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J Physiol (2003), 550.1, pp. 255-261
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2003.043661
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ABSTRACT |
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Local tissue damage in newborn rats can lead to changes in skin sensitivity that last into adulthood and this is likely to be due to plasticity of developing peripheral and central sensory connections. This study examines the functional connections of dorsal horn neurons in young and adult rats that have undergone local skin damage at birth. Newborn rat pups were halothane anaesthetised and received either a unilateral subcutaneous plantar injection of 1 %-carrageenan or a unilateral plantar foot injury made by removal of 2 mm
2 mm of skin. At 3 weeks, (postnatal day (P) 19-23) and 6 weeks (P40-44) in vivo extracellular recordings of single dorsal horn cells with plantar cutaneous receptive fields were made under urethane anaesthesia (2 g kg-1) and responses to mechanical and electrical stimulation of the skin were assessed. Following neonatal carrageenan inflammation, dorsal horn neuron properties and receptive field sizes at 3 weeks were the same as those of controls. In contrast, following neonatal skin injury, dorsal horn cell receptive field sizes were significantly greater than those of controls at 3 weeks (2.5-fold) and at 6 weeks (2.2-fold). Mechanical thresholds, mechanical response magnitudes and evoked responses to single and repeated A and C fibre stimulation remained unaffected. These results show that early skin injury can cause prolonged changes in central sensory connections that persist into adult life, long after the skin has healed. Enlarged dorsal horn neuron receptive field sizes provide a physiological mechanism for the persistent behavioural hypersensitivity that follows neonatal skin injury in rats and for the prolonged sensory changes reported in human infants after early pain and injury.
(Resubmitted 25 March 2003; accepted after revision 9 April 2003; first published online 23 May 2003)
Corresponding author M. Fitzgerald: Department of Anatomy and Developmental Biology, Gower Street, University College London, London WC1E 6BT, UK. Email: m.fitzgerald{at}ucl.ac.uk
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INTRODUCTION |
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The normal pattern of connections within the CNS is determined by neural activity patterns during development. The influence of sensory activity or experience upon the formation of somatosensory synaptic connections is well established in the rodent trigeminal system, where alterations in whisker stimulation during a critical period of postnatal development results in receptive field reorganisation in the thalamus and cortex (O'Leary et al. 1994; Fox, 2002).
Recently, the postnatal structural and functional development of cutaneous sensory synaptic connections within the spinal cord have also been shown to be activity dependent and to require NMDA receptor activation (Beggs et al. 2002). This may mean that alterations in the pattern of sensory inputs arising from tissue injury and pain in early life will disrupt normal synaptic organisation (Fitzgerald & Walker, 2003). If so, abnormal or excessive activity related to skin inflammation or injury in the neonate may have the potential to cause long-term changes in spinal sensory processing. This is supported by clinical studies suggesting that early pain related to surgical and procedural interventions during intensive care management of premature neonates has long-term consequences upon pain behaviour and perception in later life (Porter et al. 1999; Anand, 2000; Grunau, 2000).
While it is clear that neonatal nerve injury can permanently alter central spinal cord connections (Fitzgerald et al. 1990; Shortland & Fitzgerald, 1991), studies on the long-term effects of neonatal pain arising from tissue injury and inflammation upon synaptic connections are less clear. Both structural and functional alterations in the nervous system have been reported but they vary in degree and duration depending upon the model used (Reynolds & Fitzgerald, 1995; Anand et al. 1999; Dickenson & Rahman, 1999; Ruda et al. 2000; Beland & Fitzgerald, 2001; Bhutta et al. 2001; Lidow et al. 2001; Walker et al. 2003). To date, there has been no investigation of the long-term consequences of early pain and injury upon the physiological properties of sensory neurons in the adult spinal cord. Here we have examined the effects of two types of early injury, a local inflammation and a defined skin injury to the hindpaw of newborn rat pups, upon the electrophysiological properties of adult dorsal horn sensory neurons.
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METHODS |
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All experiments were approved and licensed by the UK Home Office Animals (Scientific Procedures) Act 1986.
Neonatal inflammation and skin injury
Sprague-Dawley rat pups were anaesthetised with 2-4 % halothane in oxygen and received either a subcutaneous injection of 1 % -carrageenan (10 µl, Sigma) into the plantar surface of the left hindpaw using a 30 gauge sterile needle and a calibrated Hamilton syringe or a full thickness skin injury by pinching the plantar skin with forceps and cutting a 2 mm 2 mm flap of skin within the pad region of the hindpaw. This size of skin flap occupies approximately 16 % of the plantar surface area of the newborn hindpaw as employed in previous studies of neonatal skin injury (Reynolds & Fitzgerald, 1995). Pups recovered uneventfully and were returned to their mother. Control animals were untreated.
