Dopamine Regulation During Context Processing

上下文处理过程中的多巴胺调节

• 批准号: 7652879
• 负责人: SHERI J. Y. MIZUMORI
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2009-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652879
• 关键词: Adaptive Behaviors; Affect; Animals; Area; Attention; Basal Ganglia; Behavior; Behavior Control; Behavioral; Brain; Cell Nucleus; Cells; Code; Cognition; Collaborations; Condition; Consensus; Corpus striatum structure; Cues; Decision Making; Dependency; Development; Disease; Dopamine; Dorsal; Evaluation; Exhibits; FOS gene; Figs - dietary; Fire - disasters; Frequencies; GABA Agonists; Generations; Genetically Engineered Mouse; Glutamates; Goals; Grant; Head; Hippocampus (Brain); Laboratories; Lateral; Lateral Dorsal Nucleus; Learning; Location; Mediating; Memory; Midbrain structure; Modeling; Movement; Mus; Muscimol; N-Methylaspartate; NR1 gene; Nature; Neuromodulator; Neurons; Outcome; Output; Pathway interactions; Pattern; Performance; Personal Satisfaction; Play; Prefrontal Cortex; Primates; Process; Property; Psychological reinforcement; Rattus; Regulation; Relative (related person); Reporting; Rewards; Rodent; Role; Sensory; Short-Term Memory; Signal Transduction; Sorting - Cell Movement; Source; Specificity; Structure; Substantia nigra structure; System; Task Performances; Tegmentum Mesencephali; Testing; Therapeutic; Thinking; Time; Ventral Tegmental Area; Work; base; cognitive function; density; dopamine system; dopaminergic neuron; drug relapse; expectation; experience; genetic analysis; human NR1 protein; insight; interest; neural circuit; neurobehavioral; normal aging; pars compacta; prospective; receptor; relating to nervous system; response; sensory gating; sensory stimulus; theories

A prominent theory argues that DA cells generate predictive signals for impending reward and/or they signal when reinforcement contingencies change. It is argued here that by taking a more dynamic and broad systems view of DA¿s contribution to cognition, we can better understand the significance of DA function; we need to consider not only how DA regulates plasticity in efferent structures, but also how DA neurons themselves are regulated by experience. Studies from the last grant period provide compelling evidence that DA function is context-dependent. The present proposal includes four Specific Aims that will allow us to test the hypothesis that context regulation of DA neuronal signaling of reward information is derived from a combination of inputs from existing memory and decision making systems of the prefrontal cortex (PFC) and context evaluation by hippocampus (HPC). PFC and HPC are thought to impact the timing of the DA reward signal relative to salient cues by experience-dependent gating of sensory information to DA neurons via the tegmentum. This work incorporates a combination of 1) high density single unit recording so that we can understand (relative to DA signals) the neural codes within the PFC, HPC, and two tegmental areas, the pedunculopontine nucleus (PPTg) and the lateral dorsal tegmental nucleus (LDTg), 2) reversible inactivation of brain structures to test for functional connectivity between regions of interest, and 3) behavioral genetic analysis to identify the role of the NMDA system in DA regulation. Aim 1 will determine the nature of neural representation in structures that regulate DA activity: PPTg, LDTg, HPC and PFC. Aim 2 will determine whether the context-sensitivity of DA neurons in the ventral tegmental area (VTA) and the substantia nigra (SNc) is due to PPTg, LDT, HPC, or PFC input. Aim 3 will determine whether context-sensitivity of PPTg, LDTg and PFC neural representations is ultimately derived from HPC or PFC. Aim 4 will test whether it is the glutamate (NMDA) component of the afferent input that regulates burst firing by DA cells by testing these cellular properties in freely behaving mice that are selectively missing NR1 receptors on DA cells. Broad Significance: Understanding how context information regulates signaling by DA neurons is of fundamental importance for therapeutic development in cases of drug relapse, Parkinson¿s disease, and normal age associated decline in learning.

一个著名的理论认为DA细胞会产生即将到来的奖励的预测信号 和/或它们在强化偶然性改变时发出信号。这里有人认为， 从一个更动态和更广泛的系统观点来看待DA对认知的贡献，我们可以 更好地理解DA功能的重要性;我们不仅需要考虑DA如何 调节传出结构的可塑性，也调节DA神经元本身是如何 受经验的制约。上一个资助期的研究提供了令人信服的证据 DA函数是依赖于上下文的本建议包括四个具体目标 这将使我们能够测试这一假设，即背景调节DA神经元信号传导， 奖励信息从来自现有存储器的输入的组合中导出， 前额叶皮层（PFC）的决策系统和上下文评估， 海马区（HPC）。PFC和HPC被认为会影响DA奖励的时间 通过感觉信息对DA经验依赖性门控与显著线索相关的信号 神经元通过被盖。这项工作结合了1）高密度单 单位记录，以便我们可以理解（相对于DA信号）神经代码内 PFC，HPC和两个被盖区，脚桥核（PPTg）和 外侧背侧被盖核（LDTg），2）可逆性失活的大脑结构，以测试 用于感兴趣区域之间的功能连接，以及3）行为遗传分析， 确定NMDA系统在DA调节中的作用。目标1将决定 调节DA活性的结构中的神经表征：PPTg、LDTg、HPC和PFC。 目的2：探讨腹侧被盖区DA能神经元的情境敏感性是否与海马神经元的情境敏感性有关 区域（VTA）和黑质（SNc）是由于PPTg，LDT，HPC或PFC输入。目标3 将确定PPTg，LDTg和PFC神经表征的上下文敏感性是否 目的4将测试它是否是谷氨酸（NMDA） 这是传入输入的一个组成部分，它通过测试这些神经元来调节DA细胞的爆发性放电。 选择性缺失DA上NR 1受体的自由行为小鼠的细胞特性 细胞广泛的意义：理解背景信息如何通过DA调节信号传导 神经元对于药物治疗的发展具有根本的重要性。 复发、帕金森病和正常年龄相关的学习能力下降。