INVESTIGATING THE ROLE OF HIPPOCAMPUS - ORBITOFRONTAL CIRCUITS FOR COGNITIVE FLEXIBILITY

项目总结 认知灵活性使个人能够调整既定的思维模式和行为反应，以适应小说 可能需要比以前学到的方法更新的方法才能解决的情况 正确。因此，认知灵活性是必要的，以灵活地调整自己的思维和行为，而不是 沉思思绪和忧虑，或者不表现出可能不会产生成效的习惯行为 有效地处理新情况或解决新问题。认知灵活性的损害可能会发生 作为慢性压力的结果，这是许多精神疾病的主要致病因素。 因此，认知灵活性缺陷在广泛的精神疾病中很常见，而且通常 对其他有效的药物没有反应。此外，认知灵活性水平较高的个体 被证明能更好地应对日常压力，更不容易受到精神疾病的影响 精神错乱。如果我们能够理解认知灵活性背后的神经回路，我们或许能够识别出新的 先进疗法的目标是治疗许多精神疾病的衰弱认知障碍。 在这个方案中，我们将研究一种新的神经回路组件，它是认知的一种重要形式。 灵活性：反转学习。我们将专门研究腹侧海马区的神经投射是如何 到眼眶前额叶皮质(OFC)，调节反转学习和压力恢复。在目标1中，我们将抑制直接 从腹侧海马到内侧OFC的输入投射和来自内侧OFC的输出投射 到横向OFC，以测试该电路对于反转学习是否具有重要功能。在目标2中，我们将在体内使用 对腹侧海马、内侧OFC和外侧OFC神经活动的CA2成像，以检查第一次 计算这些脑区神经元存储、处理和更新有关行动结果价值的信息的时间 对反转学习很重要的联想。在目标3中，我们将研究这些相同的大脑是如何 在慢性应激的情况下，这些区域会变得功能失调，如果刺激这一回路可以产生压力 反转学习中的恢复力和对抗应激诱导的缺陷。总之，这些实验将提供 首先洞察认知灵活性和压力韧性背后的神经回路的新元素，这是 具有为新药或高级认知行为揭示新的神经回路靶点的巨大潜力 旨在提高精神障碍患者认知灵活性的治疗。

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.