Rebecca E. Nordquist

Augmented reinforcer value and accelerated habit formation after repeated amphetamine treatment.

Various processes might explain the progression from casual to compulsive drug use underlying the development of drug addiction. Two of these, accelerated stimulus-response (S-R) habit learning and augmented assignment of motivational value to reinforcers, could be mediated via neuroadaptations associated with long-lasting sensitization to psychostimulant drugs, i.e. augmented dopaminergic neurotransmission in the striatum. Here, we tested the hypothesis that both processes, which are often regarded as mutually exclusive alternatives, are present in amphetamine-sensitized rats. Amphetamine-sensitized rats showed increased responding for food under a random ratio schedule of reinforcement, indicating increased incentive motivational value of food. In addition, satiety-specific devaluation experiments under a random interval schedule of reinforcement showed that amphetamine-sensitized animals exhibit accelerated development of S-R habits. These data show that both habit formation and motivational value of reinforcers are augmented in amphetamine-sensitized rats, and suggest that the task demands determine which behavioral alteration is most prominently expressed.

Assessing learning and memory in pigs

In recent years, there has been a surge of interest in (mini) pigs (Sus scrofa) as species for cognitive research. A major reason for this is their physiological and anatomical similarity with humans. For example, pigs possess a well-developed, large brain. Assessment of the learning and memory functions of pigs is not only relevant to human research but also to animal welfare, given the nature of current farming practices and the demands they make on animal health and behavior. In this article, we review studies of pig cognition, focusing on the underlying processes and mechanisms, with a view to identifying. Our goal is to aid the selection of appropriate cognitive tasks for research into pig cognition. To this end, we formulated several basic criteria for pig cognition tests and then applied these criteria and knowledge about pig-specific sensorimotor abilities and behavior to evaluate the merits, drawbacks, and limitations of the different types of tests used to date. While behavioral studies using (mini) pigs have shown that this species can perform learning and memory tasks, and much has been learned about pig cognition, results have not been replicated or proven replicable because of the lack of validated, translational behavioral paradigms that are specially suited to tap specific aspects of pig cognition. We identified several promising types of tasks for use in studies of pig cognition, such as versatile spatial free-choice type tasks that allow the simultaneous measurement of several behavioral domains. The use of appropriate tasks will facilitate the collection of reliable and valid data on pig cognition.

Learning-related changes in response patterns of prefrontal neurons during instrumental conditioning.

A crucial aspect of organizing goal-directed behavior is the ability to form neural representations of relationships between environmental stimuli, actions and reinforcement. Very little is known yet about the neural encoding of response-reward relationships, a process which is deemed essential for purposeful behavior. To investigate this, tetrode recordings were made in the medial prefrontal cortex (PFC) of rats performing a Go-NoGo task. After task acquisition, a subset of neurons showed a sustained change in firing during the rewarded action sequence that was triggered by a specific visual cue. When these changes were monitored in the course of learning, they were seen to develop in parallel with the behavioral learning curve and were highly sensitive to a switch in reward contingencies. These sustained changes correlated with the reward-associated action sequence, not with sensory or reward-predicting properties of the cue or individual motor acts per se. This novel type of neural plasticity may contribute to the formation of response-reinforcer associations and of behavioral strategies for guiding goal-directed action.

The prevention and control of feather pecking in laying hens: identifying the underlying principles

Feather pecking (FP) in laying hens remains an important economic and welfare issue. This paper reviews the literature on causes of FP in laying hens. With the ban on conventional cages in the EU from 2012 and the expected future ban on beak trimming in many European countries, addressing this welfare issue has become more pressing than ever. The aim of this review paper is to provide a detailed overview of underlying principles of FP. FP is affected by many different factors and any approach to prevent or reduce FP in commercial flocks should acknowledge that fact and use a multifactorial approach to address this issue. Two forms of FP can be distinguished: gentle FP and severe FP. Severe FP causes the most welfare issues in commercial flocks. Severe FP is clearly related to feeding and foraging behaviour and its development seems to be enhanced in conditions where birds have difficulty in coping with environmental stressors. Stimulating feeding and foraging behaviour by providing high-fibre diets and suitable litter from an early age onwards, and controlling fear and stress levels through genetic selection, reducing maternal stress and improving the stockmanship skills of the farmer, together offer the best prospect for preventing or controlling FP.

