Prefrontal cortical and nucleus accumbens contributions to discriminative conditioned suppression of reward-seeking

Abstract

Fear can potently inhibit ongoing behavior, including reward-seeking, yet the neural circuits that underlie such suppression remain to be clarified. Prior studies have demonstrated that distinct subregions of the rodent medial prefrontal cortex (mPFC) differentially affect fear behavior, whereby fear expression is promoted by the more dorsal prelimbic cortex (PL) and inhibited by the more ventral infralimbic cortex (IL). These mPFC regions project to subregions of the nucleus accumbens, the core (NAcC) and shell (NAcS), that differentially contribute to reward-seeking as well as affective processes that may be relevant to fear expression. Here, we investigated how these mPFC and NAc subregions contribute to discriminative fear conditioning, assessed by conditioned suppression of reward-seeking. Bilateral inactivation of the NAcS or PL reduced the expression of conditioned suppression to a shock-associated CS+, whereas NAcC inactivation reduced reward-seeking without affecting suppression. IL inactivation caused a general reduction in conditioned suppression following discriminative conditioning, but not when using a single-stimulus design. Pharmacological disconnection of the PL → NAcS pathway revealed that this projection mediates conditioned suppression. These data add to a growing literature implicating discrete cortico-striatal pathways in the suppression of reward-seeking in response to aversive stimuli. Dysfunction within related structures may contribute to aberrant patterns of behavior in psychiatric illnesses including substance use disorders.

FIGURE 1.

Discriminative fear task diagram and histology. (A) Discriminative fear task procedure. (B) Histology figure diagraming location of infusions for animals used in the bilateral inactivation experiment. Red triangles represent NAcS placements, yellow pentagons indicate NAcC placements, blue circles represent PL placements and gray circles represent IL placements. Each dot represents the most ventral extent of the infusion, as observed in Nissl stained sections and the numbers beside each plate represent mm from bregma.

FIGURE 2.

NAcS, but not NAcC, mediates the expression of conditioned suppression. (A) NAcS inactivation (B/M) selectively diminished the expression of conditioned suppression toward the CS+, as compared to SAL-infused controls. Mean suppression ratio collapsed across the four of each CS type (left), and displayed for each individual CS (right). (B) Inactivation of the NAcC had no impact on conditioned suppression expression. Mean suppression ratio collapsed across the four of each CS type (left), and displayed for each individual CS (right). Open star represents a main effect of CS Type or Treatment, P < 0.05. Closed star represents a significant difference between the Treatment conditions on suppression induced by the CS+, P < 0.05.

FIGURE 3.

Both PL and IL mPFC subregions control the expression of conditioned suppression. (A) PL cortex was necessary for the appropriate expression of discriminative suppression, as B/M treatment diminished the degree of suppression to the CS+, as compared to SAL treatment. Mean suppression ratio collapsed across the four of each CS type (left), and displayed for each individual CS (right). (B) Inactivation of IL produced a qualitatively similar effect, diminishing overall suppression. Mean suppression ratio collapsed across the four of each CS type (left), and displayed for each individual CS (right). Open star represents a main effect of CS Type or Treatment, P < 0.05. n.s.: nonsignificant.

FIGURE 4.

IL inactivation has no impact on conditioned suppression expression conducted using a standard, single-stimulus design. (A) Histology schematic for animals in the single-stimulus fear conditioning experiment. Yellow circles represent the ventral extent of infusion into the IL cortex. (B) Infusion of B/M into the IL had no impact on the expression of conditioned suppression when evaluated using a single-stimulus. Suppression data are plotted as blocks of 2 CS+ presentations.

FIGURE 5.

A PL-NAcS projection contributes to the expression of conditioned suppression. (A) Histology schematic illustrating the ventral extent of each infusion in the NAcS (left) or PL cortex (right). Closed circles represent contralateral infusions (SAL or Contra-Disc), closed triangles represent ipsilateral disconnections (Ipsi-Disc), and gray pentagons represent unilateral inactivation (Uni-Inact). (B) Animals that underwent contralateral disconnection (Contra-Disc) or ipsilateral disconnection (Ipsi-disc) expressed less fear toward the CS+, as compared to control animals (SAL). Conditioned suppression induced by the CS+ in the unilateral inactivation group (Uni-Inact) was significantly higher from contralateral disconnection animals, but did not differ from the Ipsi-Disc or SAL groups. Closed star: comparison of suppression to the CS+, P < 0.05 between the SAL group and the Contra-Disc or Ipsi-Disc groups, and open star, P < 0.05 Contra-Disc versus Uni-Inact group.