Dopamine modulation of network activity in the prefrontal cortex.

多巴胺调节前额皮质网络活动。

• 批准号: 7369668
• 负责人: SVEN KROENER
• 金额: $ 16.02万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-05 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369668
• 关键词: Action Potentials; Acute; Animals; Architecture; Brain; Brain Diseases; Calcium; Cells; Charge; Coculture Techniques; Computer Simulation; Condition; Depth; Dopamine; Dose; Exhibits; Fire - disasters; Functional disorder; Hippocampus (Brain); Image; In Vitro; Information Networks; Investigation; Knowledge; Maintenance; Measures; Membrane; Memory; Mental disorders; Monitor; N-Methylaspartate; Neuromodulator; Neurons; Performance; Prefrontal Cortex; Preparation; Primates; Property; Range; Rattus; Recurrence; Resolution; Rodent; Scanning; Schizophrenia; Sensory; Serotonin; Short-Term Memory; Slice; Source; Study models; Symptoms; Synapses; Synaptic Transmission; Testing; Thinking; Ventral Tegmental Area; awake; base; cell assembly; cognitive function; extracellular; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vivo; insight; memory process; nerve supply; research study; voltage clamp

DESCRIPTION (provided by applicant): Cortical activity in the intact brain is characterized by intermittent sustained membrane depolarizations called "up-states". The task-specific computations of a given cortical region are superimposed on top of this heightened activity. In the case of the prefrontal cortex (PFC), recurrent excitation of deep layer neurons is thought to underlie sustained activity during working memory. Dopamine (DA) modulates working memory, however, it has not been feasible to investigate its detailed biophysical effects in the awake animal. Instead, most of our knowledge about dopamine's effects on membrane excitability or synaptic transmission derives from recordings in "quiet" acute brain slice preparations. However, up-states and sustained activity are a network phenomenon and the asynchronous firing that occurs across neurons results from the interplay between intrinsic excitability and recurrent synaptic transmission. The present proposal investigates DA modulation of active cortex using an organotypic co-culture preparation of the PFC, hippocampus and ventral tegmental area (VTA). These cultures exhibit sustained activity (up-states) and possess key inputs required for working memory, namely the hippocampus and the DA input from the VTA. The present proposal tests two hypotheses generated from in vitro brain slice preparations and computational modeling studies. The first hypothesis posits that sustained activity during up-states can be modulated by DA in a dose-dependent manner. Experiments in Specific Aim 1 will use whole-cell current clamp recordings to test whether there is an "optimal" range of DA modulation in which action-potential firing and up-state duration are enhanced, while outside of this optimal range sustained activity will be reduced. Control experiments will assess the contribution of tonic vs. phasic release of DA from the VTA, and will test whether DA has network specific effects. The concentration of DA in the slice will be monitored simultaneously via fast-scan cyclic voltammetry. The second hypothesis states that DA acts on GABA and NMDA currents to modulate persistent activity during up-states. Combined voltage-clamp and calcium imaging experiments will be used to measure the modulation of GABA and NMDA currents by a high dose or low dose of DA, respectively. These studies will provide insights into the architecture of sustained activity and DA modulation of active PFC networks; information critical for our understanding of the normal and pathological conditions of the PFC.

描述（由申请人提供）：完整大脑中的皮质活动的特征是间歇性持续的膜去极化，称为“上状态”。给定皮质区域的特定于任务的计算叠加在这种增强的活动之上。就前额皮质（PFC）而言，深层神经元的反复兴奋被认为是工作记忆期间持续活动的基础。多巴胺（DA）调节工作记忆，然而，在清醒动物中研究其详细的生物物理效应尚不可行。相反，我们关于多巴胺对膜兴奋性或突触传递的影响的大部分知识都来自于“安静”的急性脑切片制剂的记录。然而，上态和持续活动是一种网络现象，神经元之间发生的异步放电是内在兴奋性和反复突触传递之间相互作用的结果。本提案利用 PFC、海马体和腹侧被盖区 (VTA) 的器官型共培养制剂来研究 DA 对活动皮质的调节。这些文化表现出持续的活动（上态）并拥有工作记忆所需的关键输入，即海马体和来自 VTA 的 DA 输入。本提案测试了体外脑切片制备和计算建模研究产生的两个假设。第一个假设认为，DA 可以以剂量依赖性方式调节上状态期间的持续活动。具体目标 1 中的实验将使用全细胞电流钳记录来测试是否存在 DA 调制的“最佳”范围，其中动作电位放电和上态持续时间增强，而在该最佳范围之外，持续活动将受到影响。减少。对照实验将评估 VTA 中 DA 的强直性与阶段性释放的贡献，并测试 DA 是否具有网络特定效应。通过快速扫描循环伏安法同时监测切片中 DA 的浓度。第二个假设指出，DA 作用于 GABA 和 NMDA 电流，以调节上升状态期间的持续活动。结合电压钳和钙成像实验将分别用于测量高剂量或低剂量 DA 对 GABA 和 NMDA 电流的调节。这些研究将为主动 PFC 网络的持续活动和 DA 调制的架构提供见解；对于我们了解 PFC 的正常和病理状况至关重要的信息。