Developmental regulation of mood states by 5-HT1A heteroreceptors

 描述(由申请人提供)：当前提案的目的是描述一个敏感时期，在这段时期内，情绪的终生设定值被确立。到目前为止的证据表明，在动物模型中，出生后发育过程中5-羟色胺系统的破坏会导致成年动物焦虑和情绪相关行为的改变。在这方面特别相关的一个受体是5-HT1a受体。IF在神经系统中以两种形式存在；作为中缝核内产生5-羟色胺的神经元上的自身受体，在那里它调节5-羟色胺系统的整体音调；作为非5-羟色胺能神经元上的异种受体，在那里它介导对释放的5-羟色胺的反应。最近的数据表明，发育过程中自身受体功能的失调会导致终生焦虑。这项建议研究了5-HT1A异源受体在调节终生情绪设定点中的作用。到目前为止，来自小鼠模型的证据表明，异型受体功能的选择性丧失会导致抑郁症样表型，这种表型是由于小鼠在完全成熟之前受体的破坏。目前的提议验证了一种假设，即在青春期，通过异种受体传递的5-羟色胺信号对于设定对压力和逆境的终生反应非常重要。这一假说将使用转基因和病毒方法进行验证，这些方法依赖于5-HT1A异源受体的可逆敲除，以将其功能定位到特定的时间和特定的结构。除了功能丧失方法外，还将使用使用5-HT1A异源受体选择性激动剂的功能获得方法来测试在敏感期进行短暂治疗以提高终生韧性的可能性。如果成功，这种方法可能会转化为一种有价值的治疗策略，用于患有抑郁症或其他压力相关疾病的高危青少年。

 DESCRIPTION (provided by applicant): The aim of the current proposal is to characterize a sensitive period during which lifelong setpoints for mood are established. Evidence to date suggests that disruption of the serotonin system during post-natal development in animal models results in altered anxiety and mood related behaviors in the full-grown adult animal. One receptor that is particularly relevant in this regard is the 5-HT1A receptor. If exists in two form in the nervous system; as an autoreceptor on the serotonin producing neurons in the raphe nucleus where it regulates the overall tone of the serotonin system, and as a heteroreceptor on non-serotonergic neurons, where it mediates responses to released serotonin. Recent data suggest that dysregulation of autoreceptor function in development leads to lifelong anxiety. This proposal examines the role of 5-HT1A heteroreceptors in mediated lifelong mood setpoints. Evidence to date from mouse models suggests that selective loss of heteroreceptor function leads to a depression-like phenotype, and that this phenotype is due to disruption of the receptors before the mice reach full maturity. The current proposal tests the hypothesis that serotonin signaling through heteroreceptors specifically in adolescence is important for setting lifelong response to stress and adversity. The hypothesis will be tested using transgenic as well as viral approaches that rely on reversible knockouts of the 5-HT1A heteroreceptor to localize their function both to a particular time and a particular structure. In addition to a loss of functon approach, a gain of function approach using a 5-HT1A heteroreceptor selective agonist will be used to test the possibility of using a brief treatment during a sensitive period to increase resilience throughout life. If successful, such an approach could translate into a valuable treatment strategy for youth at high risk for depression or other stress related disorders.