Available online at www.sciencedirect.
com
Learning and cognitive flexibility: frontostriatal function and
monoaminergic modulation
Angie A Kehagia1,2, Graham K Murray1,3 and Trevor W Robbins1,2
Learning in a constant environment, and adapting flexibly to a
changing one, through changes in reinforcement contingencies
or valence-free cues, depends on overlapping circuitry that
interconnects the prefrontal cortex (PFC) with the striatum and
is subject to several forms of neurochemical modulation. We
present evidence from recent studies in animals employing
electrophysiological, pharmacological and lesion techniques,
and neuroimaging, neuropsychological and pharmacological
investigations of healthy humans and clinical patients.
Dopamine (DA) neurotransmission in the medial striatum and
PFC is critical for basic reinforcement learning and the
integration of negative feedback during reversal learning, whilst
orbitofrontal 5-hydroxytryptamine (5-HT) likely mediates this
type of low level flexibility, perhaps by reducing interference
from salient stimuli. The role of prefrontal noradrenaline (NA) in
higher order flexibility indexed through attentional set-shifting
has recently received significant empirical support, and similar
avenues appear promising in the field of task switching.
Addresses
1
Behavioural and Clinical Neuroscience Institute, University of
Cambridge, Downing Street, Cambridge CB2 3EB, UK
2
Department of Experimental Psychology, University of Cambridge,
Downing Street, Cambridge CB2 3EB, UK
3
Brain Mapping Unit, Department of Psychiatry, University of
Cambridge, Box 255, Addenbrooke’s Hospital, Cambridge CB2 2QQ,
UK
Corresponding author: Kehagia, Angie A (ak423@cam.ac.uk),
Murray, Graham K (gm285@cam.ac.uk) and Robbins, Trevor W
(twr2@cam.ac.uk)
Current Opinion in Neurobiology 2010, 20:199–204
This review comes from a themed issue on
Cognitive neuroscience
Edited by Earl Miller and Liz Phelps
Available online 16th February 2010
0959-4388/$ – see front matter
# 2010 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.conb.2010.01.007
Introduction
The ability to learn, or acquire associations between
stimuli, actions and environmental outcomes, and flexibly
adapt ongoing behaviour according to salient changes in
the environment or our current intentions, carries survival
value and is arguably fundamental to what cognitive
agents perceive as voluntary action. Research on neural
mechanisms subserving learning and flexibility over the
www.sciencedirect.com
last decade has focused on the prefrontal cortex (PFC)
and basal ganglia, particularly the striatum, and their
interactions through their multiple serial and parallel
loops [1,2], subject to neuromodulatory inputs by the
monoamines (dopamine (DA), serotonin (5-hydroxytryp-
tamine, 5-HT) and noradrenaline (NA)).
We review developments in recent years that have con-
tributed to the state of the science, progressing through a
conceptual gradient of cognitive processes and paradigms.
First, we address basic reinforcement learning, where
behaviour is critically dependent on environmental sig-
nals or (reward) feedback. Subsequently, we focus on
reversal learning, reflecting the ability to switch respond-
ing to a previously non-reinforced exemplar, which relies
on feedback but critically incorporates flexibility. We
proceed to attentional set-shifting, which also indexes
the ability to adapt behaviour flexibly following feedback,
but pertains to broader stimulus dimensions rather than a
specific exemplar. Finally, we address task switching, a
relatively purer form of cognitive flexibility uncontami-
nated by learning and feedback processing.
The literature cited represents a corresponding gradient
in spatiotemporal scale as a function of the complexity of
cognitive paradigms, and the feasibility of interspecies
translation. Basic neuronal and molecular mechanisms of
reinforcement learning and low level flexibility emerge
predominantly from animal studies employing invasive
techniques such as single unit recordings, microdialysis
and selective gene knock-out. More cognitively complex
forms of flexibility are tapped mostly through systemic
pharmacology (across species), lesion studies in animals
and functional neuroimaging in humans.
Cortico-striatal anatomy
Before addressing the cognitive neuroscience of cortico-
striatal interactions, we note developments in the field of
anatomy. The landmark proposal of anatomically and
functionally segregated cortico-striatal loops by Alexan-
der and colleagues is gradually becoming superseded by
evidence for more complex cross-talk and convergence
enabling integration of processing across these circuits
[3,4]. Thus, functional connectivity network effects that
may underpin learning and flexible cognition are consist-
ent with new functional models emerging from rodent
and primate electrophysiology [5], and human neuroima-
ging data [6,7]. Together, such studies provide func-
tional support to anatomical results demonstrating that
Current Opinion in Neurobiology 2010, 20:199–204
200 Cognitive neuroscience
the various cortico-striatal loops inter-relate in a partially
overlapping, mediolateral gradient.
