Alexander W. Johnson

A pathway-specific function for different AMPA receptor subunits in amygdala long-term potentiation and fear conditioning

The AMPA receptor subunit glutamate receptor 1 (GluR1 or GluR-A) contributes to amygdala-dependent emotional learning. It remains unclear, however, to what extent different amygdala pathways depend on GluR1, or other AMPA receptor subunits, for proper synaptic transmission and plasticity, and whether GluR1-dependent long-term potentiation (LTP) is necessary for auditory and contextual fear conditioning. Here, we dissected the role of GluR1 and GluR3 (GluR-C) subunits in AMPA receptor-dependent amygdala LTP and fear conditioning using knock-out mice (GluR1−/− and GluR3−/−). We found that, whereas LTP at thalamic inputs to lateral amygdala (LA) projection neurons and at glutamatergic synapses in the basal amygdala was completely absent in GluR1−/− mice, both GluR1 and GluR3 contributed to LTP in the cortico-LA pathway. Because both auditory and contextual fear conditioning were selectively impaired in GluR1−/− but not GluR3−/− mice, we conclude that GluR1-dependent synaptic plasticity is the dominant form of LTP underlying the acquisition of auditory and contextual fear conditioning, and that plasticity in distinct amygdala pathways differentially contributes to aversive conditioning.

The Basolateral Amygdala Is Critical to the Expression of Pavlovian and Instrumental Outcome-Specific Reinforcer Devaluation Effects

Considerable evidence implicates the basolateral amygdala (BLA) in the formation of outcome representations that link cues to the incentive properties of reinforcers. Animals with BLA damage show impaired performance in reinforcer devaluation tasks, in which the value of the food reinforcer is reduced by satiation or food–toxin pairings after the completion of cue or response training. Although intact animals spontaneously reduce their conditioned responding after such reinforcer devaluation procedures, animals with BLA lesions made before training typically do not, as evidenced across a range of species, training contingencies, and devaluation procedures. In contrast, the role of the BLA in devaluation task performance once such outcome representations are established is unclear. Whereas Pickens et al. (2003) found normal devaluation performance in rats when BLA lesions were made after pavlovian light–food pairings but before devaluation by food–toxin pairings, Ostlund and Balleine (2008) found impaired devaluation performance when BLA lesions were made after instrumental training with multiple instrumental responses and food reinforcers but before devaluation of one reinforcer by selective satiation. Those studies differed in their use of pavlovian or operant training contingencies, single or multiple reinforcers, and associative or motivational devaluation procedures. Here we found that, when multiple reinforcers were used, posttraining BLA lesions disrupted the expression of devaluation performance in rats, using either pavlovian or instrumental training procedures and either conditioned taste aversion or satiation devaluation procedures. Thus, BLA apparently plays a critical role in maintaining or using sensory associations of reinforcer value when multiple outcomes must be coded but not under single-outcome conditions.

Eating beyond metabolic need: how environmental cues influence feeding behavior

Animals use current, past, and projected future states of the organism and the world in a finely tuned system to control ingestion. They must not only deal effectively with current nutrient deficiencies, but also manage energy resources to meet future needs, all within the constraints of the mechanisms of metabolism. Many recent approaches to understanding the control of ingestive behavior distinguish between homeostatic mechanisms concerned with energy balance, and hedonic and incentive processes based on palatability and reward characteristics of food. In this review, I consider how learning about environmental cues influences homeostatic and hedonic brain signals, which may lead to increases in the affective taste properties of food and desire to over consume. Understanding these mechanisms may be critical for elucidating the etiology of the obesity epidemic.

Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness.

