Justin A. Harris

Using c-fos as a neural marker of pain

Just over a decade has past since Hunt et al. reported that the gene c-fos and its protein product Fos are expressed in the spinal cord of rats subjected to peripheral noxious stimulation. These authors showed that noxious stimulation (application of radiant heat or mustard oil) to the hind paw resulted in a massive increase in the expression of Fos in neurons in the dorsal horn of the lumbar spinal cord. Since then, there has been an explosion of studies in which c-fos has been used to study nociception (pain), and the number of such studies increases each year. The net result has been to establish c-fos expression as a valuable tool in pain research. Moreover, recent studies have provided evidence identifying the role of c-fos expression in spinal nociceptive processes. However, there are several important limitations to the practice of using c-fos to study nociception, and these limitations can be easily overlooked as the practice graduates to the status of an established technique. The increasing use of c-fos to study nociception necessitates a critical review of the practice, identifying the shortcomings as well as the strengths of this tool.

Modelling non-invasive brain stimulation in cognitive neuroscience

Non-invasive brain stimulation (NIBS) is a method for the study of cognitive function that is quickly gaining popularity. It bypasses the correlative approaches of other imaging techniques, making it possible to establish a causal relationship between cognitive processes and the functioning of specific brain areas. Like lesion studies, NIBS can provide information about where a particular process occurs. However, NIBS offers the opportunity to study brain mechanisms beyond process localisation, providing information about when activity in a given brain region is involved in a cognitive process, and even how it is involved. When using NIBS to explore cognitive processes, it is important to understand not only how NIBS functions but also the functioning of the neural structures themselves. We know that NIBS techniques have the potential to transiently influence behaviour by altering neuronal activity, which may have facilitatory or inhibitory behavioural effects, and these alterations can be used to understand how the brain works. Given that NIBS necessarily involves the relatively indiscriminate activation of large numbers of neurons, its impact on a neural system can be easily understood as modulation of neural activity that changes the relation between noise and signal. In this review, we describe the mutual interactions between NIBS and brain activity and provide an updated and precise perspective on the theoretical frameworks of NIBS and their impact on cognitive neuroscience. By transitioning our discussion from one aspect (NIBS) to the other (cognition), we aim to provide insights to guide future research.

Evidence that GABA transmission mediates context-specific extinction of learned fear

Abstract Six experiments used rats to study the effects of the β-carboline FG 7142 on extinction of fear responses (freezing) to an auditory cue that had signalled footshock. Subcutaneous injection of FG 7142 interfered with the development of extinction without having any detectable effect on the rats’ levels of fear prior to extinction. Injection of FG 7142 also reversed extinction, partially reinstating fear responses that had been extinguished previously. A similar reinstatement of extinguished fear was seen when rats were tested for fear of the cue in a different chamber. The reinstatement produced by FG 7142 and that caused by context shift were not additive: FG 7142 did not increase extinguished fear if rats were tested in the different chamber. Finally, FG 7142 had no detectable effect on the latent inhibition of fear produced by repeatedly presenting the cue alone before conditioning with shock, even though this inhibition, like extinction, was affected by a shift in context. The present findings indicate that GABA transmission at GABAA receptors is involved in the inhibition of extinguished fear, and that this effect of GABA is regulated by those cues that constitute the extinction context.

Conditioned fear to context is associated with increased Fos expression in the caudal ventrolateral region of the midbrain periaqueductal gray.

Immunohistochemical detection of Fos was used to determine which regions of the periaqueductal gray are activated during conditioned fear to a context in the rat. More specifically, the aim of the study was to test the role of its lateral and ventrolateral columns in freezing behaviour during fear. Conditioned fear was evoked by re-exposing rats to the same footshock chamber in which they had received footshocks 4 h earlier. Conditioned Re-exposed rats were compared to Not Conditioned Re-exposed and Conditioned Not Re-exposed rats. Freezing was observed in the Conditioned-Re-exposed group only. It was associated with an overall increase in Fos expression in the entire periaqueductal gray that was significantly greater than in the two other groups. The largest and most significant increase in Fos immunoreactivity was found in the ventrolateral column (especially in its caudal part), whereas only a moderate increase was found in the lateral column. The present results argue in favour of the ventrolateral column as the region of the periaqueductal gray that is preferentially involved in expression of conditioned fear. As previous lesion studies suggested, the ventrolateral periaqueductal gray may play a role in mediating the immobility component of freezing induced by fear. Other lines of evidence suggest that it may also play a role in mediating the quiescence immobility associated with deep pain. We propose that the ventrolateral column of the periaqueductal gray acts as an integrating centre mediating behavioural inhibition.

Elemental Representations of Stimuli in Associative Learning

This article reviews evidence and theories concerning the nature of stimulus representations in Pavlovian conditioning. It focuses on the elemental approach developed in stimulus sampling theory (R. C. Atkinson & W. K. Estes, 1963; R. R. Bush & F. Mosteller, 1951b) and extended by I. P. L. McLaren and N. J. Mackintosh (2000, 2002) and contrasts this with models that invoke notions of configural representations that uniquely code for different patterns of stimulus inputs (e.g., J. M. Pearce, 1987, 1994; R. A. Rescorla & A. R. Wagner, 1972; A. R. Wagner & S. E. Brandon, 2001). The article then presents a new elemental model that emphasizes interactions between stimulus elements. This model is shown to explain a range of behavioral findings, including those (e.g., negative patterning and biconditional discriminations) traditionally thought to be beyond the explanatory capabilities of elemental models. Moreover, the model offers a ready explanation for recent findings reported by R. A. Rescorla (2000, 2001, 2002b) concerning the way that stimuli with different conditioning histories acquire associative strength when conditioned in compound.

