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（由申请人提供）：5-羟色胺（5-HT）信号传导失调强调了长期存在的回路扰动理论，该理论导致精神障碍的风险。5-HT转运蛋白SERT通过限制5-HT受体的5-HT可用性来调节5-HT信号传导。SERT拮抗剂（例如SSRIs）是精神病特征的一线治疗。然而，减少SERT基因表达/功能的多态性被发现与自闭症，抑郁症和焦虑增加有关，并赋予参与情绪处理的大脑区域结构和功能改变。对SERT机制的研究主要集中在产生5-HT并组成性表达SERT的脑干中缝神经元。我们最近发现了SERT机制在发育和成熟大脑中的差异。具体来说，我们确定了一个SERT功能在一个明确的不同的一组神经元在大脑皮层成熟的特定时间段内，在定义的大脑区域。在E17 - P10之间的小鼠中，SERT在投射所有感觉皮质的丘脑能丘脑皮质轴突（TCA）中以及PFC和海马中的锥体神经元中瞬时表达。这些神经元不合成5-HT，但摄取细胞外5-HT，称为“5-HT吸收神经元”。为了确定SERT在5-HT吸收神经元中的作用，我们产生了突变小鼠，其SERT表达在谷氨酸能TCA（SERTGluΔ）或皮质锥体神经元（SERTCortexΔ）或中缝5-HT产生神经元（SERTRapheΔ）中被破坏。对SERTGluΔ和SERTRapheΔ小鼠的研究表明，5-HT吸收TCA中的SERT，而不是中缝传入神经中的SERT，是感觉皮层的柱状图案和树突结构的决定因素。我们推测，SERT表达在5-HT吸收轴突调节回路建立过程中的营养5-HT信号，而SERT中缝神经元轴突在调节成熟皮层中的突触5-HT中发挥关键作用。我们提出了系统的遗传，解剖和行为实验研究如何时空SERT表达5-HT吸收轴突和SERT中缝神经元传入发挥影响细胞和突触结构的发展和成熟的皮层和行为。我们预计，改变的发展SERT机制可能会定义的神经回路，驱动某些功能的精神障碍的故障的起源，并阐明了行为的早期生活编程的基本机制。通过解偶联SERT在发育和成熟CNS中的功能，我们的研究将告知SERT表达的细胞位点和时间，强调发展精神障碍的风险，并有助于精神障碍的治疗。