The Medial Orbitofrontal Cortex Regulates Sensitivity to Outcome Value

Abstract

An essential component of goal-directed decision-making is the ability to maintain flexible responding based on the value of a given reward, or "reinforcer." The medial orbitofrontal cortex (mOFC), a subregion of the ventromedial prefrontal cortex, is uniquely positioned to regulate this process. We trained mice to nose poke for food reinforcers and then stimulated this region using CaMKII-driven Gs-coupled designer receptors exclusively activated by designer drugs (DREADDs). In other mice, we silenced the neuroplasticity-associated neurotrophin brain-derived neurotrophic factor (BDNF). Activation of Gs-DREADDs increased behavioral sensitivity to reinforcer devaluation, whereas Bdnf knockdown blocked sensitivity. These changes were accompanied by modifications in breakpoint ratios in a progressive ratio task, and they were recapitulated in Bdnf(+/-)mice. Replacement of BDNF selectively in the mOFC in Bdnf(+/-)mice rescued behavioral deficiencies, as well as phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2). Thus, BDNF expression in the mOFC is both necessary and sufficient for the expression of typical effort allocation relative to an anticipated reinforcer. Additional experiments indicated that expression of the immediate-early gene c-fos was aberrantly elevated in the Bdnf(+/-)dorsal striatum, and BDNF replacement in the mOFC normalized expression. Also, systemic administration of an MAP kinase kinase inhibitor increased breakpoint ratios, whereas the addition of discrete cues bridging the response-outcome contingency rescued breakpoints in Bdnf(+/-)mice. We argue that BDNF-ERK1/2 in the mOFC is a key regulator of "online" goal-directed action selection.

Significance statement: Goal-directed response selection often involves predicting the consequences of one's actions and the value of potential payoffs. Lesions or chemogenetic inactivation of the medial orbitofrontal cortex (mOFC) in rats induces failures in retrieving outcome identity memories (Bradfield et al., 2015), suggesting that the healthy mOFC serves to access outcome value information when it is not immediately observable and thereby guide goal-directed decision-making. Our findings suggest that the mOFC also bidirectionally regulates effort allocation for a given reward and that expression of the neurotrophin BDNF in the mOFC is both necessary and sufficient for mice to sustain stable representations of reinforcer value.

Keywords: cue; dorsal striatum; neurotrophin; operant; orbital; progressive ratio.

Figure 1.

Chemogenetic stimulation of the mOFC enhances behavioral sensitivity to reinforcer value and PR response requirements. a, Viral vectors expressing GFP were infused into the mOFC, annotated by the anatomical boundaries outlined at right. b, Fluorescing axons were detectable in a stereotyped pattern hugging the medial wall of the dorsal striatum, particularly in the rostral portion highlighted by the gray dashed lines (cf. Schilman et al., 2008). c, Terminals were also detected in the medial compartment of the basal amygdala. The corresponding coronal sections are shown at right. Blue boxes outline the areas shown in the photomicrographs. d, Infection spread for viral vector experiments is represented on images from the Mouse Brain Library (Rosen et al., 2000), with black indicating the largest spread and white the smallest. e, Mice expressing CaMKII-driven AAV–GFP or AAV–G_s–DREADD–mCitrine acquired the instrumental response. Breaks in the response acquisition curves indicate tests for behavioral sensitivity to reinforcer devaluation. f, Mice were fed the reinforcer pellets or regular chow ad libitum before probe tests (devalued and value conditions). Groups did not differ in food consumption. g, Activation of G_s–DREADDs augmented behavioral sensitivity to reinforcer devaluation, decreasing response rates. Meanwhile, control mice did not modify their response patterns. h, A second experience with the reinforcer devaluation procedure and injection stress ultimately resulted in response inhibition in both groups (n = 4–6 per group). i, Activating G_s–DREADDs also reduced breakpoints in a PR test (n = 6–10 per group). j, Locomotor activity was not effected by G_s–DREADDs stimulation. Ambulatory and repetitive photobeam breaks are represented in 5 min bins (left) and 1 h total counts (right). Mice in both instrumental conditioning experiments were tested. Bars and symbols represent means ± SEMs. *p < 0.05, **p < 0.001.

Figure 2.

Selective Bdnf knockdown in the mOFC decreases behavioral sensitivity to reinforcer value and PR response requirements. a, Cre-expressing viral vectors were infused into the mOFC (as in Fig. 1d) of “floxed” Bdnf mice. Mice were trained to nose poke for food reinforcers, with no differences between groups. b, After prefeeding devaluation (and in the absence of an injection stressor as in Fig. 1), control GFP-expressing mice decreased response rates relative to baseline. Meanwhile, selective Bdnf knockdown mice failed to modify response rates. Instead, response rates were indistinguishable from those generated by mice that had access to regular chow before test (value groups). c, mOFC Bdnf knockdown also increased breakpoint ratios. d, Meanwhile, response extinction was not affected; e, furthermore, spontaneous locomotor activity was unaffected. Ambulatory and repetitive photobeam breaks are represented in 5 min bins (left) and 1 h total counts (right). Symbols represent means ± SEMs. *p < 0.05. n = 8 per group.

Figure 3.

Bdnf^+/− mice are behaviorally insensitive to reinforcer devaluation. a, Bdnf^+/− mice expressed approximately half as much BDNF in hippocampal lysates as wild-type littermates (n = 11–12 per group). b, Mice acquired the nose-poke response without differences between groups. c, Mice also consumed equivalent amounts of food under ad libitum conditions. d, After freely consuming reinforcer pellets, however, only wild-type mice significantly decreased response rates, whereas Bdnf^+/− mice failed to significantly modify response patterns. e, Nonetheless, the same mice consumed equivalent amounts of a palatable sucrose solution (SUC; n = 16 wild-type, 12 Bdnf^+/− littermates). Bars and symbols represent means ± SEMs per group, *p < 0.05; **p < 0.001. wt, Wild-type.

