Serotonin and the Modulation of Brain Development

描述（由申请人提供）：在生命早期，5-羟色胺调节神经发育过程。因此，改变血清素信号的遗传和环境因素会影响大脑成熟。我们已经确定了一个敏感的发育期（出生后第2-11天），在此期间，血清素信号的升高会导致小鼠焦虑和抑郁相关行为以及认知障碍的终身增加。我们还确定了一系列与这些行为异常相关的神经变化：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，中缝背核5-HT能神经元的抑制驱动增加，5-HT神经元的轴突分支减少。在这里，我们的目标是进一步了解的后果引起的发展5-HT信号，专注于mPFC功能和测试其因果关系与情绪行为。这个实验选择是基于mPFC在焦虑和抑郁障碍中的重要性。例如，在抑郁状态下，膝下皮层通常会过度激活--这种情况可以通过成功的治疗（包括脑深部电刺激）逆转。mPFC和杏仁核之间的功能连接与伤害回避分数呈负相关。在啮齿动物中，mPFC-杏仁核回路控制学习恐惧的消退，腹侧前额叶皮层-mPFC θ活动的一致性与焦虑状态相关。最后，我们表明（见初步数据），病灶的边缘下皮层（IL，一个mPFC子区域）表型焦虑相关的行为引起的增加发展5-HT信号。两者合计，这些研究结果表明，关键参与的mPFC及其电路从事HC和杏仁核的抑郁和焦虑状态的调制。 我们的建议解决了总体假设，增加5-HT信号在敏感的发展时期永久改变mPFC电路，调节情绪和认知过程。在Aim 1中，我们研究了发育中5-HT信号对mPFC锥体神经元膜电特性及其与HC和杏仁核的功能连接的影响。这些数据将为Aim 2中的空隙率测试实验奠定基础，在Aim 2中，我们应用光遗传学和药物遗传学工具直接或通过HC和杏仁核的传入来调节IL和/或PL锥体神经元的活性。在Aim 3中，我们试图确定5-HT受体介导的mPFC功能的5-HT信号增加的发育影响。总之，AIMS 1 -3将影响对抑郁/焦虑和神经精神疾病的人类风险因素的理解，并改变mPFC活性。我们的初步数据表明，遗传或环境因素，单独或共同作用，以增加5-HT信号在发展过程中，构成mPFC功能障碍的危险因素。再加上我们将提供的机制见解，我们的数据可能会导致精神病学的诊断，预防和治疗策略的改进。

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.