Serotonin and the Modulation of Brain Development

描述(申请人提供)：在生命早期，5-羟色胺起到调节神经发育过程的作用。因此，改变5-羟色胺信号的遗传和环境因素会影响大脑的成熟。我们已经确定了一个敏感的发育期(出生后2-11天)，在此期间，升高的5-羟色胺信号会导致小鼠焦虑和抑郁相关行为以及认知障碍的终生增加。我们还发现了与这些行为异常相关的一系列神经变化：内侧前额叶皮质(MPFC)和海马(HC)锥体神经元的树突形态改变，mPFC神经元的兴奋性改变，对中缝背侧5-羟色胺能神经元的抑制驱动增加，以及5-羟色胺神经元的轴突树枝减少。在这里，我们的目的是进一步了解发育中5-羟色胺信号的增加所引起的后果，重点是mPFC功能，并测试它们与情绪行为的因果关系。这一实验选择是基于mPFC在焦虑和抑郁障碍中的重要性。例如，在抑郁状态下，膝下皮层通常处于过度激活状态--这种情况被成功的治疗逆转，包括大脑深部刺激。MPFC和杏仁核之间的功能连接与伤害避免分数呈负相关。在啮齿动物中，mPFC-杏仁核回路控制获得性恐惧的消退，而腹侧海马区-mPFC theta活动的一致性与焦虑状态相关。最后，我们显示(见初步数据)，损伤的下缘皮质(IL，一个mPFC亚区)表现出焦虑相关的行为，是由发育中的5-羟色胺信号增加引起的。综上所述，这些发现证明了mPFC及其参与HC和杏仁核调节抑郁和焦虑状态的回路的关键参与。我们的建议解决了最重要的假设，即在敏感的发育时期增加5-羟色胺信号会永久性地改变mPFC-调节情绪和认知过程的电路。在Aim1中，我们研究了发育中的5-羟色胺信号对mPFC锥体神经元膜电特性及其与HC和杏仁核功能连接的影响。这些数据将为AIM2的因果关系测试实验奠定基础，在AIM2中，我们应用光遗传和药物遗传学工具来直接或通过来自HC和杏仁核的传入调节IL和/或PL锥体神经元的活动。在Aim3中，我们试图确定5-羟色胺受体介导5-羟色胺信号增加对mPFC功能的发育影响。总之，目标1-3将影响对人类抑郁/焦虑和mPFC活性改变的神经精神障碍风险因素的理解。我们的初步数据表明，遗传或环境因素单独或共同作用，在发育过程中增加5-羟色胺信号，构成mPFC功能障碍的危险因素。再加上我们将提供的机械洞察力，我们的数据可能会改进精神病学的诊断、预防和治疗策略。

DESCRIPTION (provided by applicant): During early life, serotonin acts to modulate neurodevelopmental processes. Genetic and environmental factors that alter serotonin signaling can therefore impact brain maturation. We have identified a sensitive developmental period (postnatal day 2-11) during which elevated serotonin signaling elicits life-long increases in anxiety and depression-related behaviors as well as cognitive impairments in mice. We also identified an array of neural changes associated with these behavioral abnormalities: altered dendritic morphology of medial prefrontal cortex (mPFC) and hippocampal (HC) pyramidal neurons, altered excitability of mPFC neurons, increased inhibitory drive to 5-HTergic neurons of the dorsal raphe, and diminished axonal arborization of 5-HT neurons. Here we aim at furthering our knowledge of consequences elicited by increased developmental 5-HT signaling, focusing on mPFC function and testing their causal relationship with emotional behavior. This experimental choice is based on the importance of the mPFC in disorders of anxiety and depression. For example, the subgenual cortex is typically hyperactivated in depressive states - a condition reversed by successful treatment, including deep brain stimulation. Functional connectivity between the mPFC and the amygdala is inversely correlated with harm avoidance scores. In rodents, mPFC-amygdala circuits control extinction of learned fear and ventral hippocampal-mPFC theta activity coherence correlates with anxiety states. Lastly, we show (see preliminary data) that lesions of the infralimbic cortex (IL, an mPFC sub-region) phenocopy anxiety-related behaviors elicited by increased developmental 5-HT signaling. Taken together, these findings demonstrate a critical involvement of the mPFC and its circuitry engaging the HC and the amygdala in the modulation of depressive and anxiety states. Our proposal addresses the overarching hypothesis that increased 5-HT signaling during a sensitive developmental period permanently alters mPFC-circuitry that modulates emotional and cognitive processes. In Aim1 we study the effect of developmental 5-HT signaling on membrane electrical properties of mPFC pyramidal neurons and their functional connectivity with the HC and amygdala. These data will set the stage for causality-testing experiments in Aim2, where we apply optogenetic and pharmacogenetic tools to modulate the activity of IL and/or PL pyramidal neurons directly or through afferents from the HC and amygdala. In Aim3 we seek to identify 5-HT receptors mediating the developmental effects of increased 5-HT signaling on mPFC function. Together, Aims1-3 will impact the understanding of human risk factors for depression/anxiety and neuropsychiatric disorders with altered mPFC activity. Our preliminary data suggest that genetic or environmental factors, which act alone or in concert to increase 5-HT signaling during development, constitute risk factors for mPFC dysfunction. Together with the mechanistic insight we will provide, our data could lead to improved diagnosis, prevention and treatment strategies in psychiatry.