Chemogenetic disconnection of monkey orbitofrontal and rhinal cortex reversibly disrupts reward value

Abstract

To study how the interaction between orbitofrontal (OFC) and rhinal (Rh) cortices influences the judgment of reward size, we reversibly disconnected these regions using hM4Di-DREADD (designer receptor exclusively activated by designer drug). Repeated inactivation reduced sensitivity to differences in reward size in two monkeys. These results suggest that retrieval of relative stimulus values from memory depends on the interaction between Rh and OFC.

Fig. 1

Task and experimental design. (A) A trial in the reward size task - at the beginning of each trial, a visual cue signaled the amount of reward (1, 2, 4 or 8 drops) that would be delivered after a correct red-green color discrimination. After each correct trial, a new cue-reward size pair was picked from the set of 4 at random. (B) Relationship between cues and reward sizes. (C) Experimental design and timeline: unilateral Rh lesion (black) paired with contralateral injection of hM4Di vector in OFC (cyan) to produce functional disconnection when hM4Di receptors are activated with CNO.

Fig. 2

Behavioral effects of CNO (10 mg/kg, i.m.) (A) Monkey D and (B) Monkey S, after injection of OFC with hM4Di vector. Error rates as a function of reward size are shown. Pre-CNO: two days prior to CNO treatment. CNO: treatment day. Post-CNO: two days after CNO treatment.

Fig. 3

Histology analysis of hM4Di-CFP DREADD expression. (A and B) Flatmap reconstructions of DREADD expression from DAB-stained sections – e.g. sections i, ii, iii, iv presented below flatmaps. Brodmann regions indicated by blue numbers. Sulci: mo – medial orbital, lo – lateral orbital, olf – olfactory, rs – retrospenial. (C–D) Confocal fluorescent images of DREADD expression (green) and somata (red). (C) DREADD expression in OFC. Cellular expression areas are outlined in white. Black square in left panel indicates area enlarged in the right panel. (D) DREADD-expressing axonal projections in Rh. White square in left panel indicates area enlarged in the right panel. Synaptic boutons are visible along projections (white arrows).