Guided by features of molecular, cellular, and circuit dysfunction affecting the prefrontal cortex in clinical investigations, we targeted prefrontal cortex in studies of a model for neuropsychiatric illness using transgenic mice expressing a putative dominant-negative disrupted in schizophrenia 1 (DN-DISC1). We detected marked augmentation of GAPDH–seven in absentia homolog Siah protein binding in the DISC1 mice, a major hallmark of a nuclear GAPDH cascade that is activated in response to oxidative stress. Furthermore, deficits were observed in well-defined tests for the cognitive control of adaptive behavior using reversal learning and reinforcer devaluation paradigms. These deficits occurred even though DN-DISC1 mice showed intact performance in simple associative learning and normal responses in consumption of reward. In an additional series of assessments, motivational functions also were impoverished in DN-DISC1 mice, including tests of the dynamic modulation of reward value by effortful action, progressive ratio performance, and social behavior. Augmentation of an oxidative stress-associated cascade (e.g., a nuclear GAPDH cascade) points to an underlying condition that may contribute to the profile of cognitive and motivational impairments in DN-DISC1 mice by affecting the functional integrity of the prefrontal cortex and dysfunction within its connected networks. As such, this model should be useful for further preclinical research and drug discovery efforts relevant to the burden of prefrontal dysfunction in neuropsychiatric illness.

Learning processes affecting human decision making: An assessment of reinforcer-selective pavlovian-to-instrumental transfer following reinforcer devaluation

In reinforcer-selective transfer, Pavlovian stimuli that are predictive of specific outcomes bias performance toward responses associated with those outcomes. Although this phenomenon has been extensively examined in rodents, recent assessments have extended to humans. Using a stock market paradigm adults were trained to associate particular symbols and responses with particular currencies. During the first test, individuals showed a preference for responding on actions associated with the same outcome as that predicted by the presented stimulus (i.e., a reinforcer-selective transfer effect). In the second test of the experiment, one of the currencies was devalued. We found it notable that this served to reduce responses to those stimuli associated with the devalued currency. This finding is in contrast to that typically observed in rodent studies, and suggests that participants in this task represented the sensory features that differentiate the reinforcers and their value during reinforcer-selective transfer. These results are discussed in terms of implications for understanding associative learning processes in humans and the ability of reward-paired cues to direct adaptive and maladaptive behavior.

A Selective Role for Neuronal Activity Regulated Pentraxin in the Processing of Sensory-Specific Incentive Value

Neuronal activity regulated pentraxin (Narp) is a secreted neuronal product which clusters AMPA receptors and regulates excitatory synaptogenesis. Although Narp is selectively enriched in brain, its role in behavior is not known. As Narp is expressed prominently in limbic regions, we examined whether Narp deletion affects performance on tasks used to assess motivational consequences of food-rewarded learning. Narp knock-out (KO) mice were unimpaired in learning simple pavlovian discriminations, instrumental lever pressing, and in acquisition of at least two aspects of pavlovian incentive learning, conditioned reinforcement and pavlovian–instrumental transfer. In contrast, Narp deletion resulted in a substantial deficit in the ability to use specific outcome expectancies to modulate instrumental performance in a devaluation task. In this task, mice were trained to respond on two levers for two different rewards. After training, mice were prefed with one of the two rewards, devaluing it. Responding on both levers was then assessed in extinction. Whereas control mice showed a significant preference in responding on the lever associated with the nondevalued reward, Narp KO mice responded equally on both levers, failing to suppress responding on the lever associated with the devalued reward. Both groups consumed more of the nondevalued reward in a subsequent choice test, indicating Narp KO mice could distinguish between the rewards themselves. These data suggest Narp has a selective role in processing sensory-specific information necessary for appropriate devaluation performance, but not in general motivational effects of reward-predictive cues on performance.

Greater effort boosts the affective taste properties of food

Actions can create preferences, increasing the value ascribed to commodities acquired at greater cost. This behavioural finding has been observed in a variety of species; however, the causal factors underlying the phenomenon are relatively unknown. We sought to develop a behavioural platform to examine the relationship between effort and reinforcer value in mice trained under demanding or lenient schedules of reinforcement to obtain food. In the initial experiment, expenditure of effort enhanced the value of the associated food via relatively lasting changes in its hedonic attributes, promoting an acquired preference for these reinforcers when tested outside of the training environment. Moreover, otherwise neutral cues associated with those reinforcers during training similarly acquired greater reinforcing value, as assessed under conditioned reinforcement. In a separate experiment, expenditure of effort was also capable of enhancing the value of less-preferred low-caloric reinforcers. Analysis of licking microstructure revealed the basis for this increased valuation was, in part, due to increased palatability of the associated reinforcer. This change in the hedonic taste properties of the food can not only serve as a basis for preference, but also guide decision-making and foraging behaviour by coordinating a potentially adaptive repertoire of incentive motivation, goal-directed action and consumption.

