Developmental origin of serotonin dysfunction in cortical map disruption

皮质图破坏中血清素功能障碍的发育起源

• 批准号: 8965243
• 负责人: JI Y SZE
• 金额: $ 44.63万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965243
• 关键词: Adult; Afferent Neurons; Anxiety; Architecture; Autistic Disorder; Axon; Behavior; Behavioral; Brain; Brain Stem; Brain region; Contralateral; Depression and Suicide; Development; Elderly; Emotions; Etiology; Extracellular Space; Fright; Functional disorder; Gene Expression; Genetic; Genetic Polymorphism; Genetic Programming; Glutamates; Goals; Hippocampus (Brain); Lead; Life; Maps; Mental Depression; Mental disorders; Molecular; Mus; Mutant Strains Mice; Mutation; Neurons; Pathway interactions; Pattern; Play; Prefrontal Cortex; Presynaptic Terminals; Prevention; Process; Psychiatric therapeutic procedure; Risk; Role; Selective Serotonin Reuptake Inhibitor; Sensory; Serotonin; Shapes; Signal Transduction; Site; Synapses; Testing; Time; barrel cortex; cortex mapping; extracellular; hippocampal pyramidal neuron; mouse model; neural circuit; neuronal patterning; novel; postsynaptic; programs; public health relevance; receptor; research study; sensory cortex; serotonin transporter; spatiotemporal; synaptogenesis; theories; trait; uptake

 DESCRIPTION (provided by applicant): Dysregulation of serotonin (5-HT) signaling underscores the long-standing theory of circuit perturbations that lead to risks for mental disorders. 5-HT transporter SERT is a critical regulator of 5-HT signaling by limiting 5-HT availability at 5-HT receptors. SERT antagonists (e.g. SSRIs) are the first-line treatments for psychiatric traits. However, polymorphisms that reduce SERT gene expression/functionality are found to be associated with autism, depression, and increased anxiety, and confer structural and functional alterations in brain regions involved in emotion processing. The majority studies of SERT mechanisms focus on brainstem raphe neurons, which produce 5-HT and constitutively express SERT. We recently uncovered previously unknown differences between SERT mechanisms in developing and mature brain. Specifically, we identified a SERT function operating in a distinctly different set of neurons in defined brain regions during a specific time period of cortical maturation. In mice between E17 - P10, SERT is transiently expressed in glutamatergic thalamocortical axons (TCAs) projecting all the sensory cortices and in pyramidal neurons in the PFC and hippocampus. These neurons do not synthesize 5-HT but uptake extracellular 5-HT, termed "5-HT-absorbing neurons". To identify the role of SERT in 5-HT-absorbing neurons, we generated mutant mice with SERT expression disrupted in glutamatergic TCAs (SERTGluΔ), or in pyramidal neurons in the cortex (SERTCortexΔ), or in raphe 5-HT-producing neurons (SERTRapheΔ). Studies of SERTGluΔ and SERTRapheΔ mice revealed that SERT in 5-HT-absorbing TCAs, not SERT in raphe afferents, is a determinant of columnar patterning and dendritic architecture of the sensory cortex. We hypothesize that SERT expressed in 5-HT-absorbing axons regulates trophic 5-HT signals during circuit establishment, whereas SERT in raphe neuron axons assumes a critical role in regulating synaptic 5-HT in the mature cortex. We propose systematic genetic, anatomical and behavioral experiments investigating how spatiotemporal SERT expression in 5-HT-absorbing axons and SERT in raphe neuron afferents play out to influence cyto- and synapto-architecture in developing and mature cortex and behavior. We anticipate that altered developmental SERT mechanism is likely to define the origins of malfunction of the neural circuits that drive certaub features of te mental disorders, and illuminate the fundamental mechanisms of early life programming of behavior. By uncoupling SERT function in the developing and mature CNS, our studies will inform the cellular sites and timing of SERT expression that underscore the risks for developing mental disorders and that contribute to mental disorder treatments.

 描述（通过应用程序提供）：血清素（5-HT）信号传导的失调强调了导致精神疾病风险的回路扰动理论。 5-HT转运蛋白SERT是通过限制5-HT接收器的5-HT可用性的5-HT信号传导的关键调节器。 SERT拮抗剂（例如SSRI）是精神病特征的一线治疗方法。但是，发现降低SERT基因表达/功能的多态性与自闭症，抑郁和焦虑增加有关，以及与情绪处理有关的大脑区域的会议结构和功能改变。 SERT机制的多数研究集中于脑干Raphe神经元，该神经元产生5-HT并组成型表达SERT。我们最近发现了发育和成熟大脑中Sert机制之间以前未知的差异。具体而言，我们在特定的皮质成熟时间期间确定了在定义的大脑区域中在明显不同的神经元集中工作的SERT功能。在E17 -P10之间的小鼠中，SERT在谷氨酸能丘脑皮质轴突（TCAS）中瞬时表达，这些轴突（TCAS）投射了所有感觉皮层和PFC和海马室中的金字塔神经元中。这些神经元不能合成5-HT，而是摄取细胞外5-HT，称为“ 5-HT吸收神经元”。 To identify the role of SERT in 5-HT-absorbing neurons, we generated mutant mice with SERT expression disrupted in glutamatergic TCAs (SERTGluΔ), or in pyramidal neurons in the cortex (SERTCortexΔ), or in raphe 5-HT-producing neurons (SERTRApheΔ).对SertgluΔ和串联螺旋δ小鼠的研究表明，在5-HT吸收的TCA中，不是Raphe传入中的sert，而不是sert，我们确定了柱状，我们假设在5-HT吸收轴突中表达的Sert表达在5-HT吸收的轴突中表达的sert在RICTION NEUREN中调节了raphe neuron在RAPHENES中的TROPHIC 5-HT信号。成熟的皮质。我们提出了系统的遗传，解剖学和行为实验，研究了5-HT吸收轴突中的空间时间SERT表达如何在Raphe神经元传入中如何影响在发育和成熟的皮质和行为中影响细胞和突触架构。我们预计，改变的SERT机制可能会定义神经元电路故障的起源，这些神经元电路的起源是驱动TE精神障碍特征的特征，并阐明了行为早期生活编程的基本机制。通过解开发育中心和成熟中枢神经系统中的SERT功能，我们的研究将为SERT表达的细胞部位和时机提供了强调发展精神障碍风险的人，并导致精神障碍治疗。