UPREGULATION OF SPINAL GLUTAMATE RECEPTORS IN CHRONIC PAIN

Recent studies indicate that glutamate binding to N-methyl-D-aspartate receptors in the spinal cord is involved in triggering the development of chronic pain However, the processes which directly underlie the increased pain remain unclear. Here we report that, following peripheral nerve injury (ligation of the sciatic nerve) in the rat, there is an increase in immunoreactive labelling of non-N-methyl-D-asparatate, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate), glutamate receptors in the superficial laminae of the lumbar spinal cord ipsilateral to the ligation. The increase in AMPA receptor expression peaks 14 days after nerve ligation and decreases 35 days post-ligation, corresponding to the time-course of heightened sensitivity to mechanical and thermal noxious stimuli (hyperalgesia) induced by the ligation. Given evidence that AMPA receptors in the superficial laminae mediate fast nociceptive transmission in the spinal cord, our findings suggest that an upregulation of spinal AMPA receptors contributes to hyperalgesia following peripheral nerve injury.

Reinstatement of Fear to an Extinguished Conditioned Stimulus: Two Roles for Context

The authors studied the role of context in reinstatement. Freezing was reinstated when the conditioned stimulus (CS) was extinguished in 1 context and rats moved to another context for reexposure to the shock unconditioned stimulus (US) and test. It was also reinstated (rather than renewed) when rats were shocked in the extinction context and moved to another context for test. This reinstatement was CS specific and reduced by nonreinforced exposures to the extinction context. Rats shocked in the context in which a stimulus had been preexposed froze when tested in another context. These findings suggest 2 roles for context in reinstatement: conditioning of the test context (M. E. Bouton, 1993) and mediated conditioning by the extinction context (P. C. Holland, 1990).

The functional effect of transcranial magnetic stimulation: Signal suppression or neural noise generation?

Transcranial magnetic stimulation (TMS) is a popular tool for mapping perceptual and cognitive processes in the human brain. It uses a magnetic field to stimulate the brain, modifying ongoing activity in neural tissue under the stimulating coil, producing an effect that has been likened to a virtual lesion. However, research into the functional basis of this effect, essential for the interpretation of findings, lags behind its application. Acutely, TMS may disable neuronal function, thereby interrupting ongoing neural processes. Alternatively, the effects of TMS have been attributed to an injection of neural noise, consistent with its immediate and effectively random depolarization of neurons. Here we apply an added-noise paradigm to test these alternatives. We delivered TMS to the visual cortex and measured its effect on a simple visual discrimination task, while concurrently manipulating the level of image noise in the visual stimulus itself. TMS increased thresholds overall; and increasing the amount of image noise systematically increased discrimination thresholds. However, these two effects were not independent. Rather, TMS interacted multiplicatively with the image noise, consistent with a reduction in the strength of the visual signal. Indeed, in this paradigm, there was no evidence that TMS independently added noise to the visual process. Thus, our findings indicate that the virtual lesion produced by TMS can take the form of a loss of signal strength which may reflect a momentary interruption to ongoing neural processing.

Contextual control over conditioned responding in a latent inhibition paradigm.

We used 1-, 2-, and 3-context designs to study the control exerted by contexts over freezing in rats exposed to a conditioned stimulus (CS) in advance of its pairing with a shock unconditioned stimulus. The latent inhibition observed when preexposure, conditioning, and testing occurred in the same context was attenuated if preexposure occurred in a different context to conditioning and testing. Latent inhibition (i.e., attenuated performance) was restored in a CS-specific manner if preexposure and testing occurred in the same context and conditioning in a different one. Latent inhibition was also reduced by a long retention interval but remained specific for a particular context-CS relation. Finally, CS preexposure resulted in contextual control over the expression of excitatory conditioned performance. The results are discussed in terms of memory, associative, and associative-performance models of CS-preexposure effects.

Descending antinociceptive mechanisms in the brainstem: Their role in the animal's defensive system

The identification of specialized mechanisms in the mammalian brainstem that function to inhibit the rostral transmission of nociceptive (pain-related) information in the spinal cord led to an explosion of research into the neuroanatomical and neurochemical substrates of these antinociceptive systems. As outlined in the present paper, most attention was directed at those mechanisms in the periaqueductal grey (PAG) and rostral ventromedial medulla (RVM). However, comparatively little attention has been paid to the functional role of these mechanisms in animal behaviour. The purpose of the present paper is to review research into the behavioural significance of those antinociceptive mechanisms in the PAG and RVM. It is concluded that these mechanisms function as part of the animals fear or defensive system, serving to make a threatened animal insensitive to noxious stimulation and thereby allowing that animal to engage in defensive responses instead of recuperative activities. Further, it is argued that the organization of these antinociceptive circuits reflects the animals increasing capacity for early detection of danger. Specifically, nociception itself is held to signify the presence of immediate threat, and consequently, nociceptive input directly activates antinociceptive circuits at either the spinal level (during intense noxious stimulation) or RVM (following exposure to moderate noxious stimuli). In contrast, events that are themselves innocuous but which signal threat (either learned or innate danger signals) activate fear and defensive systems in the amygdala and PAG which engage the descending antinociceptive projections in the RVM.