Plasticity in Flexible Goal-Directed Action

项目总结 灵活决策是认知/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 以及世界上的环境。贬值任务是用来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的实验室模型限制了 可供选择的应对措施以及表明这些应对措施结果的线索。然而，个人 参与货币贬值的大脑区域高度依赖于所使用的模型任务，而这种简化的 任务可以导致贬值任务的不同版本，而不需要在人类中激活的某些大脑区域 货币贬值实验，这是灵活的人类决策所必需的。拟议的研究将 验证更类似于人类决策环境的任务，以及其多响应 偶然性和发出偶然性信号的线索可以用来研究 货币贬值。一个明确的目标是调查一项更接近人类决策的贬值任务-- 以确保它在学习过程中对失活敏感的三个关键脑区参与灵活 人类的决策：杏仁基底外侧核(BLA)、丘脑背内侧核(MD)和眶前叶 皮质(OFC)。第二个目标是调查这些脑区之间的相互作用是否必要 用于了解贬值任务所需的信息。我们将有选择地停用连接 在MD和其他两个脑区之间通过微量注射化学生成病毒(选择性地由 通常是惰性的配体)进入一个大脑区域，并将该配体微量注射到第二个大脑区域。第三 AIM还将确定这些大脑区域是否通过直接投影相互通信 在贬值测试后，将示踪剂逆行注入OFC与神经元活动标记物Fos结合。 这将确定BLA和MD中投射到OFC的神经元是否与在 一次货币贬值测试。BLA功能障碍对MD和OFC神经元通讯的影响 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 负责导致人类决策的适应性和非适应性可塑性的回路 功能和功能障碍。确定用于决策的神经生物回路的确切性质将 促进进一步发展靶向治疗技术，以减轻决策障碍 这可能是由于受伤、接触滥用药物或其他毒素、遗传疾病或其他 发育问题。该项目的重点是检查发生在电路层面上的可塑性 在学习过程中，以及这种可塑性的变化如何对后来的目标导向行动产生不利影响， 还将推进C-NAP任务，加强神经生物学的交叉C-NAP研究主题 奖赏和决断。

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.