Reinforcement learning
For some years it has been clear that both the striatum and
the frontal cortex play key roles in learning, being active
during the expectation of reward and following its deliv-
ery, as well as coding prediction error during learning
[8,9]. Beyond the postulated role of synaptic plasticity
[10], monkey cell recording suggests that changes in
dynamic network states of caudate and lateral PFC
neurons may also be critical for learning [11]. These
regions exhibit sustained activity during simple learning
and reversal learning, when contingencies are reversed.
This activity persists over the course of several seconds
following the outcome of a behavioural trial to influence
behaviour on the subsequent one.
At the neurochemical level, research which illustrated
that primary prefrontal lesions can cause secondary
impairments in striatal DA function [12] has been influ-
ential, for example, in models of schizophrenia patho-
physiology. In a re-examination of the causal relationship
between striatal D2 receptor activity and frontal function,
Bach et al. showed that mesolimbic/mesostriatal hyper-
function can also lead to frontal dysfunction [13,14].
Over-expression of striatal D2 receptors caused frontal-
like cognitive deficits (working memory and go/no-go
conditional associative learning), possibly mediated by
altered D1 receptor activation (see [15]; working memory
deficits remediated by D1 agonist administration), and
decreased DA turnover in PFC consequent upon the
striatal abnormality.
Although rodent behavioural pharmacology has been
dominated by studies in rats, a number of key exper-
iments have recently been performed in genetically
modified mice to elucidate the role of phasic DA in
learning. A novel procedure employed by Zweifel et al.
[16] examined the differential effects of tonic and phasic
DA neuron activity, by eliminating the latter through the
inactivation of NMDA receptors on DA neurons. These
mice were slower to reach criterion on free operant
learning and develop food conditioned place preference,
and were impaired on cue-driven learning in the Morris
water maze. The role of burst DA firing in learning is
corroborated by a fascinating optogenetics study demon-
strating that phasic activation of ascending VTA dopa-
minergic neurons is sufficient to drive conditioned place
preference [17]. Cellular mechanisms underlying
reinforcement learning have also been elucidated by
Stuber et al. [18]. Striatal DA release in response to
reward-predicting cues and enhanced synaptic strengths
with VTA DA neurons develop during learning; specifi-
cally, cue-reward learning was mediated by greater
AMPA receptor currents impacting on DA neurons.
Further insights into the plasticity underpinning learning
Current Opinion in Neurobiology 2010, 20:199–204
emerge from studies in brain slices from transgenic mice.
Previously, it was hypothesized that, within the striatum,
D1 receptor-type medium spiny neurons (MSNs) express
LTP at the glutamatergic synapse, and D2 receptor-type
MSNs express LDP. It is now evident that both types of
MSN are subject to both types of synaptic plasticity,
although they exhibit opposite effects in terms of LTP
and LDP in the context of stimulation and in its absence
[19].
Reversal learning
Deficits in reversal learning, the ability to switch respond-
ing to a previously non-reinforced stimulus, are present
not just in chronic illness but also in the early stages of
disorders such as Parkinson’s disease (PD) [20], schizo-
phrenia and bipolar disorder [21,22]. Catecholamines,
specifically cortico-striatal DA, and indoleamines, in
particular orbitofrontal (OFC) 5-HT, are considered
critical for this type of flexibility. Reversal learning is
impaired not only following infusions of a D2 agonist into
the rat medial striatum by reducing prefrontal cortical
input [23], but also following serotonergic depletion in
the OFC in monkeys [24], which causes specific deficits
in serial reversal learning that are underpinned by a
failure to inhibit responding to the previously rewarded
stimulus, rather than proactive interference or enhanced
learned avoidance [25]. Work from the same laboratory
has gone on to clarify the roles of OFC and medial
(associative) striatum in learning and contingency reversal
[26]. Whilst discrete OFC lesions impair learning reward
contingencies by disrupting reversal following both
positive and negative reinforcement, striatal lesions
impaired reversal following negative feedback only,
suggesting abnormal prediction error processing. A recent
rat electrophysiological study also supports the role of the
medial striatum in reversal learning: medial but not
ventral striatal activity changes preceded go/no-go beha-
viour upon reversal [27].