An analysis of licking microstructure in three strains of mice

Mouse models of feeding provide a useful tool for elucidating the molecular pathways of energy regulation. The majority of studies in mice have been limited to intake analyses conducted over extended periods of time, which fail to distinguish between a variety of factors that influence nutrient intake. Using licking microstructure analyses we examined both the size and number of licking bursts for water, polycose, sucrose and lecithin in three strains of mice (C57BL/6J, 129Sv/ImJ and C57129F1 hybrids), using pause criteria (250-500, >500 and >1000 ms) that have previously been described in the rat. Burst size and number varied both as a function of tastant concentration and mouse strain; however, these differences were most evident with the >1000 ms pause criterion. Consistent with previous reports, during water consumption C57 mice showed longer mean interlick intervals, a larger number of bursts but reduced burst size relative to the two other strains. F1 mice showed larger burst sizes for polycose, while C57 mice displayed a greater number of bursts for both polycose and sucrose. Both 129 and F1 mice were insensitive to sucrose concentration, whereas C57 mice showed attenuated lecithin intake influenced by a reduction in the size of bursts for this tastant. These results suggest that these strains of mice display differences in the pattern of licking that are most evident with the use of larger pause criteria. These differences in licking behavior might reflect influences of genetic background on pre- and post-ingestive factors controlling intake, the reinforcing properties of each tastant, or native differences in licking style.

The role of melanin-concentrating hormone in conditioned reward learning

The orexigenic neuropeptide melanin‐concentrating hormone (MCH) is well positioned to play a key role in connecting brain reward and homeostatic systems due to its synthesis in hypothalamic circuitry and receptor expression throughout the cortico‐striatal reward circuit. Here we examined whether targeted‐deletion of the MCH receptor (MCH‐1R) in gene‐targeted heterozygote and knockout mice (KO), or systemic treatment with pharmacological agents designed to antagonise MCH‐1R in C57BL/6J mice would disrupt two putative consequences of reward learning that rely on different neural circuitries: conditioned reinforcement (CRf) and Pavlovian‐instrumental transfer (PIT). Mice were trained to discriminate between presentations of a reward‐paired cue (CS+) and an unpaired CS−. Following normal acquisition of the Pavlovian discrimination in all mice, we assessed the capacity for the CS+ to act as a reinforcer for new nose‐poke learning (CRf). Pharmacological disruption in control mice and genetic deletion in KO mice impaired CRf test performance, suggesting MCH‐1R is necessary for initiating and maintaining behaviors that are under the control of conditioned reinforcers. To examine a dissociable form of reward learning (PIT), a naïve group of mice were trained in separate Pavlovian and instrumental lever training sessions followed by the PIT test. For all mice the CS+ was capable of augmenting ongoing lever responding relative to CS− periods. These results suggest a role for MCH in guiding behavior based on the conditioned reinforcing value of a cue, but not on its incentive motivational value.

Impaired outcome-specific devaluation of instrumental responding in mice with a targeted deletion of the AMPA receptor glutamate receptor 1 subunit.

The present study evaluated the proposal that mice with a targeted deletion of the glutamate receptor 1 (GluR1) subunit of the AMPA receptor are impaired in using an instrumental or pavlovian signal to gain access to a representation of the sensory-specific motivational properties of a primary reward. In experiment 1, mice were trained to approach two goal boxes in a plus-maze; each goal box contained a different reward (sucrose solution vs food pellet). After acquisition, one of the rewards was devalued by an outcome-specific satiety procedure. Subsequent test trials performed in extinction showed an increase in the latency to enter the devalued goal arm, relative to the nondevalued goal arm in control but not GluR1-/- mice. In experiment 2, a similar outcome-specific satiety procedure was used to examine the effects of reward devaluation on an instrumental nose-poke response. During testing, control but not GluR1-/- mice decreased their rate of responding on a nose poke associated with a devalued reward. A subsequent choice test showed that GluR1-/- mice were able to discriminate between the devalued and nondevalued outcomes used in both experiments. These deficits mirror those seen after lesions of the basolateral amygdala and suggests that GluR1-mediated neurotransmission in this region contributes to encoding the relationship between sensory-specific aspects of reward and their incentive value.