Contributions of basolateral amygdala and nucleus accumbens subregions to mediating motivational conflict during punished reward-seeking

https://doi.org/10.1016/j.nlm.2017.02.017Get rights and content

Highlights

  • The basolateral amygdala and accumbens shell suppress punished reward seeking.

  • These regions also promote reward seeking in aversive contexts.

  • The accumbens core facilitates reward seeking independent of motivational conflict.

Abstract

The involvement of different nodes within meso-cortico-limbic-striatal circuitry in mediating reward-seeking has been well described, yet comparatively less is known about how such circuitry may regulate appetitively-motivated behaviors that may be punished. The basolateral amygdala (BLA) is one nucleus that has been implicated in suppressing punished reward-seeking, and this structure can modulate goal-directed behavior via projections to subregions of the nucleus accumbens (NAc). Here, we examined the effects of reversible inactivations of the BLA, NAc Shell (NAcS), and core (NAcC) on performance of a “Conflict” task where rats pressed a lever for sucrose reinforcement during three distinct 5 min phases. During the first and last phases of a session, rats lever-pressed for food reward delivered on a VI-15/FR5 schedule. In between these phases was a signaled “Conflict” period, where each lever-press yielded food, but 50% of presses were also punished with foot-shock. Under control conditions, well-trained rats responded vigorously during the two “safe” VI-15/FR5 periods, but reduced responding during the punished Conflict period. Inactivation of either the BLA or the NAcS via infusions of baclofen/muscimol disinhibited punished seeking, increasing lever-pressing during the conflict period, while attenuating pressing during VI-15/FR5 phases. In contrast, NAcC inactivation markedly decreased responding across all three phases. Similar inactivation of the BLA or NAcS did not alter responding in a separate control experiment where rats pressed for food on schedules identical to the Conflict task in the absence of any punishment, while NAcC inactivation again suppressed responding. These results imply that BLA and NAcS are part of a circuit that suppresses reward-seeking in the face of danger, which in turn may have implications for disorders characterized by punishment resistance, including substance abuse and obsessive–compulsive disorder.

Introduction

The ability to use information regarding the aversive or rewarding consequences of actions to guide subsequent behavior is a key function of the nervous system. Considerable research has been dedicated to clarifying the influence of positive reinforcement on decision-making, implicating meso-cortico-limbic-striatal circuitry in such reinforcement learning (Cardinal et al., 2002, Floresco, 2015, Parkinson et al., 2000). In contrast, less is known about how this system guides behavior in response to punishment, a process by which an instrumental action co-occurs with a negative consequence, such as a lever-press-contingent foot-shock in rodents. In a majority of individuals, punishment serves to suppress the instrumental action with which it occurs. However, neuropsychiatric conditions such as obsessive–compulsive disorder and substance abuse are characterized by compulsivity, whereby punishment is less effective in curtailing detrimental behavioral patterns (Everitt, 2014, Feil et al., 2010, Figee et al., 2016, Jentsch and Taylor, 1999, Lubman et al., 2004, Perry and Carroll, 2008). As such, investigation of the circuitry underlying punishment-induced inhibitory control may provide insight into the pathophysiological underpinnings of these symptoms in various disease states.

Compulsivity in the face of punishment is recognized by the DSM-5 as a core symptom of substance abuse and other disorders, and pre-clinical findings suggests that these symptoms may be driven by alterations within cortico-limbic circuitry (Chen et al., 2013, Limpens et al., 2014, Pelloux et al., 2013, Radke et al., 2015, Radke et al., 2015). Prolonged access to cocaine produces punishment-resistant drug seeking, concomitant with hypofunction of medial prefrontal cortex (mPFC) (Chen et al., 2013). Optogenetic inhibition or activation of mPFC decreases or increases, respectively, the impact of punishment on cocaine seeking (but see Pelloux et al., 2013), suggesting that mPFC activity may be causally related to the punishment-mediated inhibition of seeking. Similarly, pharmacological inactivation or lesions of the mPFC produces operant responding for both cocaine and sucrose that is insensitive to potential punishment (Limpens et al., 2015, Resstel et al., 2008). Prefrontal regions seem to perform a top-down inhibitory function, acting as a break when responding is directly punished, or in the presence of a fear-inducing stimulus. Likewise, the basolateral amygdala (BLA) promotes behavioral suppression during punishment. Jean-Richard-Dit-Bressel and McNally (2015) recently showed that inactivation of caudal (but not rostral) BLA eliminated the inhibition of lever-pressing produced by contingent foot-shock. Inactivated rats made more lever-presses during punishment, and did not display the typical increase in latency to press caused by punishment. Thus, both mPFC and BLA may contribute to punishment avoidance during appetitively-motivated behavior in a similar manner.

