State-dependent regulation of mesolimbic dopamine and ventral striatal neuron activity

中脑边缘多巴胺和腹侧纹状体神经元活动的状态依赖性调节

• 批准号: 10294944
• 负责人: Aphroditi Mamaligas
• 金额: $ 6.64万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294944
• 关键词: Address; Affect; Animals; Area; Automobile Driving; Axon; Basal Ganglia; Behavior; Behavioral; Brain; Brain region; Calcium; Cells; Corpus striatum structure; Critical Pathways; Cues; Data Analyses; Decision Making; Development; Discrimination; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Environment; Esthesia; Experimental Water Deprivation; Fasting; Fiber; Fire - disasters; Fluid Balance; Food; Food deprivation (experimental); Goals; Head; Hunger; Hypothalamic structure; Image; Imaging Device; Individual; Institution; Knowledge; Lateral; Learning; Learning Skill; Link; Measures; Mediating; Microscope; Midbrain structure; Monkeys; Motivation; Mus; Neuraxis; Neurons; Neurotransmitters; Nucleus Accumbens; Optics; Outcome; Output; Pathway interactions; Pattern; Perception; Phase; Photometry; Play; Psychological reinforcement; Regulation; Research; Resolution; Rewards; Role; Signal Transduction; Stimulus; Structure of nucleus infundibularis hypothalami; Subfornical Organ; System; Techniques; Testing; Thirst; Translating; Ventral Striatum; Ventral Tegmental Area; Water; Work; base; deprivation; design; designer receptors exclusively activated by designer drugs; dopaminergic neuron; drug of abuse; energy balance; flexibility; in vivo; mesolimbic system; motivated behavior; neural circuit; optogenetics; response; reward circuitry; sensor; spatiotemporal

PROJECT SUMMARY/ABSTRACT The mesolimbic dopamine system, projecting from the ventral tegmental area (VTA) to the nucleus accumbens, strongly controls motivation to seek rewards in the environment, including drugs of abuse and rewards that alter fluid and energy balance. Natural imbalances in internal state that occur over prolonged timecourses, such as the sensations of hunger and thirst, are critical for expression of motivated behavior. However, the circuit mechanisms underlying basal ganglia circuit activity during different homeostatic states remains unclear. With the recent development of single neuron resolution imaging tools, optical calcium sensors, and optical neurotransmitter sensors, dopamine activity in the ventral midbrain as well as in the ventral striatum can be easily measured. The goal of this work is to determine how selective activity patterns in VTA dopamine neurons change during different internal states and how those changes in activity drive differences in firing patterns of medium spiny output neurons in the nucleus accumbens during action selection. To address this, I will use a freely-moving cued approach tone discrimination task in which food- and water-predictive cues are randomly delivered while performing single-neuron resolution imaging of dopamine neuron calcium activity using a head-mounted mini-microscope. I hypothesize that dopamine neurons will preferentially respond to the deprived cue and reward while also weakly responding to the non-deprived stimuli, and that this will depend on activity in upstream brain regions required for hunger and thirst expression. Further, I hypothesize that this difference in dopamine cell activity will lead to a bidirectional modulation of striatal output activity that tracks local dopamine release and deprivation-evoked action selection. This work will build on prior research done on striatal circuits in our lab as well as on interoceptive circuitry in other labs at our institution. I will learn skills in in vivo recording techniques as well as behavioral design and data analysis. With this project, I hope to further understand fundamental pre- and post-synaptic circuit mechanisms underlying dopaminergic activity in state-dependent motivation.

项目摘要/摘要 中脑边缘多巴胺系统，从腹侧被盖区投射到核团 伏隔，强烈控制在环境中寻求奖励的动机，包括滥用药物和 改变体液和能量平衡的奖励。长期出现的内部状态的自然失衡 时间周期，如饥渴的感觉，对于表达有动机的行为至关重要。 然而，在不同的动态平衡状态下，基础神经节回路活动的回路机制 目前仍不清楚。随着单神经元分辨率成像工具的最新发展，光学钙 感受器和光学神经递质感受器，腹侧中脑以及 腹侧纹状体很容易测量。这项工作的目标是确定选择性活动如何 VTA多巴胺神经元的模式在不同的内部状态下发生变化，以及这些变化是如何在 活动驱动伏核中棘突输出神经元放电模式的差异 在动作选择过程中。为了解决这个问题，我将使用自由移动的线索方法声调辨别任务 在执行单神经元分辨时，随机传递哪些食物和水的预测线索 使用头戴式微型显微镜对多巴胺神经元钙活动进行成像。我假设 多巴胺神经元将优先对被剥夺的线索和奖赏作出反应，而对被剥夺的线索和奖赏也有微弱的反应 非剥夺刺激，这将取决于饥饿和饥饿所需的上游大脑区域的活动 口渴的表情。此外，我假设这种多巴胺细胞活动的差异将导致双向 纹状体输出活动的调节跟踪局部多巴胺的释放和剥夺诱发的行为 选择。这项工作将建立在我们实验室对纹状体回路以及内感的先前研究的基础上。 我们机构其他实验室的电路。我将学习活体记录技术以及行为技能 设计和数据分析。通过这个项目，我希望进一步了解突触前和突触后的基本情况 状态依赖动机中潜在的多巴胺能活动的电路机制。