Identifying the Role of Serotonergic Signaling in the Maturation ofDendritic Spines

确定血清素信号在树突棘成熟中的作用

• 批准号: 10613909
• 负责人: Roberto Ogelman
• 金额: $ 3.72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613909
• 关键词: Acute; Adult; Affect; Bathing; Behavioral; Brain; Brain Diseases; Brain region; Cerebral cortex; Clinical Research; Cognition Disorders; Cognitive; Cognitive deficits; Color; Communication; Complex; Data; Decision Making; Dendritic Spines; Denervation; Development; Disease; Electrophysiology (science); Etiology; Excitatory Synapse; Fluorescence Resonance Energy Transfer; Frequencies; Functional disorder; Glutamates; Human; Image; Imaging Techniques; Impairment; Individual; Knowledge; Life; Link; Long-Term Potentiation; Mediating; Molecular; Mus; Neuromodulator; Neurons; Neurotransmitters; Oral Administration; Pathology; Pharmacology; Play; Prefrontal Cortex; Receptor Activation; Research; Rodent; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT2A; Signal Transduction; Signaling Molecule; Slice; Social Behavior; Synapses; Techniques; Testing; Time; Vertebral column; autism spectrum disorder; cognitive disability; cognitive function; density; design; developmental disease; experimental study; fluorescence lifetime imaging; hippocampal pyramidal neuron; insight; nerve supply; neural circuit; neurochemistry; neuron development; neuronal circuitry; novel; optogenetics; pharmacologic; postnatal development; postnatal period; postsynaptic; prenatal; serotonergic regulation; serotonin 7 receptor; survivorship; tool; two-photon

PROJECT SUMMARY Functional brain development requires the precise coordination of neurochemicals that allow neurons to form synapses and communicate with one another. Improper synaptic maturation during critical developmental time windows often lead to cognitive disabilities, such as those observed in autism spectrum disorders, that can persist into adulthood. Studies in humans and rodents have linked disbalances of serotonin (5-HT) during prenatal and early postnatal development to increased rates of behavioral and cognitive deficits and irregular neuronal development. The prefrontal cortex (PFC) is a region of the brain that plays a key role in processing higher order cognitive functions that are disrupted when 5-HT levels are altered. During early PFC development, circuit formation is dependent on the functional maturation and stabilization of excitatory synapses, located on dendritic spines. Our preliminary studies identified a critical role for 5-HT in the development of dendritic spines within the PFC, indicating that both spine density and size are directly altered after manipulating 5-HT levels in early postnatal periods. This proposal is comprised of two aims which seek to test the hypothesis that 5-HT can potentiate and stabilize dendritic spines at a single synapse level. The first aim uses a combination of techniques including two-color, two-photon uncaging of 5-HT and glutamate neurotransmitters, electrophysiology, optogenetics, and pharmacology to determine whether 5-HT can induce functional long-term potentiation of individual dendritic spines. The second aim is designed to identify whether endogenous 5-HT signaling can stabilize nascent dendritic spines, which will be investigated by using optogenetics, two-photon 5-HT uncaging and mechanistic studies that include pharmacological approaches and fluorescence lifetime imaging. Together, these studies seek to establish the role of 5-HT dependent signaling in synapse maturation and stabilization at a cellular and molecular level. Results from this project will be essential knowledge towards better mitigating the cognitive disabilities that result from early 5-HT disbalances in the developing brain.

项目总结