742 | OCTOBER 2004 | VOLUME 5 www.nature.com/reviews/neuro

Radial glial cells are important in neuronalmigration and also serve as neuronal progeni-tors, but signalling mechanisms among themare not well understood. Reporting in Neuron,Weissman and colleagues describe the discoveryof a novel mechanism whereby proliferation ofradial glial cells in the cortical ventricular zone(VZ) during development is regulated by spon-taneous waves of calcium.

Using time-lapse calcium imaging, theauthors first observed spontaneous calciumwaves within the VZ of explants from thebrains of embryonic day (E) 16–17 rats, whichthey could reproduce with electrical ormechanical stimulation. Calcium waves couldbe transmitted between two stimulated brainslices separated by up to 130 µm, indicatingthat the propagation might be mediated by dif-fusible signals.

By using various receptor antagonists, theauthors found that extracellular ATP wasinvolved in spontaneous and stimulated cal-cium waves. Direct application of ATP resultedin an increase in the intracellular calciumconcentration of the VZ cells. Initiation andpropagation of spontaneous and stimulated calcium waves occurred in the absence ofextracellular calcium, but were reduced whenintracellular calcium was depleted, indicatingthat the release of calcium from internal storesmight have a crucial role in the initiation andpropagation of calcium waves. This is consistentwith the finding that inhibitors of either inositoltriphosphate or Gq-phospholipase C (PLC) significantly attenuated calcium waves.

To determine which cells in the VZ areinvolved in calcium waves, Weissman and col-leagues stimulated the E16 coronal brain sliceswith ATP and monitored the calcium waves in

randomly selected cells using patch electrodes.They observed that most VZ cells that displayedcalcium increases in response to ATP had radialglial morphology.

The authors then assessed the functionalconsequence of calcium waves in radial glialcells in the VZ. They found that the cellsinvolved in calcium waves are located in theupper third of the VZ, which represents the S-phase zone (where most cells are in the S phaseof the cell cycle). The expression of spontaneousand stimulated calcium waves is maximal atE16, when neurogenesis also peaks. This devel-opmental profile of calcium waves correlateswith the sensitivity of the VZ cells to ATP. Whencalcium waves in E16 brain slices were disruptedby an ATP-receptor antagonist, the incorpora-tion of 5-bromo-2′-deoxyuridine by the VZcells — an indication of DNA synthesis in the Sphase — was significantly reduced. This defectin proliferation was rescued when calciumwaves were restored by a PLC activator. Theauthors conclude that calcium waves modulatethe proliferation of radial glial cells duringdevelopment and, therefore, might be impor-tant in regulating the production of neocorticalneurons.

Jane QiuReferences and links

ORIGINAL RESEARCH PAPER Weissman, T. A. et al. Calciumwaves propagate through radial glial cells and modulateproliferation in the developing neocortex. Neuron 11, 647–661(2004)FURTHER READING Rakic, P. Elusive radial glial cells:historical and evolutionary perspective. Glia 43, 19–32 (2003)WEBSITEKriegstein’s laboratory:http://www.research.hs.columbia.edu/Faculty_Profiles/profiles/kriegstein_ar.html

Our responses to pain and our ability to tolerateit are known to be affected by the extent towhich pain is perceived to be controllable. Astudy published in The Journal of Neurosciencenow shows how differences in perceived paincontrol influence the activation of the insularcortex, secondary somatosensory cortex (SII)and anterior cingulate cortex (ACC), all ofwhich are involved in pain processing.

Salomons et al. used painful thermal stimuliand different cues signalling controllable oruncontrollable pain to test whether subjects’perception of pain and the associated neuralprocessing varied according to perceived con-trollability. Although the subjects were able todistinguish between cues signalling controllableand uncontrollable pain, there was no differ-

ence between the mean pain rating given forstimuli perceived to be controllable or uncon-trollable.

The authors also used overlapping brainmaps created using fMRI studies, and sub-tracted the activation seen in areas of interestwhen pain was perceived to be controllablefrom that seen when pain was perceived to beuncontrollable. Although parts of all three areaswere activated when pain was perceived toeither be controllable or uncontrollable, thedegree of activation was significantly greaterwhen pain was perceived to be uncontrollable;in particular in the dorsocaudal area of the ACCand the anterior area of the right insula. As thesubjects did not give the two conditions differ-ent pain ratings, Salomons et al. conclude that

the results of the overlap study cannot beexplained by just the subjects’ perception ofpain.

The authors suggest that the results of previ-ous pain studies might have been influenced bysubjects’ perceived lack of pain control, which,in imaging studies, could have led researchers tobelieve that pain itself caused exaggerated acti-vation of particular areas of the brain. They alsopropose that further research be carried out toestablish whether different subjects use differenttechniques, such as distraction, to help themcope with pain. Furthermore, they suggest thatdifferences in perceived pain control might beused in studies of chronic pain and possibletreatments for this condition.

Sarah Archibald

References and linksORIGINAL REFERENCE PAPER Salomons, T. V. et al.Perceived controllability modulates the neural response topain. J. Neurosci. 24, 7199–7203 (2004)FURTHER READING Hunt, S. P. The molecular dynamics of pain control. Nature Rev. Neurosci. 2, 83–91 (2001)

Less pain when you’re in control?

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Waves of proliferation

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