Molecular Pain

BioMed Central

CommentaryOpen Access

A pain in the ACC
Paul W Frankland*1,2 and Cátia M Teixeira1
Address: 1Programs in Integrative Biology and Brain & Behaviour, Hospital for Sick Children, Toronto, Canada and 2Department of Physiology
and Institute of Medical Science, University of Toronto, Toronto, Canada
Email: Paul W Frankland* - paul.frankland@sickkids.ca; Cátia M Teixeira - teixeira.catia@gmail.com* Corresponding author

Published: 31 March 2005
Molecular Pain 2005, 1:14

doi:10.1186/1744-8069-1-14

Received: 28 March 2005
Accepted: 31 March 2005

This article is available from: http://www.molecularpain.com/content/1/1/14© 2005 Frankland and Teixeira; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
An emerging theme in systems neurobiology is that even simple forms of memory depend on
activity in a broad network of cortical and subcortical brain regions. One key challenge is tounderstand how different components of these complex networks contribute to memory. In a new
study in Molecular Pain, Tang and colleagues use a novel set of approaches to characterize the roleof the anterior cingulate cortex (ACC) in the formation of Pavlovian fear memories.

Because survival may depend upon it, we learn about
painful stimuli quickly and efficiently through a process
known as Pavolvian fear conditioning [1]. Viewed in thisframework, stimuli present in the environment at the timeof injury (or conditioned stimuli; CSs) are likely to become
associated with the painful stimulus (or unconditionedstimulus; US). This is adaptive since when these cues arenext encountered, an animal can take measures (or conditioned responses; CRs) that help to reduce the likelihood ofinjury.
A painful stimulus may have a number of differentattributes [2]. These include sensory-discriminativeattributes, such its location, intensity and quality, as well
as affective attributes, such as its unpleasantness (or negative emotional valence). Recent studies in humans andexperimental animals have established that these different
attributes are processed by partially dissociable brain networks [2,3]. For example, in human imaging studies activity in the primary somatosensory cortex is closely related
to the sensory-discriminative properties of a painful stimulus, whereas activity in the anterior cingulate cortex(ACC) is closely related to the affective features of pain,
such as subjective feelings of unpleasantness [4]. Taking

their lead from these studies, Tang and colleagues [5] first
asked whether the ACC plays a similar role in processing
the affective features of pain stimuli in mice. They reasoned that activation of the ACC should evoke a similar
set of behaviors as would presentation of an actual painfulstimulus, such as a footshock. Consistent with this, theyfirst show that electrical stimulation of the ACC evokes
high frequency ultrasonic vocalizations – a typical sign ofdistress in rodents. Similarly, chemical stimulation ofthese neurons evokes immobility or freezing – speciestypical signs of fear. While it is difficult to evaluate subjective feelings of unpleasantness in animals, this set ofbehaviors evoked by ACC activation is clearly consistent
with such an affective state.
Having established that activation of the ACC produces acluster of behaviors consistent with fear or unpleasantness, Tang and colleagues posed a more ambitious question: Would it be possible to artificially fear condition ananimal by replacing a footshock with electrical stimulation of the ACC? In a normal fear conditioning experiment, an otherwise neutral stimulus, such as a tone, isrepeatedly paired with an aversive stimulus, such as ashock, in a particular context. Later an animal exhibits aPage 1 of 3(page number not for citation purposes)

Molecular Pain 2005, 1:14a.

http://www.molecularpain.com/content/1/1/14b.

FigureTheanatomy
1of Pavlovian fear
The anatomy of Pavlovian fear. a. Mouse brain sections illustrating key brain regions involved in processing CS information(blue), US information (red) and CS-US associations (purple). b. Simplified schematic of pathways involved in the formation ofPavolvian fear memories. Direct and indirect connections from thalamic nuclei convey information about the CS and US to theamygdala. Tang and colleagues provide evidence that the ACC processes the affective features of painful stimuli, and that pairing a tone with ACC activation can artificially induce Pavlovian fear memories. Abbreviations: ACC, anterior cingulate cortex;
Au, primary auditory cortex; Amy, amygdala; Pr, perirhinal cortex; S1, primary somatosensory cortex.

