The neural basis of reversal learning: An updated perspective

doi:10.1016/j.neuroscience.2016.03.021

Neuroscience

Volume 345, 14 March 2017, Pages 12-26

https://doi.org/10.1016/j.neuroscience.2016.03.021 Get rights and content

Highlights

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Reversal learning is a widely used test of cognitive flexibility across species.
•
The idea that this learning primarily measures response inhibition has been revised.
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We describe how it is measured and present new definitions for its construct validity.
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We also present an update of the brain regions and neurotransmitters that support it.

Abstract

Reversal learning paradigms are among the most widely used tests of cognitive flexibility and have been used as assays, across species, for altered cognitive processes in a host of neuropsychiatric conditions. Based on recent studies in humans, non-human primates, and rodents, the notion that reversal learning tasks primarily measure response inhibition, has been revised. In this review, we describe how cognitive flexibility is measured by reversal learning and discuss new definitions of the construct validity of the task that are serving as a heuristic to guide future research in this field. We also provide an update on the available evidence implicating certain cortical and subcortical brain regions in the mediation of reversal learning, and an overview of the principal neurotransmitter systems involved.

Introduction

Cognitive flexibility, the ability to rapidly change behavior in the face of changing circumstances, is disrupted in many psychiatric and neurological disorders. Determining the neural basis of cognitive flexibility is therefore important for understanding the pathophysiology of these disorders and potentially developing treatments. To study the neural substrates of cognitive flexibility in rodents, nonhuman primates, and humans, researchers have often used a set of paradigms collectively referred to as reversal learning. Across species, these paradigms are subtly different, but importantly they all assess cognitive flexibility by evaluating adaptive responding in the face of changing stimulus-outcome (S-O) or response-outcome (R-O) contingencies.

Over the years, reversal learning has become a pre-eminent test of cognitive flexibility and has been used to characterize altered cognitive processes in a host of neuropsychiatric disorders, including substance abuse, obsessive compulsive disorder, psychopathy, Parkinson’s disease, schizophrenia, and to assess cognition at certain developmental time periods such as adolescence (Swainson et al., 2000, Remijnse et al., 2006, Finger et al., 2008, Brigman et al., 2009, Leeson et al., 2009, van der Schaaf et al., 2011, Izquierdo and Jentsch, 2012). Despite its long history of use, reversal learning continues to be an essential experimental paradigm for assessing cognitive function. Indeed, recent years have seen a precipitous rise in the number of published studies using reversal learning, with almost equal focus on rodent, monkey and human subjects (Fig. 1).

While the literature on the neural basis of reversal and the interpretation of findings using this task have been reviewed elsewhere (Clark et al., 2004, Izquierdo and Jentsch, 2012, Costa et al., 2015, Hamilton and Brigman, 2015, Wassum and Izquierdo, 2015), our aim here is to: (1) consider how reversal can be measured and compare different versions of the paradigm across species; (2) provide an updated perspective on the construct validity of reversal learning paradigms; (3) discuss current thinking on the major neural circuits mediating the ability to flexibly change behavior; and (4) review the neurochemical modulation of the cognitive processes engaged during reversal learning.

Section snippets

Reversal learning paradigms across species

In the classic reversal learning paradigm used in humans (Fellows and Farah, 2003a), monkeys (Butter, 1969) and rodents (Schoenbaum et al., 2000), subjects are trained to discriminate between two visual stimuli or spatial locations, one of which is rewarded every time it is chosen and the other which is not. After successful discrimination learning has been demonstrated by reaching a criterion level of performance, the outcomes associated with the two stimuli are reversed and subjects are again

What does reversal learning measure?

Reversal learning requires a subject to flexibly adjust their behavior when the reward-related contingencies that they have previously learned are reversed. For some time, a widely voiced idea was that reversal leaning paradigms primarily measured inhibitory control of responding (Jones and Mishkin, 1972). Based on experiments in humans, monkeys, and rodents (Fellows and Farah, 2005, Chudasama et al., 2007, Schoenbaum et al., 2009a), this view has been revisited and other tasks have been

Cortical regions

Neuroimaging studies report increased activity in orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) in human subjects performing reversals (Nagahama et al., 2001, Cools et al., 2002, Kringelbach and Rolls, 2003, Remijnse et al., 2005, Ghahremani et al., 2010), and patients with lesions of these regions exhibit reversal learning deficits (Rolls et al., 1994b, Fellows and Farah, 2003b, Hornak et al., 2004). Furthermore, a consistent finding from over fifty years of work in nonhuman

Neurochemical modulation of reversal

The molecular and neurochemical factors influencing reversal learning and the associated cognitive domains affected are yet to be fully understood (Izquierdo and Jentsch, 2012). Here we consider what have been the most intensively studied neurotransmitter systems in reversal learning – serotonin, dopamine and glutamate.

