奋电流和抑制电流的比率，以及平均PRH和BLA扣带AMPA/NMDA的比率(目标2)。我们还将研究青春期应激和认知训练对PRH和BLA传入的可塑性(目标1)和连接性(目标2)的影响。我们预测，在让PRH和被扣带区一起参与的任务中进行认知训练将防止PRH：BLA失衡的发展，并减少焦虑行为。我们的实验将有助于了解焦虑和伤害避免障碍的发育病因学，提供可转移到人类研究的内部表型，并测试认知治疗的形式，以重新平衡电路发育。7.项目叙事过度焦虑或其反面，低伤害避免，可能会深刻扰乱人类生活。在我们的模型中，异常的青少年发育导致输入缺乏平衡，这些输入将有关安全和危险的信息传递到额叶皮质，对决策产生不利影响。我们将测试这个模型，以阐明焦虑和伤害避免障碍的发育原因，提供一种可以转移到人类研究中的生物学措施，并测试认知疗法的形式，以修复这些回路中的失衡。

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.