Effects of aripiprazole/OPC-14597 on motor activity, pharmacological models of psychosis, and brain activity in rats.

Aripiprazole (OPC-14597) is an antipsychotic with a unique pharmacology as a dopamine D2 receptor partial agonist, which has been demonstrated to reduce symptoms of schizophrenia. To further profile this compound in preclinical models, we examined aripiprazole-induced activity changes as measured by pharmacological magnetic resonance imaging (MRI) and characterized the drug in several rodent models of motor behaviors and of psychosis. Continuous arterial spin labeling MRI measuring blood perfusion (as an indirect measure of activity) reveals that aripiprazole dose-dependently decreased brain activity in the entorhinal piriform cortex, perirhinal cortex, nucleus accumbens shell, and basolateral amygdala. While no deficits were observed in the rotarod test for motor coordination in the simpler (8 RPM) version, in the more challenging condition (16 RPM) doses of 10 and 30mg/kg i.p. produced deficits. Catalepsy was seen only at the highest dose tested (30mg/kg i.p.) and only at the 3 and 6h time points, not at the 1h time point. In pharmacological models of psychosis, 1-30mg/kg aripiprazole i.p. effectively reduced locomotor activity induced by dopamine agonists (amphetamine and apomorphine), NMDA antagonists (MK-801 and phencyclidine (PCP)), and a serotonin agonist (2,5-dimethoxy-4-iodoamphetamine (DOI)). However, aripiprazole reversed prepulse inhibition deficits induced by amphetamine, but not by any of the other agents tested. Aripiprazole alters brain activity in regions relevant to schizophrenia, and furthermore, has a pharmacological profile that differs for the two psychosis models tested and does not match the typical or atypical psychotics. Thus, D2 partial agonists may constitute a new group of antipsychotics.

mGlu5 receptor antagonists and their therapeutic potential

Background: Glutamate mediates its effects via ionotropic and metabotropic glutamate (mGlu) receptors. mGlu receptors are G protein-coupled receptors that are classified into three clusters, group I-III. This review focuses on the mGlu5 receptors of group I. mGlu5 receptors are highly expressed in limbic brain regions and are located postsynaptically. Objective: Following the discovery of the prototypical negative allosteric modulator MPEP, the therapeutic potential of mGlu5 receptors has been steadily explored and expanded. This review highlights present developments in drug discovery and the therapeutic potential of negative allosteric modulators. Methods: Material evaluated ranged from patents to published literature, but also included information that is available from public-accessible websites. Results/conclusion: Based on the wide and consistent effects of prototypical antagonists, such as MPEP, it is concluded that mGlu5 receptor antagonists have treatment potential for both peripheral and central nervous system disorders ranging from psychiatric, neurological to neuromuscular, including illnesses with no apparent nervous system link, such as cancer.

Making Decisions under Ambiguity: Judgment Bias Tasks for Assessing Emotional State in Animals

Judgment bias tasks (JBTs) are considered as a family of promising tools in the assessment of emotional states of animals. JBTs provide a cognitive measure of optimism and/or pessimism by recording behavioral responses to ambiguous stimuli. For instance, a negative emotional state is expected to produce a negative or pessimistic judgment of an ambiguous stimulus, whereas a positive emotional state produces a positive or optimistic judgment of the same ambiguous stimulus. Measuring an animal’s emotional state or mood is relevant in both animal welfare research and biomedical research. This is reflected in the increasing use of JBTs in both research areas. We discuss the different implementations of JBTs with animals, with a focus on their potential as an accurate measure of emotional state. JBTs have been successfully applied to a very broad range of species, using many different types of testing equipment and experimental protocols. However, further validation of this test is deemed necessary. For example, the often extensive training period required for successful judgment bias testing remains a possible factor confounding results. Also, the issue of ambiguous stimuli losing their ambiguity with repeated testing requires additional attention. Possible improvements are suggested to further develop the JBTs in both animal welfare and biomedical research.

