GABAergic inhibition of NMDA-mediated bursting in midbrain dopaminergic neurons

GABA 能抑制 NMDA 介导的中脑多巴胺能神经元爆发

基本信息

批准号：
7908913
负责人：
Collin Jethro Lobb
金额：
$ 1.82万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-14 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7908913
关键词：
Accounting Action Potentials Agonist Basal Ganglia Bathing Behavioral Complement Computer Simulation Conditioned Stimulus Corpus striatum structure Coupled Dendrites Disinhibition Distal Dose Drug Addiction Effectiveness Electrodes Fire - disasters Frequencies Future Generations Globus Pallidus Glutamates In Vitro Learning Location Measures Mediating Midbrain structure Modeling N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurons Parkinson Disease Patch-Clamp Techniques Pattern Pharmacology Phase Preparation Psychological reinforcement Rattus Receptor Activation Research Design Research Personnel Rewards Role Signal Transduction Source Specificity Substantia nigra structure Synapses Testing Thalamic structure base computer studies dopaminergic neuron extracellular feeding gamma-Aminobutyric Acid in vivo insight programs public health relevance receptor research study response simulation

项目摘要

DESCRIPTION (provided by applicant): Midbrain dopaminergic neurons are strongly implicated in Parkinson's disease, drug addiction, and reinforcement learning. Within reinforcement learning, they encode reward prediction error in their firing patterns. They fire bursts of action potentials in response to unexpected rewards or a conditioned stimulus that accurately predicts a future reward. Two plausible models that can account for reward-related responses are the disinhibition and two-signal, seesaw models. Both of these models require that NMDAmediated bursts can be suppressed by activation of post-synaptic GABAA or GABAB receptors. A combination of in vitro and in vivo experiments is proposed here to investigate GABAergic inhibition of bursting in midbrain dopaminergic neurons. NMDA-mediated bursts will be generated via local application of a NMDA agonist in vitro. Inhibition of these bursts by bath and locally applied GABAA or GABAB agonists will be investigated. Bursts will also be generated in vivo via local application of a NMDA agonist. GABAergic afferents will be electrically stimulated and inhibition of bursting by stimulation will be measured. Each proposed experiment also has a complementary computational component which is used to further explore the mechanisms of inhibition and generate predictions which are experimentally testable. GABAA and GABAB receptors will be added to a recent model of dopaminergic neuron bursting. The mechanisms of inhibition of NMDA-mediated bursting by activation of these receptors will be determined. Activation will first be modeled by stepwise changes in channel conductance. Next, we will model receptor activation according to the temporal pattern of synaptic inputs that a dopaminergic neuron receives as an integrated part of the basal ganglia network. Dopaminergic neurons were added to a recent model of the basal ganglia. Network activity evoked by GABAergic afferent activation will be recorded and GABAA or GABAB receptors will be activated according to this input. Inhibition of NMDA-mediated bursting by this network activity will be investigated. PUBLIC HEALTH RELEVANCE: By using a combination of in vitro and in vivo experiments complemented with computational studies, the role of GABAergic receptor activation in burst firing may be better understood. The proposed aims will provide insight into the role of GABA in reward prediction error studies and the afferent sources involved. The proposal would be strengthened by a better explanation of the experimental framework and underlying assumptions that guide the experiments.

描述（由申请人提供）：中脑多巴胺能神经元与帕金森病、药物成瘾和强化学习密切相关。在强化学习中，它们将奖励预测错误编码到其发射模式中。它们会激发动作电位的爆发，以响应意想不到的奖励或准确预测未来奖励的条件刺激。可以解释与奖励相关的反应的两个看似合理的模型是去抑制模型和双信号跷跷板模型。这两种模型都需要通过激活突触后 GABAA 或 GABAB 受体来抑制 NMDA 介导的爆发。本文提出结合体外和体内实验来研究 GABA 能对中脑多巴胺能神经元爆发的抑制。 NMDA 介导的爆发将通过体外局部应用 NMDA 激动剂产生。将研究通过浴和局部应用 GABAA 或 GABAB 激动剂对这些爆发的抑制。还可以通过局部应用 NMDA 激动剂在体内产生爆发。 GABA能传入神经将受到电刺激，并且将测量刺激对爆发的抑制。每个提议的实验还具有补充的计算组件，用于进一步探索抑制机制并生成可通过实验测试的预测。氨基丁酸 GABAB 受体将被添加到最近的多巴胺能神经元爆发模型中。将确定通过激活这些受体来抑制 NMDA 介导的爆发的机制。首先将通过通道电导的逐步变化来模拟激活。接下来，我们将根据多巴胺能神经元作为基底神经节网络的组成部分接收的突触输入的时间模式来模拟受体激活。多巴胺能神经元被添加到最近的基底神经节模型中。由 GABA 能传入激活引起的网络活动将被记录，并且 GABAA 或 GABAB 受体将根据此输入被激活。将研究该网络活动对 NMDA 介导的爆发的抑制。公共健康相关性：通过结合体外和体内实验并辅以计算研究，可以更好地理解 GABA 受体激活在爆发放电中的作用。拟议的目标将深入了解 GABA 在奖励预测误差研究中的作用以及所涉及的传入源。通过更好地解释实验框架和指导实验的基本假设，该提案将得到加强。