Although the BLA and PFC appear to subserve complementary roles in punishment avoidance, the downstream structure mediating this effect is currently unknown. The nucleus accumbens (NAc) receives dense glutamatergic input from both mPFC and BLA, and is known to regulate various forms of appetitive conditioning via its meso-cortico-limbic efferents (Cardinal et al., 2002, Floresco, 2015, Sesack and Grace, 2010). The NAc is primarily composed of two functionally and anatomically distinct subregions, the more lateral Core (NAcC) and more medial Shell (NAcS) (Heimer et al., 1997, Zahm and Brog, 1992). These two subregions have been suggested to serve dissociable yet complementary functions during reward-seeking, with the NAcC driving approach towards motivationally-relevant stimuli, and the NAcS facilitating inhibition of inappropriate behaviors (Ambroggi et al., 2011, Floresco, 2015). In this regard, the ventral regions of the mPFC and caudal BLA project strongly to the medial NAcS (Berendse et al., 1992, Brog et al., 1993, Groenewegen et al., 1999, Heilbronner et al., 2016, Kita and Kitai, 1990, Wright et al., 1996), suggesting that this nucleus may facilitate inhibition of punished behavior regulated by these upstream cortical and limbic regions. It is therefore possible that NAc subregions may differentially contribute to adjusting behavior in response to punishment, with NAcS suppressing reward-seeking in the face of punishment in a manner similar to the BLA or PFC, and NAcC generally promoting action.

The present series of experiments were designed to both confirm a role for BLA in mediating reward/punishment conflict, and explore the potential differential contribution of NAcS versus NAcC to the same behavior. To this end, separate groups of well-trained rats received reversible inactivation of BLA, NAcS, or NAcC while performing an operant-based “Conflict” task. During this task, sucrose reward was available on a lean reinforcement schedule, without punishment, during two safe “Safe/Reward” periods. Interspersed between these periods was a separate “Conflict” period, wherein sucrose was available on a richer schedule, but 50% of lever-presses triggered a foot-shock punishment. Results using this Conflict task, and a “No-Conflict” (identical schedules of reinforcement, but no punishment) control variant, suggested that BLA and NAcS promote punishment-induced behavioral suppression, while NAcC plays a more general role in driving reward-seeking.

Section snippets

Animals

All experimental protocols were approved by the Animal Care Committee, University of British Columbia, and conducted in compliance with guidelines provided by the Canadian Council on Animal Care. All reasonable efforts were made to minimize the number and suffering of animals used. Male Long-Evans rats arrived weighing 225–350 g (Charles River) and were group housed (4–5 per cage) and allowed 6–7 d of acclimation to the colony. Colony temperature (21 °C) and light cycle (12-h light/dark) were kept

BLA inactivation

Under control conditions, rats that were well-trained on the Conflict task (n = 11) apportioned their lever-pressing in an adaptive manner across the three, 5-min phases (Fig. 2A), as they had done during the later phases of training. These animals displayed robust levels of responding during the un-punished, but less frequently reinforced Safe/Reward phases, whereas during the punished Conflict phase, rats showed a dramatic reduction in lever-pressing. BLA inactivation markedly altered this

Summary

The present findings reveal complementary roles for the BLA and NAcS in mediating responding in situations involving motivational conflict where actions may yield both reward and potential punishment. Neural activity in these two nuclei facilitated response-suppression when lever-presses yielded both food and shock, while in the same context, these regions invigorated responding when the effort requirements to obtain unpunished rewards were greater. These effects on the Conflict task did not

Conclusion

These findings point to complementary roles for the BLA and NAcS in suppressing appetitively-motivated behaviors in the face of punishment. This form of response-suppression mechanism is adaptive, with survival often predicated on weighing potential benefits against punishments when seeking food, or other primary rewards. In addition, all of the regions investigated here played an important role during safe reward-seeking, although NAcS and BLA were selectively recruited following a history of

Acknowledgements

This work was supported by a Discovery Grant from the National Science and Engineering Research Council of Canada to SBF. We thank Mr. Maric T. Tse and Ms. Desire M. Haluk for their assistance with behavioral testing.

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