Concluding remarks

In this review we summarized evidence that reversal learning paradigms generally test the ability to learn specific S-O associations, to estimate the likelihood that reversals can occur given accumulated evidence, and/or to generate a representation of option or task space. More investigation is needed to design behavioral tasks to extract and further describe the neural mechanisms of these individual processes, which should then allow even better comparisons between species and across

Conflict of interest

The authors report no conflicts of interest.

Acknowledgments

We are very grateful to Dr. Russel Morton for constructing some of the figures and helpful comments from the Izquierdo lab on a previous version of this manuscript. AI is supported by the UCLA Division of Life Sciences Recruitment and Retention fund. JLB is supported by National Institute on Alcohol Abuse and Alcoholism grant 1P50AA022534-01. PHR is supported by generous seed funds from the Icahn School of Medicine at Mount Sinai and a Brain and Behavior Research Foundation Young Investigator

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ReviewThe neural basis of reversal learning: An updated perspective

Highlights

Abstract

Introduction

Section snippets

Reversal learning paradigms across species

What does reversal learning measure?

Cortical regions

Neurochemical modulation of reversal

Concluding remarks

Conflict of interest

Acknowledgments

Neuropharmacology

Neuron

Behav Brain Res

Behav Brain Res

Behav Brain Res

Behav Brain Res

Behav Brain Res

Behav Brain Res

Physiol Behav

Exp Neurol

Neuron

Neuron

Trends Neurosci

Behav Brain Res

Neuron

Brain Cogn

Behav Brain Res

Curr Opin Neurobiol

Neuroscience

Neuron

Neural Netw

Eur Neuropsychopharmacol

Behav Brain Res

Neurobiol Learn Memory

Biol Psychiatry

Neuron

Neuropharmacology

Behav Brain Res

Behav Brain Res

Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat

J Psychopharmacol

Optogenetic interrogation of dopaminergic modulation of the multiple phases of reward-seeking behavior

J Neurosci

The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study

Psychopharmacology

GluR-A-deficient mice display normal acquisition of a hippocampus-dependent spatial reference memory task but are impaired during spatial reversal

Behav Neurosci

Serotonin modulates sensitivity to reward and negative feedback in a probabilistic reversal learning task in rats

Neuropsychopharmacology

Markers of serotonergic function in the orbitofrontal cortex and dorsal raphe nucleus predict individual variation in spatial-discrimination serial reversal learning

Neuropsychopharmacology

Comparison of the effects of frontal and caudate lesions on discrimination learning in monkeys

J Comp Physiol Psychol

Responses of amygdala neurons to positive reward-predicting stimuli depend on background reward (contingency) rather than stimulus-reward pairing (contiguity)

J Neurophysiol

Medial frontal cortex mediates perceptual attentional set shifting in the rat

J Neurosci

Double dissociation of the effects of medial and orbital prefrontal cortical lesions on attentional and affective shifts in mice

J Neurosci

Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior

Psychopharmacology

Dissociable effects of selective 5-HT2A and 5-HT2C receptor antagonists on serial spatial reversal learning in rats

Neuropsychopharmacology

Enhancement of spatial reversal learning by 5-HT2C receptor antagonism is neuroanatomically specific

J Neurosci

GluN2B in corticostriatal circuits governs choice learning and choice shifting

Nat Neurosci

Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit

Learn Mem

Predictably irrational: assaying cognitive inflexibility in mouse models of schizophrenia

Front Neurosci

Effects of subchronic phencyclidine (PCP) treatment on social behaviors, and operant discrimination and reversal learning in C57BL/6J mice

Front Behav Neurosci

Pharmacological or genetic inactivation of the serotonin transporter improves reversal learning in mice

Cereb Cortex

The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning

J Psychopharmacol

Orbitofrontal inactivation impairs reversal of Pavlovian learning by interfering with ‘disinhibition’ of responding for previously unrewarded cues

Review
The neural basis of reversal learning: An updated perspective