Shauna L. Parkes

Incentive Memory: Evidence the Basolateral Amygdala Encodes and the Insular Cortex Retrieves Outcome Values to Guide Choice between Goal-Directed Actions

Choice between goal-directed actions is determined by the relative value of their consequences. Such values are encoded during incentive learning and later retrieved to guide performance. Although the basolateral amygdala (BLA) and the gustatory region of insular cortex (IC) have been implicated in these processes, their relative contribution is still a matter of debate. Here we assessed whether these structures interact during incentive learning and retrieval to guide choice. In these experiments, rats were trained on two actions for distinct outcomes after which one of the two outcomes was devalued by specific satiety immediately before a choice extinction test. We first confirmed that, relative to appropriate controls, outcome devaluation recruited both the BLA and IC based on activation of the immediate early gene Arc; however, we found that infusion of the NMDAr antagonist ifenprodil into the BLA only abolished outcome devaluation when given before devaluation. In contrast, ifenprodil infusion into the IC was effective whether made before devaluation or test. We hypothesized that the BLA encodes and the IC retrieves incentive value for choice and, to test this, developed a novel sequential disconnection procedure. Blocking NMDAr activation unilaterally in the BLA before devaluation and then contralaterally in the IC before test abolished selective devaluation. In contrast, reversing the order of these infusions left devaluation intact. These results confirm that the BLA and IC form a circuit mediating the encoding and retrieval of outcome values, with the BLA encoding and the IC retrieving such values to guide choice.

The Basolateral Amygdala Is Critical for the Acquisition and Extinction of Associations between a Neutral Stimulus and a Learned Danger Signal But Not between Two Neutral Stimuli

We studied the neural substrates of higher-order conditioned fear in rats. We first studied acquisition and extinction of second-order fear. One stimulus (S1) was paired with a footshock unconditioned stimulus (US), a second stimulus (S2) was paired with S1, and, finally, fear of S2 was extinguished by S2 alone exposures. Reversible inactivation of the basolateral amygdala (BLA) via muscimol, systemic injection of the NMDA receptor (NMDAr) antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], or intra-amygdala infusion of the NMDAr NR2B subunit selective antagonist ifenprodil impaired both acquisition and extinction of fear to S2. We then studied acquisition and extinction of sensory preconditioned fear. S2 was first paired with S1, S1 was then paired with the US, and, finally, fear of S2 was extinguished by S2 alone exposures. Extinction of sensory preconditioned fear was impaired by a BLA infusion of muscimol or ifenprodil and by MK-801. Acquisition of the S2–S1 association and extinction of this association by S2 alone exposures before conditioning of S1 was impaired by MK-801 but not by a BLA infusion of muscimol. These results show that NMDAr activation in the BLA is critical for acquisition of second-order conditioned fear and for the extinction of both second-order and sensory preconditioned fear just as it is for acquisition and extinction of first-order conditioned fear. Acquisition and extinction of an association between two neutral stimuli also require NMDAr activation. However, the present results show that the acquisition and extinction of these associations do not require the BLA.

Interaction of Insular Cortex and Ventral Striatum Mediates the Effect of Incentive Memory on Choice Between Goal-Directed Actions

The anterior insular cortex (IC) and the nucleus accumbens (NAc) core have been separately implicated in the selection and performance of actions based on the incentive value of the instrumental outcome. Here, we examined the role of connections between the IC and the NAc core in the performance of goal-directed actions. Rats were trained on two actions for distinct outcomes, after which one of the two outcomes was devalued by specific satiety immediately before a choice extinction test. We first confirmed the projection from the IC to the NAc core and then disconnected these structures via asymmetrical excitotoxic lesions before training. Contralateral, but not ipsilateral, disconnection of the IC and NAc core disrupted outcome devaluation. We hypothesized that communication between the IC and NAc core is necessary for the retrieval of incentive value at test. To test this, we infused the GABAA agonist muscimol into the IC and the μ-opioid receptor antagonist CTAP into the contralateral NAc before the choice extinction test. As expected, inactivation of the IC in one hemisphere and blocking μ-opioid receptors in the contralateral NAc core abolished outcome-selective devaluation. These results suggest that the IC and NAc core form part of a circuit mediating the retrieval of outcome values and the subsequent choice between goal-directed actions based on those values.

