Dopaminergic modulation of dentritic excitability

树突兴奋性的多巴胺能调节

• 批准号: 7582592
• 负责人: SRDJAN D ANTIC
• 金额: $ 41.87万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-10 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582592
• 关键词: Action Potentials; Affect; Apical; Area; Autopsy; Brain; Calcium; Calcium Signaling; Calcium ion; Chronic; Clinical Research; Cognition; Cyclic AMP; Data; Decision Making; Dendrites; Dendritic Spines; Disease; Distal; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine Receptor; Dopaminergic Agents; Drug usage; Dyes; Electron Microscope; Emotions; Fiber; Functional disorder; G-Protein-Coupled Receptors; Glass; Glutamates; Health; Human; Impaired cognition; Impairment; In Vitro; Individual; Laboratories; Learning; Location; Mediating; Medical; Membrane; Membrane Potentials; Mental disorders; Microscopic; Molecular; Nature; Neurons; Neurotransmitters; Onset of illness; Optics; Pathway interactions; Patients; Pharmacotherapy; Phase; Physiologic pulse; Physiological; Postsynaptic Membrane; Prefrontal Cortex; Presynaptic Terminals; Preventive; Principal Investigator; Property; Pyramidal Cells; Receptor Activation; Regulation; Role; Schizophrenia; Shapes; Short-Term Memory; Signal Transduction; Site; Staurosporine; Structure; Synapses; System; Therapeutic; Thick; Time; Trees; Triad Acrylic Resin; Work; clinically relevant; depression; experience; gray matter; hippocampal pyramidal neuron; improved; information processing; inhibitor/antagonist; neocortical; neuronal cell body; neurotransmission; postsynaptic; presynaptic; programs; research study; transmission process; voltage

Medical drugs used in treatment of schizophrenia or depression exert their action through the modulation of dopaminergic neurotransmission. The exact mechanism of such therapy is unknown, partly because the normal physiological role of dopamine release in the cortex is also not fully understood. Electron microscope studies, performed postmortem on the brains of people who suffered from schizophrenia, revealed microscopic structural abnormalities that affect the dendrites of cortical pyramidal neurons. Changes in cortical thickness and dendritic ultrastructure, detected postmortem, could be due to a very long (lifetime) duration of the mental illness and/or a very long (chronic) drug therapy. However, recent clinical studies revealed clear changes in grey matter volume in schizophrenic patients at the very onset of the disease; during the transition from pre-psychotic to psychotic phase. What is the causal relation between the efficacy of dopaminergic drugs, and impairment in dendritic structure and function? The answer to this question may lie in the anatomical juxtaposition of the glutamatergic and dopaminergic systems in the frontal part of human brain, responsible for cognition, planning, control of emotions and decision making. In the prefrontal cortex (an area strongly implicated in pathophysiology of schizophrenia) individual dendritic spines are occupied by two presynaptic terminals; one axon terminal that secretes the excitatory transmitter (glutamate), and the other one that secretes modulatory transmitter dopamine. Twenty years after the discovery of direct dopamine synapse onto a cortical pyramidal neuron, the exact functional consequence of dopamine release at the postsynaptic membrane, in distal dendrites, is still unknown. In the laboratory, we are mimicking the arrival of glutamatergic and dopaminergic cortical inputs by combining excitatory synaptic stimulation of individual dendritic branches with local application of dopamine through a glass micropipette. This approach allows precise control of the location of excitatory input in the dendritic tree; precise timing and duration. Local applications of exogenous glutamate and dopamine eliminate presynaptic mechanisms in the interpretation of experimental results. With the help of voltage-sensitive dyes, the effects of dopamine on dendritic membrane potential will be analyzed simultaneously at the synaptic stimulation site, as well as in the neighboring dendrites that are exposed to neither glutamate nor dopamine. The proposed experiments are expected to yield a more complete picture of how local fluctuations in dopamine level can shape integration of signals in individual neurons, and provide impetus for new preventive and therapeutic approaches in treatment of psychiatric disorders associated with dopaminergic dysfunction.

用于治疗精神分裂症或抑郁症的药物通过调节多巴胺能神经传递发挥作用。这种疗法的确切机制尚不清楚，部分原因是皮质中多巴胺释放的正常生理作用也不完全清楚。对精神分裂症患者的大脑进行了尸检后的电子显微镜研究，发现了影响皮质锥体神经元树突的微观结构异常。皮质厚度和树突超微结构的变化， 死后被发现，可能是由于精神疾病持续时间很长(终生)和/或很长时间(慢性)药物治疗。然而，最近的临床研究显示，精神分裂症患者在从精神病前期到精神病阶段的转变过程中，灰质体积在疾病一开始就发生了明显的变化。多巴胺能药物的疗效与树突状细胞结构和功能损害之间的因果关系是什么？这个问题的答案可能在于前额叶内谷氨酸能和多巴胺能系统的解剖并列。 人脑，负责认知、计划、情绪控制和决策。在前额叶皮质(与精神分裂症的病理生理学密切相关的区域)，单个树突棘被两个突触前终末占据；一个轴突终末分泌兴奋性递质(谷氨酸)，另一个分泌调制递质多巴胺。在发现多巴胺直接突触到皮质锥体神经元20年后，在远端树突的突触后膜上释放多巴胺的确切功能后果仍不清楚。在实验室里，我们正在通过结合兴奋性突触刺激个体来模拟谷氨酸和多巴胺能皮质输入的到来。 通过玻璃微吸管局部应用多巴胺的树突状分支。这种方法允许精确控制兴奋性输入在树突树中的位置；精确的计时和持续时间。局部应用外源性谷氨酸和多巴胺消除了解释实验结果的突触前机制。在电压敏感染料的帮助下，将同时分析多巴胺对突触刺激部位以及邻近既不暴露于谷氨酸也不暴露于多巴胺的树突中树突膜电位的影响。这些拟议的实验有望对多巴胺水平的局部波动如何塑造单个神经元中信号的整合产生更完整的图景，并为新的预防和治疗方法提供动力。 与多巴胺能功能障碍相关的精神障碍。