INVESTIGATING THE ROLE OF HIPPOCAMPUS - ORBITOFRONTAL CIRCUITS FOR COGNITIVE FLEXIBILITY

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.

Grant Number: 5R01MH126105-04
NIH Institute/Center: NIH
Principal Investigator: Christoph Anacker