number of species-typical fear responses, including freezing behavior, when presented with the tone or placedback in the original training context. Here, Tang and colleagues conducted the same experiment except that they
replaced the footshock with stimulation of the ACC. Sureenough, mice trained in this way froze when placed themice back in the same context, or when presented with thetone in a different context. These artificially-generated
conditioned fear memories were not transient – theylasted at least 3 days, indicating that mice will condition
as readily to ACC stimulation as they might to shock
delivery. This experiment, therefore, shows that micereadily associate both the context and the tone with ACCevoked 'unpleasantness'. The formation of CS-US associations underlying fear memories depends on NMDA-mediated plasticity in the amygdala [6-8]. Consistent with this,Tang and colleagues went on to show that the formation
ACC-induced fear memories is disrupted by localized
pharmacological blockade of NMDA receptor function in
the amygdala. This series of experiments demonstrates,
therefore, that an ACC-induced fear memory looks andbehaves very much like a fear memory induced by footshock (Figure 1).

Tang and colleagues took care to rule out a number ofalternative interpretations. They first showed that the fear
conditioning to the tone depended on the pairing of thetone with ACC stimulation. When this temporal
relationship was perturbed, the mice did not freeze to thetone, indicating that the observed learning was associativein nature. A second issue they addressed was the possibility that ACC stimulation produces analgesic effects [9]. If
this were the case, then ACC stimulation would beexpected to inhibit, rather than facilitate, aversively-motivated learning as well as behavioral responses to noxious
stimuli. Here, Tang and colleagues showed that ACC stimulation potentiates responses in the tail-flick and hotplate tests, and facilitates learning in a hot-plate avoidance task [10]. These data demonstrate that ACC activation, rather than producing analgesia, facilitates responses
to noxious stimuli in a broad range of experimentalsituations.
A third control experiment yielded a particularly interesting dissociation. They considered the possibility thatbrain stimulation, regardless of site, is aversive. To address
this they conducted the same experiment but paired aPage 2 of 3
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Molecular Pain 2005, 1:14

tone with stimulation of the primary somatosensory cortex. Under these conditions, no fear developed to the tone
(nor to the context in which conditioning occurred). This
first demonstrates that their effects are specific to ACC
stimulation, and secondly, suggests an important dissociation. Whereas the sensory features of a pain stimulus areprocessed by the primary somatosensory cortex and theaffective features by the ACC, only ACC stimulation
appears to functionally substitute for a shock during fearconditioning. This suggests that fear conditioning critically depends on the affective qualities (or emotionalvalence) of the US. When the US is stripped down to its
sensory properties alone, conditioning proceeds very
slowly (or not at all). This conclusion is further supported
in another experiment in which mice were fear conditioned with a tone-shock pairing. Tang and colleagues
showed that inactivating the ACC during training blocked
the development of conditioned fear. This suggests that
disrupting processing of the affective (but not sensory)
features of a US is sufficient to disrupt conditioning.
This clever series of studies starts to dissociate the contribution of different cortical regions to the formation ofeven simple memories. Tang and colleagues provide evidence that the ACC specifically processes the affective features of painful stimuli, and that ACC activation canartificially induce Pavlovian fear memories. But how dothese findings fit into the broader context of functional
studies on the ACC? While other rodent studies have also
provided evidence that the ACC processes Pavolvian fear
memories, these have emphasized the role of the ACC inmemory recall rather than memory formation [11,12].
Furthermore, these studies provide evidence that the ACC
is preferentially involved in the recall of remote (ratherthan recent) fear memories, and this role in processing
remote memories extends to appetitively-motivated spatial tasks [13,14]. When we also consider functional imaging studies in human subjects showing that, besides
processing pain stimuli, the ACC is involved in a large
number of different cognitive processes (e.g., attention,error monitoring, target detection and effortful recall)[15], it becomes clear that we are a long way from a complete understanding of the ACC [16]. In some instances itis possible that the ACC performs similar functions acrosssituations – for example, retrieval of remote, rather thanrecent, memory may involve more effortful recall. However, the diversity of function attributed to the ACC suggests that this region is functionally heterogeneous, and asingle model is unlikely account for all observations.

http://www.molecularpain.com/content/1/1/14

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Acknowledgements

available free of charge to the entire biomedical community

This work is supported by a grant from the National Alliance for Researchon Schizophrenia and Depression (NARSAD). P.W.F. is supported by aCIHR Canada Research Chair in Cognitive Neurobiology. C.M.T. is supported by the Fundação para a Ciência e a Tecnologia (Portugal).

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