Central medial and paraventricular thalamic afferents to the orbitofrontal cortex have differential effects on reversal learning

Cognitive impairments are prominent in stress-related psychiatric disorders, such as depression and PTSD. While current therapies may improve mood symptoms, many patients experience persistent deficits in cognitive flexibility. One form of cognitive flexibility disrupted in such conditions is reversal learning, dependent on the orbitofrontal cortex (OFC). Chronic stress causes OFC dysfunction and reversal learning deficits. However, the circuit mechanisms by which this happens are not understood. We hypothesized that two thalamic afferents to the OFC, the central medial (CM) and paraventricular thalamus (PVT), contribute to successful reversal learning and the detrimental effects of stress, respectively. We showed a decrease in activation of lateral OFC, measured by Fos induction, following reversal learning, and increased activation of both CM and PVT. Chronic unpredictable stress (CUS) impaired reversal learning and increased ΔFosB expression in CM and PVT projections to the OFC. Next, we chemogenetically manipulated each pathway to the OFC in non-stressed and stressed rats. Inhibition of the CM to OFC pathway in non-stressed rats disrupted reversal learning, while activation of this pathway restored reversal learning in stressed rats. By contrast, activation of the PVT to OFC pathway disrupted reversal learning in non-stressed male rats. In stressed males, inhibition of the PVT to OFC pathway ameliorated the detrimental effects of CUS. Effects of PVT to OFC manipulations were absent in females. These results indicate that the CM-OFC pathway promotes successful reversal learning in both sexes, and the PVT-OFC pathway contributes to the detrimental effects of stress on reversal learning in a sex-dependent manner. • CM and PVT projections to OFC are similarly activated by chronic stress • CM input to OFC promotes reversal learning, a new role for CM in cognition • CM and PVT projections have opposing effects on reversal learning • PVT input to OFC mediates the effects of stress on reversal learning in males