Plasticity in Flexible Goal-Directed Action

项目摘要 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 和世界的环境。贬值任务是用于研究神经元的动物模型， 灵活决策的基础。使用贬值任务的决策实验室模型限制了 可用的响应选项以及指示这些响应的结果的线索。然而，个人 参与贬值的大脑区域高度依赖于所使用的模型任务，这种对模型任务的简化， 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， 贬值实验和灵活的人类决策所需的。拟议的研究将 验证一个更类似于人类决策环境的任务，其多重响应 突发事件和信号突发事件的线索，可以用来研究神经回路， 贬值。一个具体的目标是研究一个更接近人类决策的贬值任务， 使其在学习过程中对三个涉及灵活性的关键脑区的失活敏感， 在人类的决策过程中，基底外侧杏仁核（BLA），内侧背丘脑（MD）和眶额 皮质（OFC）。第二个目标将调查这些大脑区域之间的相互作用是否是必要的 用于学习贬值任务所需的信息。我们将有选择地删除连接 在MD和其他两个大脑区域之间，用化学遗传病毒（通过选择性激活）进行显微注射。 通常惰性的配体）注射到一个脑区中，并将配体显微注射到第二个脑区中。第三 aim还将决定这些大脑区域是否通过直接投射相互交流， 贬值测试后将逆行示踪剂注射到OFC与神经元活动标记物Fos结合起来。 这将确定BLA和MD中投射到OFC的神经元是否与在OFC期间活跃的神经元相同。 贬值测试破坏BLA功能对MD和OFC之间神经元通讯的影响将 也被调查。这些实验的结果将对理解大脑具有潜在的重要意义 负责适应性和适应不良可塑性的回路，可导致人类决策 功能和功能障碍。确定决策神经生物学回路的确切性质将 促进进一步开发有针对性的治疗技术，以减轻决策障碍 这可能是由于受伤，暴露于滥用药物或其他毒素，遗传疾病，或其他 发展问题。该项目的重点是检查电路级的可塑性， 在学习过程中，以及这种可塑性的改变如何对后来的目标导向行动产生不利影响， 还将推进C-NAP的使命，加强神经生物学的跨领域C-NAP研究主题， 奖励和决定。

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.