INVESTIGATING THE ROLE OF HIPPOCAMPUS - ORBITOFRONTAL CIRCUITS FOR COGNITIVE FLEXIBILITY

项目摘要 认知灵活性允许个人适应既定的思维模式和行为反应，以新的 可能需要比以前学到的新方法才能解决的情况 正确因此，认知灵活性是灵活调整思维和行为的必要条件， 反复思考的想法和担忧，或而不是表现出习惯性的行为，可能不会产生 有效地处理新情况或解决新问题。认知灵活性的损伤可能会发生 这是由于慢性压力，这是许多精神疾病的发病机制的主要贡献者。 因此，认知灵活性缺陷在各种精神疾病中很常见， 对其他有效药物无反应。此外，具有高水平认知灵活性的人 已被证明能更好地科普日常压力，并且不太容易患上精神疾病。 紊乱如果我们能够理解认知灵活性背后的神经回路，我们也许能够发现新的 目标的先进疗法，以治疗衰弱的认知障碍的许多精神疾病。 在这个提议中，我们将研究一种重要的认知形式之下的一种新的神经回路组件。 灵活性：逆向学习。我们将专门研究腹侧海马体的神经投射 眶额皮质（OFC）调节逆转学习和压力恢复能力。在目标1中，我们将禁止直接 从腹侧海马到内侧眶额皮层的输入投射，以及从内侧眶额皮层的输出投射 到横向OFC，以测试该回路对于反向学习是否在功能上重要。在目标2中，我们将使用体内 在腹侧海马、内侧OFC和外侧OFC中的神经活动的Ca2+成像，以检查第一个 记录这些大脑区域的神经元如何存储、处理和更新有关行动结果价值的信息 对逆向学习很重要的联系。在目标3中，我们将研究这些相同的大脑 在慢性压力的条件下，这些区域会变得功能失调，如果刺激这个回路会产生压力， 恢复力和抵消压力引起的逆转学习缺陷。这些实验将提供 第一次深入了解认知灵活性和压力恢复力背后的神经回路的一个新元素， 具有很大的潜力，揭示新的神经回路为基础的目标，为新的药物或先进的认知行为 旨在改善患有精神障碍的患者的认知灵活性的治疗。

PROJECT SUMMARY Cognitive flexibility allows an individual to adapt established thinking patterns and behavioral responses to novel situations that may require new approaches than those that were previously learned in order to be solved correctly. Cognitive flexibility is therefore necessary to flexibly adjust ones thinking and behavior instead of ruminating over thoughts and worries, or instead of showing habitual behavior that may not be productive to effectively engage with a new situation or to solve a new problem. Impairments in cognitive flexibility can occur as a result of chronic stress, which is a major contributor to the pathogenesis of many psychiatric disorders. Accordingly, cognitive flexibility deficits are common across a wide range of mental illnesses and often unresponsive to otherwise effective medication. Moreover, individuals with high levels of cognitive flexibility have been shown to cope better with day-to-day stressors, and to be less vulnerable to developing psychiatric disorders. If we can understand the neural circuits underlying cognitive flexibility, we may be able to identify new targets for advanced therapeutics to treat the debilitating cognitive impairments of many psychiatric disorders. In this proposal, we will study a novel neural circuit component underlying one important form of cognitive flexibility: reversal learning. We will specifically investigate how neural projections from the ventral hippocampus to the orbitofrontal cortex (OFC) regulate reversal learning and stress resilience. In Aim 1, we will inhibit direct input projections from the ventral hippocampus to the medial OFC, and output projections from the medial OFC to the lateral OFC, to test if this circuit is functionally important for reversal learning. In Aim 2, we will use in vivo Ca2+ imaging of neural activity in ventral hippocampus, medial OFC, and lateral OFC, to examine for the first time how neurons in these brain regions store, process, and update information about action-outcome value associations that are important for reversal learning. In Aim 3, we will then investigate how these same brain regions become dysfunctional under conditions of chronic stress, and if stimulating this circuitry can confer stress resilience and counteract stress-induced deficits in reversal learning. Together, these experiments will provide first insight into a new element of the neural circuitry underlying cognitive flexibility and stress resilience, which has great potential to reveal new neural circuit-based targets for novel drugs or for advanced cognitive-behavioral therapies aimed at improving cognitive flexibility in patients suffering from psychiatric disorders.