The finding that striatal lesions impair reversal behaviour
following negative reinforcement suggests that DA may
crucially modulate this form of behavioural flexibility by
virtue of its role in basic reinforcement learning. Indeed, a
recent microdialysis study demonstrated increased rever-
sal-related DA, but not NA, efflux in rat medial PFC
(which is interconnected with the medial striatum), an
effect that was particularly pronounced on early but not
late reversals [28]. Research in humans has further illu-
minated the importance of D2 receptors in mediating
negative reinforcement during reversal learning. Using
fMRI, Jocham et al. [29] showed that individuals with a
genotype that predisposes to lower striatal D2 receptor
expression exhibit reduced recruitment of the ventral
striatum and lateral OFC, which in association with
abnormal rostral cingulate activation observed following
negative feedback, underpins their subtle reversal learn-
ing deficits. These results complement behavioural
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 Frontostriatal substrates of learning and flexibility Kehagia, Murray and Robbins 201
effects associated with a D2 polymorphism [30] and
reports from human pharmacological fMRI that DA-ergic
manipulations modulate striatal reversal-related activity
[31]. Using positron emission tomography (PET), Clat-
worthy et al. demonstrated that reversal learning perform-
ance correlated with methylphenidate-induced DA
release in the medial striatum [32]. Similarly, methyl-
phenidate induced blood oxygen level dependent
(BOLD) changes in the striatum during reversals follow-
ing negative feedback [33], presumably as a consequence
of its blocking action on the DA transporter.
The open question of the precise contributions of DA and
5-HT in the OFC to conditioned reinforcement and
reversal learning has recently been addressed by Walker
et al. [34]. Collectively, the doubly dissociable deficit
patterns exhibited by marmosets with either DA or 5-HT
depletion in the OFC implicate DA in basic associative
processes of reward, and possibly in prediction error
signalling (the absence of which leads to a remarkable
persistence of responding in extinction), and 5-HT in
maintaining a flexible response set in the face of distract-
ing salient stimuli. In the rat, a similar function of redu-
cing distractibility from irrelevant stimuli during reversal
learning is ascribed to the anterior cingulate cortex:
although 2-choice reversal behaviour remains intact fol-
lowing lesions to this region, its inactivation by muscimol
microinfusion impairs four-choice reversal by increasing
never-reinforced distracter errors [35].
Attentional set-shifting
In contrast to reversal learning which pertains to a specific
exemplar, attentional set-shifting (extra-dimensional
shifting (EDS)) refers to switching between higher order
modalities (e.g. from lines to shapes, from texture to
odour) on the basis of feedback. The neural correlates
of attentional set-shifting in humans were elucidated
using fMRI [36], associating OFC with reversal learning
and ventrolateral PFC (vlPFC) with EDS. In the rat, a
well-controlled lesion study of strategy shifting demon-
strated dissociable roles for the parallel pathways from the
mediodorsal thalamic nucleus to the nucleus accumbens
and medial PFC: the former is central in eliminating
inappropriate strategies, the latter in signalling the need
to shift and the cortico-striatal projection in integrating
reinforcement with instrumental behaviour [37].
Although NA traditionally has been linked to attention,
arousal and exploration/exploitation trade-offs as a func-
tion of phasic and tonic firing in the locus coeruleus (LC),
the principal source of NA neurons in the dorsal nor-
adrenergic ascending bundle (DNAB) (e.g. [38,39]), bur-
geoning evidence now directly implicates it in attentional
set-shifting. One of the earlier studies in the rat reported
EDS enhancing effects of systemic atipamezole, an a2-
adrenergic autoreceptor antagonist, which were reversed
by a1-adrenergic but not b-adrenergic antagonist micro-
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injections into medial PFC [40]. Lapiz et al. followed this
up with a demonstration of attentional set-shifting
benefits following chronic administration of desipramine,
a selective NA reuptake inhibitor [41]. Moreover, lesions
of the DNAB produce attentional set-shifting deficits in
the rat [42]. McGaughy et al. [43] showed that NA-ergic
but not cholinergic deafferentiation of rat medial PFC led
to specific EDS deterioration, indicative of an overly
focused attentional set, rather than an intrinsic deficit
in ignoring irrelevant stimuli, which was intact in the
lesioned animals. Results from the same laboratory
extended these findings to the beneficial effects of ato-
moxetine, a NA reuptake inhibitor used for the treatment
of attention deficit/hyperactivity disorder (ADHD),
which at the low doses employed in that study only
augments cortical NA [44]. These findings are of
particular importance to the attentional set-shifting def-
icits of PD that have hitherto been found to be insensitive
to DA-ergic medication and which we are currently
investigating in a pharmacological study on the effects
of acute atomoxetine administration (see also below).
