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Neuropsychopharmacology. 2018 Jan;43(2):373-383. doi: 10.1038/npp.2017.139. Epub 2017 Jun 30.

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

Zimmermann KS1,2,3,4, Li CC2,3, Rainnie DG2,3,4, Ressler KJ2,3,4,5, Gourley SL1,2,3,4.

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Department of Pediatrics, Emory University, Atlanta, GA, USA.
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
Graduate Program in Neuroscience, Emory University, Atlanta, GA, USA.
Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.


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.

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