Role of the basolateral amygdala and NMDA receptors in higher-order conditioned fear

Abstract Laboratory rats learn to fear relatively innocuous stimuli which signal the imminent arrival of an innate source of danger, typically brief but aversive foot shock. Much is now known about the neural substrates underling the acquisition, consolidation and subsequent expression of this fear. Rats also learn to fear stimuli which signal learned sources of danger but relatively little is known about the neural substrates underlying this form of fear. Two Pavlovian conditioning paradigms used to study this form of fear are second-order conditioning and sensory preconditioning. In second-order conditioning, rats are first exposed to a signaling relationship between one stimulus, such as a tone, and aversive foot shock, and then to a signaling relationship between a second stimulus, such as a light, and the now dangerous tone. In sensory preconditioning, these phases are reversed: rats are first exposed to a signaling relationship between the light and the tone and then to a signaling relationship between the tone and the foot shock. In both paradigms, rats exhibit fear when tested with the light. In this review paper, we describe the evidence for higher-order forms of conditioning, the conditions which promote this learning and its contents. We compare and contrast the substrates of the learning underlying second-order and sensory preconditioning fear with those known to underlie the better studied first-order conditioned fear. We conclude with some comments as to the role of higher-order processes in anxiety disorders.

The Basolateral Amygdala Is Critical for Learning about Neutral Stimuli in the Presence of Danger, and the Perirhinal Cortex Is Critical in the Absence of Danger

The perirhinal cortex (PRh) and basolateral amygdala (BLA) appear to mediate distinct aspects of learning and memory. Here, we used rats to investigate the involvement of the PRh and BLA in acquisition and extinction of associations between two different environmental stimuli (e.g., a tone and a light) in higher-order conditioning. When both stimuli were neutral, infusion of the GABAA, muscimol, or the NMDA receptor (NMDAR) antagonist ifenprodil into the PRh impaired associative formation. However, when one stimulus was neutral and the other was a learned danger signal, acquisition and extinction of the association between them was unaffected by manipulations targeting the PRh. Temporary inactivation of the BLA had the opposite effect: formation and extinction of an association between two stimuli was spared when both stimuli were neutral, but impaired when one stimulus was a learned danger signal. Subsequent experiments showed that the experience of fear per se shifts processing of an association between neutral stimuli from the PRh to the BLA. When training was conducted in a dangerous environment, formation and extinction of an association between neutral stimuli was impaired by BLA inactivation or NMDAR blockade in this region, but was unaffected by PRh inactivation. These double dissociations in the roles of the PRh and BLA in learning under different stimulus and environmental conditions imply that fear-induced activation of the amygdala changes how the brain processes sensory stimuli. Harmless stimuli are treated as potentially harmful, resulting in a shift from cortical to subcortical processing in the BLA.

Microglial Activation Enhances Associative Taste Memory through Purinergic Modulation of Glutamatergic Neurotransmission

The cerebral innate immune system is able to modulate brain functioning and cognitive processes. During activation of the cerebral innate immune system, inflammatory factors produced by microglia, such as cytokines and adenosine triphosphate (ATP), have been directly linked to modulation of glutamatergic system on one hand and learning and memory functions on the other hand. However, the cellular mechanisms by which microglial activation modulates cognitive processes are still unclear. Here, we used taste memory tasks, highly dependent on glutamatergic transmission in the insular cortex, to investigate the behavioral and cellular impacts of an inflammation restricted to this cortical area in rats. We first show that intrainsular infusion of the endotoxin lipopolysaccharide induces a local inflammation and increases glutamatergic AMPA, but not NMDA, receptor expression at the synaptic level. This cortical inflammation also enhances associative, but not incidental, taste memory through increase of glutamatergic AMPA receptor trafficking. Moreover, we demonstrate that ATP, but not proinflammatory cytokines, is responsible for inflammation-induced enhancement of both associative taste memory and AMPA receptor expression in insular cortex. In conclusion, we propose that inflammation restricted to the insular cortex enhances associative taste memory through a purinergic-dependent increase of glutamatergic AMPA receptor expression at the synapse.

