INVESTIGATING THE ROLE OF HIPPOCAMPUS - ORBITOFRONTAL CIRCUITS FOR COGNITIVE FLEXIBILITY

点击翻译按钮获取中文摘要

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.