Task switching
Task switching addresses cognitive flexibility divorced
from the ability to adapt ongoing behaviour to feedback,
hence unconfounding it from the learning mechanisms
that underlie attentional set-shifting. It involves switch-
ing between rules that determine well-learned stimulus
and response (S–R) mappings, on the basis of cues. Task
switching deficits are seen in neurodegenerative disease
such as PD [45] and psychiatric illness, for example,
OCD [46], since frontoparietal areas and the basal ganglia
contribute to different aspects of a switch. For example,
whilst the human anterior cingulate underlies more gen-
eral motivational updating of the goal state on a switch of
task, the dorsolateral PFC is thought to be involved in
specifically resolving interference from irrelevant task
sets [47]. A coordinating role has recently been proposed
for the inferior parietal region on the basis of switch-
specific signal change, which precedes that seen in PFC
[48]. The basal ganglia have been implicated in response
selection, particularly under conditions of increased
response interference [49] but are thought to be involved
in tonic fluctuations in flexibility rather than transient
switch-specific processes [50].
Remarkably few pharmacological studies have been
conducted on task switching. Ketamine induced switch-
ing deficits in a marmoset analogue of task switching
[51], indicating a central role of glutamate neurotrans-
mission analogous to its role in attentional set-shifting
[52]. Furthermore, caffeine (1,3,7-trimethylxanthine),
an adenosine receptor antagonist that elevates central
catecholamines including DA and NA, enhances task
switching in humans [53]. Indeed, the role of DA in
dorsal cortico-striatal circuits during task switching
has been supported primarily by the detrimental effect
Current Opinion in Neurobiology 2010, 20:199–204
202 Cognitive neuroscience
of L-DOPA withdrawal in PD patients (e.g. [54]) and
that of sulpiride administration in healthy subjects [55].
However, we have recently shown that task switching
deficits in PD, which profoundly affects not only DA but
also NA transmission (because of LC degeneration), are
a function of disease severity and not all types of
switching deficit stem from DA dysfunction [45]. We
have proposed that task switching may exhibit distinct
neurochemical profiles depending on the abstraction of
the rule that governs a task set, similarly to those during
attentional set-shifting: switching between simple S–R
mappings governed by lower order rules may rely on DA
(similarly to reversal learning and intradimensional set-
shifting, see Dias et al. [24]) whilst switching between
higher order rules pertaining to categories of stimuli may
have a NA-ergic substrate (similarly to EDS). In support
of this proposed role of NA in cognitive flexibility,
phasic LC signals were modelled in a recent pharma-
cological fMRI study of the effects of modafinil on
switching S–R mappings [56]. Modafinil was associ-
ated with task-independent deactivation in the LC (a
reduction in tonic firing), but increased activation (tonic
firing) in the LC and cognitive control regions including
dlPFC when subjects prepared to overcome a prepotent
response.
Conclusions
Recent advances in understanding the contributions of
neurons in the striatum, orbital and prefrontal regions of
the frontal cortex to learning and flexibility reflect devel-
opments in methods and techniques in animal and human
experimentation. The roles of cortico-striatal DA and
orbitofrontal 5-HT in basic forms of learning and flexi-
bility have received growing support, and their contri-
bution to different cognitive subprocesses has been
relatively well demarcated. Conversely, the NA-ergic
substrate of higher order flexibility represents a nascent
field of scientific inquiry, with promise of therapeutic
potential in neurodegenerative and psychiatric disease,
which future studies should explore.
Acknowledgements
This work was supported by a Wellcome Trust Programme Grant (076274/Z/
04/Z) to TWR, BJ Everitt, AC Roberts and BJ Sahakian and was completed at
the University of Cambridge Behavioural and Clinical Neuroscience Institute
supported by a joint award from the Medical Research Council and the
Wellcome Trust (G00001354). AAK holds an Isaac Newton fellowship and is
additionally supported by the Parkinson’s Disease Society. GKM is supported
by the Medical Research Council and NARSAD (National Alliance for
Research on Schizophrenia and Depression).
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204 Cognitive neuroscience
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