Differential role of insular cortex muscarinic and NMDA receptors in one-trial appetitive taste learning

Our current understanding of the neurobiology of taste learning and memory has been greatly facilitated by the use of a reliable behavioural model, conditioned taste aversion (CTA). This model has revealed that the insular cortex (IC), specifically muscarinic and N-methyl-d-aspartate (NMDA) receptor activation in the IC, is critical for the formation of aversive taste memories. In contrast, current models of appetitive taste learning are less adequate, relying on the use of neophobic tastes (attenuation of neophobia) or on the integration of appetitive and aversive taste memories (latent inhibition of CTA). While these models have implicated IC muscarinic receptors, the involvement of NMDA receptors in the IC remains unclear. Here, we examined the role of both muscarinic and NMDA receptors in appetitive taste learning using a simple paradigm that is independent of neophobic and aversive components. First, we demonstrated that a single exposure to a novel taste, saccharin 0.1%, is sufficient to promote an appetitive taste memory as revealed by an increase in saccharin consumption during the second presentation. This increase was blocked by bilateral infusion in the IC of the muscarinic receptor antagonist, scopolamine. In contrast, infusion of the NMDA receptor antagonist, AP5, did not block appetitive taste learning but did abolish CTA. Therefore, common and distinct molecular substrates within the IC mediate appetitive versus aversive learning about the same taste.

The effect of high-fat diet consumption on appetitive instrumental behavior in rats

Evidence now indicates that the chronic consumption of high-calorie foods, such as a high-fat diet (HFD), is associated with impaired control over food-seeking, yet the extent of this alteration is not fully understood. Using different reinforcement schedules, we evaluated whether HFD intake from weaning to adulthood modifies instrumental responding and induces a shift from goal-directed actions to habitual responding. We first observed reduced instrumental performance and motivation for a food reward in HFD-fed rats trained under schedules of reinforcement that facilitate habitual responding [Random Interval (RI)]. However, this deficit was alleviated if rats trained under RI were subsequently trained with reinforcement schedules that promote goal-directed strategies [Random Ratio (RR)]. Using an outcome devaluation procedure, we then demonstrated that consumption of a HFD promoted habitual behavior in rats trained under RI but not RR schedules. Finally, extended HFD exposure did not interfere with the ability of RR training to overcome impaired RI instrumental performance and to favor goal-directed behavior. These results indicate that chronic consumption of a HFD changes the co-ordination of goal-directed actions and habits and that alteration of food-seeking may be reversed under particular behavioral conditions.

Switching Adolescent High-Fat Diet to Adult Control Diet Restores Neurocognitive Alterations.

In addition to metabolic and cardiovascular disorders, obesity is associated with adverse cognitive and emotional outcomes. Its growing prevalence in adolescents is particularly alarming since this is a period of ongoing maturation for brain structures (including the hippocampus and amygdala) and for the hypothalamic-pituitary-adrenal (HPA) stress axis, which is required for cognitive and emotional processing. We recently demonstrated that adolescent, but not adult, high-fat diet (HF) exposure leads to impaired hippocampal function and enhanced amygdala function through HPA axis alteration (Boitard et al., 2012, 2014, 2015). Here, we assessed whether the effects of adolescent HF consumption on brain function are permanent or reversible. After adolescent exposure to HF, switching to a standard control diet restored levels of hippocampal neurogenesis and normalized enhanced HPA axis reactivity, amygdala activity and avoidance memory. Therefore, while the adolescent period is highly vulnerable to the deleterious effects of diet-induced obesity, adult exposure to a standard diet appears sufficient to reverse alterations of brain function.

Acquisition of specific response-outcome associations requires NMDA receptor activation in the basolateral amygdala but not in the insular cortex.

The basolateral amygdala (BLA) and the gustatory region of the insular cortex (IC) are required for the encoding and retrieval of outcome value. Here, we examined if these regions are also necessary to learn associations between actions and their outcomes. Hungry rats were first trained to press two levers for a common outcome. Next, specific response-outcome (R-O) associations were introduced such that each response now earned a distinct food outcome. Prior to each specific R-O training session, rats received a bilateral infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-APV, into either the BLA or the IC. One of the two outcomes was then devalued immediately prior to a choice test. Inhibition of NMDA receptor activity in the BLA, but not the IC, during the acquisition of specific R-O associations abolished selective devaluation. These results indicate that the BLA is critical for learning the association between actions and their specific consequences.