Cognitive performance of low- and normal-birth-weight piglets in a spatial hole-board discrimination task.

Introduction:Learning impairments are often seen in children born with low birth weight (LBW). A model with translational value for long-term effects of LBW in humans is needed to further our understanding of how LBW and cognition are related. The similarities between development stages in human infants and piglets, and the high prevalence of LBW piglets make them a naturally occurring potential model in which to study cognitive impairment associated with LBW in humans.Results:Although both groups learned the configurations and rapidly reduced the number of incorrect visits, the LBW piglets showed a transiently retarded acquisition of the first reversal.Discussion:The results of the experiment support the hypothesis that LBW is related to (mild) subsequent cognitive impairments. In the future, piglets may be suitable models for testing the effects of putative therapeutics.Methods:To examine this potential model, we tested pairs of LBW and NBW (normal-birth-weight) piglets in a spatial hole-board (a matrix with 4 × 4 holes in the floor) task during one acquisition and two reversal phases in their own individual configurations of rewarded holes.

The appetitively motivated “cognitive” holeboard: A family of complex spatial discrimination tasks for assessing learning and memory

Spatial learning and memory tasks have captured a solid position in neuroscience research. A variety of holeboard-type tasks are suitable for investigating the effects of a broad range of experimental manipulations on spatial learning and memory in a broad range of species, including fish, rodents, cats, pigs, tupaias, and humans. We summarize the concepts and procedures underlying tests of spatial discrimination learning, with special emphasis on holeboard-type tasks and task-specific characteristics. Holeboard-type tasks enable a broad range of mnemonic and cognitive variables to be measured in parallel, including cognitive processes such as habituation processes, spatial working and reference memory, and search strategies, but also non-cognitive variables, such as exploration, anxiety-related behavior, and stereotypies. These tasks are sensitive to a large number of naturally occurring differences (e.g. strain differences and age effects) and to the effects of non-genetic (e.g. specific brain lesions, stress, treatment with cognition impairers or cognition enhancers) and genetic experimental manipulations. In conclusion, holeboard-type tasks provide powerful tools to investigate multiple aspects of spatial orientation behavior in the same experimental setup. Cross-species comparison of holeboard performance shows the potential for translational studies.

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

RationaleThe increasing awareness of the need to align clinical and preclinical research to facilitate rapid development of new drug therapies is reflected in the recent introduction of the term “translational medicine”. This review examines the implications of translational medicine for psychiatric disorders, focusing on metabotropic glutamate (mGlu) receptor biology in anxiety disorders and on anxiety-related biomarkers.ObjectivesThis review aims to (1) examine recent progress in translational medicine, emphasizing the role that translational research has played in understanding of the potential of mGlu receptor agonists and antagonists as anxiolytics, (2) identify lacunas where animal and human research have yet to be connected, and (3) suggest areas where translational research can be further developed.ResultsCurrent data show that animal and human mGlu5 binding can be directly compared in experiments using the PET ligand 11C-ABP688. Testing of the mGlu2/3 receptor agonist LY354740 in the fear-potentiated startle paradigm allows direct functional comparisons between animals and humans. LY354740 has been tested in panic models, but in different models in rats and humans, hindering efforts at translation. Other potentially translatable methods, such as stress-induced hyperthermia and HPA-axis measures, either have been underexploited or are associated with technical difficulties. New techniques such as quantitative trait loci (QTL) analysis may be useful for generating novel biomarkers of anxiety.ConclusionsTranslational medicine approaches can be valuable to the development of anxiolytics, but the amount of cross-fertilization between clinical and pre-clinical departments will need to be expanded to realize the full potential of these approaches.