Memory Retention Involves the Ventrolateral Orbitofrontal Cortex: Comparison with the Basolateral Amygdala.

The orbitofrontal cortex (OFC) is thought to link stimuli and actions with anticipated outcomes in order to sustain flexible behavior in an ever-changing environment. How it retains these associations to guide future behavior is less well-defined. Here we focused on one subregion of this heterogeneous structure, the ventrolateral OFC (VLO). CaMKII-driven inhibitory Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) were infused and subsequently activated by their ligand Clozapine-N-oxide (CNO) in conjunction with fear extinction training (a form of aversive conditioning) and response-outcome conditioning (a form of appetitive conditioning). Gi-DREADD-mediated inactivation of the VLO during extinction conditioning interfered with fear extinction memory, resulting in sustained freezing when mice were later tested drug-free. Similarly, Gi-DREADD-mediated inactivation in conjunction with response-outcome conditioning caused a later decay in goal-directed responding-that is, mice were unable to select actions based on the likelihood that they would be rewarded in a sustainable manner. By contrast, inhibitory Gi-DREADDs in the basolateral amygdala (BLA) impaired the acquisition of both conditioned fear extinction and response-outcome conditioning, as expected based on prior studies using other inactivation techniques. Meanwhile, DREADD-mediated inhibition of the dorsolateral striatum enhanced response-outcome conditioning, also in line with prior reports. Together, our findings suggest that learning-related neuroplasticity in the VLO may be necessary for memory retention in both appetitive and aversive domains.