Plasticity in Flexible Goal-Directed Action

灵活的目标导向行动的可塑性

• 批准号: 9209596
• 负责人: Charles Lee Pickens
• 金额: $ 18.83万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9209596
• 关键词: Affect; Alzheimer' s Disease; Amygdaloid structure; Animal Experimentation; Animal Model; Animals; Area; Behavior; Behavioral; Bilateral; Brain; Brain region; Clozapine; Cognitive; Communication; Cues; Data; Decision Making; Development; Drug Receptors; Ensure; Environment; Exposure to; Functional disorder; Goals; Hereditary Disease; Human; Impairment; Impulsivity; Individual; Injectable; Injection of therapeutic agent; Injury; Interneurons; Ischemia; Laboratories; Lead; Learning; Lesion; Ligands; Macaca; Macaca mulatta; Measures; Microinjections; Mission; Modeling; Motor; Nature; Neurobiology; Neurons; Outcome; Oxides; Performance; Play; Population; Rattus; Research; Rewards; Role; Route; Signal Transduction; Site; Structure; Techniques; Testing; Thalamic structure; Toxin; Tracer; Training; Virus; activity marker; base; behavioral plasticity; brain circuitry; design; designer receptors exclusively activated by designer drugs; drug addict; drug of abuse; experimental study; flexibility; neural circuit; neuronal patterning; psychostimulant; response; social; targeted treatment

PROJECT SUMMARY Flexible decision-making, a form of cognitive/behavioral plasticity, is important for adapting to changing demands and circumstances in the world. The devaluation task is an animal model used to investigate the neuronal substrates of flexible decision-making. Laboratory models of decision-making using the devaluation task limit the response options available and the cues indicating the outcomes of these responses. However, the individual brain areas involved in devaluation are highly dependent on the model task used, and this simplification of the task can lead to versions of the devaluation task not requiring certain brain areas that are activated in human devaluation experiments and that are required for flexible human decision-making. The proposed research will validate that a task that is more similar to the human decision-making environment, with its multiple-response contingencies and cues that signal the contingencies, can be used to investigate the neural circuits of devaluation. One specific aim will investigate a devaluation task that more closely resembles human decision- making to ensure that it is sensitive to inactivation during learning of three key brain areas involved in flexible decision-making in humans, the basolateral amygdala (BLA), mediodorsal thalamus (MD), and orbitofrontal cortex (OFC). A second aim will then investigate whether interactions between these brain areas are necessary for learning the information necessary for the devaluation task. We will selectively inactivate connections between MD and the other two brain areas with microinjections of a chemogenetic virus (selectively activated by a normally inert ligand) into one brain area and microinjections of the ligand into a second brain area. The third aim will also determine whether these brains areas communicate with one another through direct projection by combining retrograde tracer injections into OFC with the neuronal activity marker Fos after a devaluation test. This will determine if the neurons in BLA and MD that project to OFC are the same neurons that are active during a devaluation test. The effects of disrupting BLA function on neuronal communication between MD and OFC will also be investigated. The results of these experiments will be potentially significant for understanding the brain circuitry that is responsible for adaptive and maladaptive plasticity that can lead to human decision-making function and dysfunction. Determining the exact nature of the neurobiological circuits for decision-making will promote the further development of targeted therapeutic techniques to mitigate decision-making impairments that could result from injuries, exposure to drugs of abuse or other toxins, genetic disorders, or other developmental problems. The project’s strong emphasis on examining the circuits-level plasticity that occurs during learning, and how alterations in this plasticity can have a detrimental effect on later goal-directed action, will also advance the C-NAP mission, enhancing the cross-cutting C-NAP research theme of the neurobiology of reward and decision.

项目概要 灵活的决策是认知/行为可塑性的一种形式，对于适应不断变化的需求非常重要 贬值任务是用于研究神经网络的动物模型。 使用贬值任务进行决策的实验室模型限制了灵活决策的基础。 然而，可用的反应选项和表明这些反应结果的线索。 参与贬值的大脑区域高度依赖于所使用的模型任务，并且这种简化 任务可以导致贬值任务的版本不需要人类激活的某些大脑区域 贬值实验以及灵活的人类决策所需的研究将。 验证一个更类似于人类决策环境的任务，具有多重响应 突发事件和发出突发事件信号的线索可用于研究神经回路 一个具体目标是研究一项更类似于人类决策的贬值任务—— 确保在学习涉及灵活性的三个关键大脑区域期间，它对失活敏感 人类的决策、基底外侧杏仁核 (BLA)、内侧丘脑 (MD) 和眶额 第二个目标是研究这些大脑区域之间的相互作用是否必要。 为了了解贬值任务所需的信息，我们将有选择地停用连接。 在 MD 和其他两个大脑区域之间注射化学遗传病毒（通过选择性激活） 将通常惰性的配体）注射到一个大脑区域，然后将配体显微注射到第二个大脑区域。 目标还将确定这些大脑区域是否通过直接投影相互交流 在贬值测试后将逆行示踪剂注射到 OFC 与神经元活动标记 Fos 相结合。 这将确定投射到 OFC 的 BLA 和 MD 中的神经元是否与在 破坏 BLA 功能对 MD 和 OFC 之间神经通讯的影响将进行贬值测试。 这些实验的结果对于理解大脑也具有潜在的重要意义。 负责适应性和适应不良可塑性的电路，可导致人类决策 确定决策神经生物学回路的确切性质。 促进靶向治疗技术的进一步发展，以减轻决策障碍 可能是由于受伤、接触滥用药物或其他毒素、遗传性疾病或其他原因造成的 该项目非常重视检查发生的电路级可塑性。 在学习过程中，以及这种可塑性的改变如何对以后的目标导向行动产生痛苦影响， 还将推进 C-NAP 使命，增强神经生物学的跨领域 C-NAP 研究主题 的奖励和决定。