Figure 4.

Responding on a PR schedule is inflated in Bdnf^+/− mice. a, Bdnf^+/− mice achieved higher breakpoint ratios on a PR schedule of reinforcement, particularly during test sessions 4–7. b, Despite this, responding was equally selective for the active, relative to inactive, apertures between groups. c, d, Comparisons of the average first, median, and last PRPs from sessions 1–3, when breakpoint ratios did not significantly differ, and sessions 4–7, when breakpoints differed, revealed main effects of time as expected, but no genotype effects. These patterns suggest that motivational differences between wild-type and Bdnf^+/− mice cannot obviously account for differences in breakpoints. e, vmPFC expression of p-trk, GluR1, and pERK1/2 were decreased in Bdnf^+/− mice. The latter could be attributed reduced phosphorylation of the ERK2 isoform. Representative bands are adjacent. Bars and symbols represent means ± SEMs per group. *p < 0.05; **p < 0.001. wt, Wild-type. n = 13–14 per group.

Figure 5.

mOFC BDNF infusion enhances pERK1/2 expression. a, Experimental timeline. Mice were infused into the mOFC with saline or BDNF, then brains were collected 24 h later. b, BDNF increased expression of c-fos and pERK1/2, as measured by Western blot. Representative bands are adjacent. n = 6 per group. c, In another cohort of mice, pERK1/2 expression was quantified in concentric rings radiating from the base of the infusion site in fixed, hemisected coronal sections. The schematic represents the rings overlaid on representations of the largest, smallest, and representative (middle line) pERK1/2 fluorescence signal. d, Quantitative immunostaining revealed increased pERK1/2 expression at the infusion site 24 h after infusion, and the pERK1/2 signal was further elevated in BDNF-infused mice. Representative image is adjacent. n = 3–4 per group. Bars and symbols represent means ± SEMs per group. *p < 0.05. sal, Saline.

Figure 6.

mOFC BDNF infusion rescues behavioral sensitivity to a PR schedule of reinforcement in Bdnf^+/− mice. a, Baseline responding on a PR schedule was established in Bdnf^+/− mice and wild-type littermates before intracranial BDNF infusion. b, A single mOFC BDNF infusion occluded the expected increase in PR responding in Bdnf^+/− mice. Mean breakpoint ratios achieved during three test sessions are shown. Inset, Needle tracks terminated within the anatomical boundaries drawn at approximately +2.46 and +2.1 mm from bregma on images from the Mouse Brain Atlas (Rosen et al., 2000). n = 8–13 per group. c, Mice were killed immediately after the last session. As expected, pERK2 expression was decreased by 30–40% in Bdnf^+/− mice infused with saline compared to wild-type mice infused with saline. BDNF infusion blocked this deficit. Representative blots are below. d, In the dorsal striatum, c-fos patterns mirrored behavioral response patterns (compare with b), with elevated c-fos associated with high breakpoint ratios. Representative blots are adjacent. e, Breakpoint ratios covaried with striatal c-fos. Bars and symbols represent means ± SEMs per group, except in e, in which each symbol represents a single mouse. *p ≤ 0.05, **p < 0.001. wt, Wild-type; sal, saline.

Figure 7.

Cues signaling reinforcer delivery rescue PR responding in Bdnf^+/− mice. No differences in extinction conditioning or locomotor activity. a, A group of wild-type and Bdnf^+/− mice was tested on a PR schedule as in previous experiments but with the addition of discrete stimuli that signaled reinforcer delivery. Instrumental response acquisition (with stimuli presentation) was unaffected by genotype. b, When presented with stimuli signaling reinforcer delivery, Bdnf^+/− mice were able to regulate their responding identically to wild-type mice. Gray bars sit at the overall mean breakpoint for each group, with the width representing ± SEM. Light gray, Wild-type; dark gray, Bdnf^+/−. b′, We replicated this experiment in another group of naive mice, and again, breakpoints did not differ when mice were provided discrete stimuli signaling reinforcer delivery. c, Responding in extinction was also unaffected. d, Ambulation counts were also equivalent in food-restricted Bdnf^+/− and wild-type mice. Symbols represent means ± SEMs. wt, Wild-type. n = 6–18 per group throughout.

Figure 8.

Pretest but not posttest MEK inhibition reduces breakpoint ratios. a, Naive mice were initially trained to perform the instrumental response. b, When a MEK inhibitor [PD0184161 (PD)] was administered before the session, responding on a PR schedule was elevated. Mice were given a 3 week drug washout period and retested, revealing no persistent effects on responding. c, As a control, other mice were injected after the sessions; in this case, breakpoint ratios were unchanged. Bars and symbols represent means ± SEMs per treatment group. *p < 0.05 versus vehicle. n = 10–11 per group.

Figure 9.

Endogenous prefrontal, but not dorsal striatal, BDNF covaries with instrumental responding in intact mice. a, A large group of naive mice was trained to perform the nose-poke response, and then several PR tests were conducted. Total responses on the active aperture are represented. b, vmPFC BDNF expression correlated with response number during the last test session. c, In contrast, dorsal striatal BDNF did not covary with the same measure. Symbols represent means ± SEMs per group in a; symbols in b and c represent individual mice. n = 15.