© 2001 Macmillan Magazines Ltd

H I G H L I G H T S

NATURE REVIEWS | NEUROSCIENCE VOLUME 2 | JULY 2001 | 457

Profile of a neuropathy

G L I A

Worth the wait

D E C I S I O N M A K I N G

Many demyelinating diseases have a genetic basis. Although someof these disorders are associated with mutations in myelinproteins such as myelin protein zero and periaxin, this is notalways the case. For example, mutations in the transcriptionfactor EGR2 are found in some patients with inherited peripheralneuropathies. Intriguingly, these neuropathies are transmitted ina dominant manner, but mice heterozygous for an Egr2 null alleleare normal. This observation prompted the suggestion that themutant EGR2 gene encodes a dominant-negative mutant proteinin people with the disease. But as Nagarajan et al. report inNeuron, testing this seemingly straightforward hypothesis has ledto deeper, unanticipated insights into the mechanisms behindthese demyelinating diseases.

The authors first used a conventional approach to test whethermutant Egr2 acted as a dominant-negative inhibitor and couldblock the expression of a reporter gene. As the results werenegative, they wondered whether any dominant-negative activityof the mutant transcription factor would only become manifest ifthe target genes were in their endogenous loci. However, toexplore this idea required the previous identification of Egr2targets. So, the authors used microarray expression profiling ofSchwann cells to identify genes induced by Egr2 expression, andfound that several myelin genes were under the control of thistranscription factor. Now, when they tested the effect of mutantEgr2 on the expression of these myelin genes in Schwann cells,Nagarajan et al. observed the dominant-negative activity thatthey had originally tried to find.

So, an inability of the Schwann cells to produce crucial myelinproteins and execute the myelination programme seems to be atthe core of the inherited peripheral neuropathies. Importantly,Nagarajan et al. obtained evidence that reintroducing the normalEgr2 gene to cells that express low levels of the protein can lead tothe expression of the missing myelin proteins. This finding raisesthe possibility that the myelination defect might be reversible andopens new avenues for the development of therapeutic measuresto treat these debilitating disorders.

Juan Carlos López

References and linksORIGINAL RESEARCH PAPER Nagarajan, R. et al. EGR2 mutations in inheritedneuropathies dominant-negatively inhibit myelin gene expression. Neuron 30, 355–368(2001)FURTHER READING Warner, L. E. et al. Mutations in the early growth response 2 (EGR2)gene are associated with hereditary myelinopathies. Nature Genet. 18, 382–384 (1998)

How do we control our impulses? Ifthe choice is between a small treatnow and a large treat later, most of uswould choose the large treat, eventhough we have to wait for it. Theinability to overcome the desire forimmediate reward in this way isknown as impulsive choice; it hasbeen implicated in addiction, atten-tion deficit hyperactivity disorder(ADHD) and some personality disor-ders, but its cause is unclear.

Rudolf Cardinal and colleagueshave investigated the neural sub-strates of impulsive choice by lookingat the preferences of rats for a small,immediate reward or a larger, delayedone. They found that lesions of thenucleus accumbens core reduced therats’ preference for the larger, delayedreward, apparently by making themunable to overcome their impulsivedesire for immediate gratification.Unlesioned rats would choose thelarger reward on some trials even if itwas delayed by up to 60 seconds, butlesioned animals usually chose thesmaller reward even if the delay to thelarger one was only 10 seconds.

Cardinal et al. also tested rats inwhich either the medial prefrontalcortex (mPFC) or the anterior cingu-late cortex (ACC) was lesioned. Bothof these areas project to the core ofthe nucleus accumbens and havebeen implicated in impulsive behav-iour. Surprisingly, neither of theselesions induced impulsive choice in

the rats. ACC lesions had no effect onthe task, even though such lesionshave been implicated in response dis-inhibition. The authors attribute thisapparent contradiction to a dissocia-tion between motor impulsivity andimpulsive choice. Rats with mPFClesions chose the large, delayedreward less frequently than shams atzero delay, but more frequently at themaximum delay. This may reflect aninteraction of the mPFC lesion withthe specific task used.

It remains to be seen which accum-bens afferents are involved in control-ling impulsive choice. But these datasuggest that the nucleus accumbensmay be important in our ability tomake rational decisions when facedwith this kind of choice, and in its dis-ruption in various disorders. Cardinalet al. also suggest that the results mayindicate that the nucleus accumbensis the site of action of methyl-phenidate (Ritalin), which modifiesdopamine signalling and can relievethe symptoms of ADHD.

Rachel Jones

References and linksORIGINAL RESEARCH PAPER Cardinal, R. N. et al. Impulsive choice induced in rats by lesions ofthe nucleus accumbens core. Science 24 May2001 (10.1126/science.1060818)FURTHER READING Evenden, J. L. Varieties ofimpulsivity. Psychopharmacology 146, 348–361(1999) | Sagvolden, T. & Sergeant, J. A. Attentiondeficit/hyperactivity disorder — from braindysfunctions to behaviour. Behav. Brain Res. 94,1–10 (1998) | Paus, T. Primate anterior cingulatecortex: where motor control, drive and cognitioninterface. Nature Rev. Neurosci. 2, 417–424 (2001)

Electron micrograph of sciatic nerve. Courtesy of J. Milbrandt, Washington University, St Louis, Missouri, USA.