INVESTIGATING THE ROLE OF HIPPOCAMPUS - ORBITOFRONTAL CIRCUITS FOR COGNITIVE FLEXIBILITY

研究海马体 - 眼眶额叶回路对认知灵活性的作用

基本信息

批准号：
10589862
负责人：
Christoph Anacker
金额：
$ 69.89万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-10 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589862
关键词：
Affect Behavior Behavioral Brain region Chronic stress Cognitive Cognitive Therapy Data Disease Elements Environment Genetic Hippocampus Image Impaired cognition Impairment Impulsivity Individual Individual Differences Intervention Knowledge Label Lateral Learning Major Depressive Disorder Measures Medial Mediator Mental disorders Microscope Mus Neurobiology Neurons Neurosciences Obsessive-Compulsive Disorder Outcome Outcome Assessment Output Pathogenesis Patients Pattern Pharmaceutical Preparations Post-Traumatic Stress Disorders Predisposition Process Productivity Psyche structure Publishing Research Reversal Learning Risk Factors Role Stress Stressful Event Techniques Technology Testing Therapeutic Thinking Time Update Virus Work behavioral response cognitive function coping designer receptors exclusively activated by designer drugs environmental change executive function experimental study flexibility generalized anxiety improved in vivo ineffective therapies insight learned behavior neural neural circuit neuroimaging new therapeutic target novel novel strategies optogenetics promote resilience receptor resilience rumination social defeat stress resilience stressor

项目摘要

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.

项目概要认知灵活性使个人能够适应既定的思维模式和行为反应以适应新事物可能需要新方法而不是以前学到的方法才能解决的情况正确。因此，需要认知灵活性来灵活调整自己的思维和行为，而不是反思想法和忧虑，或者不表现出可能无益的习惯行为有效地应对新情况或解决新问题。认知灵活性可能会受损慢性压力是导致许多精神疾病发病机制的主要原因。因此，认知灵活性缺陷在多种精神疾病中都很常见，而且常常对其他有效药物无反应。此外，具有高认知灵活性的个体研究表明，他们能够更好地应对日常压力，并且不易患上精神疾病失调。如果我们能够理解认知灵活性背后的神经回路，我们也许能够识别出新的先进疗法的目标是治疗许多精神疾病造成的衰弱性认知障碍。在本提案中，我们将研究一种新的神经回路组件，它是一种重要的认知形式的基础灵活性：逆向学习。我们将专门研究腹侧海马体的神经投射如何眶额皮质（OFC）调节逆转学习和压力恢复能力。在目标 1 中，我们将抑制直接从腹侧海马到内侧 OFC 的输入投影，以及从内侧 OFC 的输出投影到外侧 OFC，以测试该电路对于反向学习是否具有重要功能。在目标 2 中，我们将使用 vivo 腹侧海马、内侧 OFC 和外侧 OFC 神经活动的 Ca2+ 成像，首先进行检查这些大脑区域中的神经元如何存储、处理和更新有关行动结果值的信息的时间对于逆向学习很重要的关联。在目标 3 中，我们将研究这些相同的大脑如何在慢性压力的情况下，该区域会变得功能失调，如果刺激该电路就会带来压力恢复力并抵消逆向学习中压力引起的缺陷。这些实验将共同提供首次深入了解认知灵活性和压力恢复能力背后的神经回路新元素，具有揭示新药物或高级认知行为的新的基于神经回路的目标的巨大潜力旨在提高精神疾病患者认知灵活性的疗法。