Preparation for electrophysiological recording
Three and six weeks later, the animals were prepared for 'in vivo' electrophysiological recording. Animals were anaesthetised with 2 g kg-1 urethane I.P. (Sigma, UK). This dose of urethane causes anaesthesia for at least 8 h, and our experiments never lasted more than 6 h. The trachea was cannulated and intermittent positive pressure ventilation was achieved using a T-piece system in conjunction with a small animal lung ventilator pump (Harvard Apparatus Ltd). Animals were set up in a small animal Kopf stereotaxic frame, with the head and pelvis firmly held and a small clamp at L1 to stabilise the cord. The lumbar cord was exposed by laminectomy, the dura mater (and arachnoid) removed, and the surface of the cord was bathed in mineral oil. When the animal was deeply anaesthetised, as shown by areflexia, it underwent neuromuscular blockade with 0.1 ml Flaxedil (May and Baker Ltd, UK). Finally the hind limbs were supported with a suture under the Achilles tendon. Body temperature was maintained at physiological levels with a thermostatically controlled heating blanket and the heart rate was monitored throughout the experiment and remained within the range of 350-500 beats min-1. Animals were killed with an overdose of Lethobarb (pentobarbitone sodium BP) at the end of the experiment.
Electrophysiological recording
Single unit extracellular recordings were made from cells in the dorsal horn of the L4-L5 lumbar cord using glass-coated tungsten microelectrodes (tip diameter 10 µm). Single units were isolated by mechanical skin stimulation of the hindpaw while moving the electrode down through the cord in 10 µm steps until spikes of constant size and shape could be clearly discriminated. The depth of cells from the surface of the cord was measured with a microdrive. Using this method cells were grouped into those recorded in the superficial dorsal horn (I and II) and those recorded in deep dorsal horn (III, IV and V). The superficial/deep boundary values measured from Nissl-stained lumbar cord sections are as follows: 300 µm from the dorsal surface of the cord at postnatal day (P) 21 and 400 µm at P42. Single cells with receptive fields on the hindpaw were mapped using natural mechanical stimuli, i.e. light brush, touch and pinch. The receptive fields of the cells used in this study were all cutaneous mechanoreceptive fields of the slowly adapting or rapidly adapting type located on the pad region of the plantar surface of the hindpaw. Low threshold (LT, responding to brush only), wide dynamic range (WDR, responding to brush and pinch) and high threshold (HT, responding to pinch only) cells were isolated and receptive field size was assessed with innocuous mechanical stimulation (light touch/stroke with tip of blunt forceps) except in cells which responded to pinch stimulation only, where noxious mechanical stimulation (pinch skin between forceps) was applied. The receptive field was drawn onto a template of the hindpaw from which the receptive field size, as a percentage of the total plantar hindpaw surface area, was calculated following scanning and analysis with Leica Qwin image analysis software. Mechanical thresholds were determined by applying von Frey hairs to the centre of the receptive field. The series of von Frey hairs used in the present study was 0.03, 0.048, 0.07, 0.09, 0.44, 0.8, 1.13, 1.52, 3.12, 3.8, 4.72, 7.48 and 9.4 g. Each von Frey hair was applied three times for 1 s and the mechanical threshold was defined as the lowest von Frey hair required to evoke spike activity in all three trials. The magnitude of response to threshold and suprathreshold (three von Frey hairs above threshold) mechanical stimulation was also recorded as the number of spikes over a 12 s period from the onset of the stimulus. This time window was chosen to ensure that prolonged after-discharges as well as the immediate response evoked during the stimulus were included. Electrical stimulation of the skin was applied through subcutaneous pin electrodes in the centre of the receptive field at stimulus intensities of 100 µA to 10 mA, 100-500 µs. The A fibre threshold was defined as the minimum electrical stimulus intensity (100 µs) needed to produce a short-latency response from the dorsal horn cell and A fibre response amplitude was measured as the number of spikes in the first 70 ms period following stimulation. All cells were also tested at higher stimulus intensities (1-10 mA, 500 µs) for a longer-latency C fibre input. In addition, a train of 16 stimuli at 0.5 Hz at either two times the A fibre threshold or three times the C fibre threshold were applied and the spike activity in each sweep during a 200-2000 ms window recorded as a measure of sensitisation and wind-up. Background or spontaneous activity was measured for 1 min prior to electrical stimulation. Spike recordings were captured and analysed by computer using a Maclab interface and Spike2 software (AD Instruments).
Single unit recordings were made from both superficial and deep L4-L5 spinal cord dorsal horn neurons in the following experimental groups:
(1) Neonatal inflammation group: (i) 3-week-old (P19-23) controls, n = 34; (ii) 3-week-old (P19-23) carrageenan treated, n = 43.
(2) Neonatal skin injury group: (i) 3-week-old (P19-23) controls, n = 32; (ii) 3-week-old (P19-23) injured, n = 42; (iii) 6-week-old (P40-44) controls, n = 17; (iv) 6-week-old (P40-44) injured, n = 17.
Statistical analysis was carried out using unpaired t tests or the Mann-Whitney test depending on normality of data.
Hindpaw surface area was calculated by scanning an outline of the hindpaw and comparing this with a defined area (10 mm 10 mm) using Leica Qwin image analysis software.
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RESULTS |
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The cells used in this study all had cutaneous mechanoreceptive fields located on the plantar surface of the hindpaw. Neither carrageenan inflammation nor skin injury at birth significantly altered the proportion of low threshold (responding to brush only), wide dynamic range (responding to brush and pinch) and high threshold (responding to pinch only) cells in each group, when recorded 3 and 6 weeks later. In P21 control animals the proportions were 15, 67 and 18 %; in P21 neonatally inflamed animals, they were 18, 69 and 13 %; and in P21 neonatally skin injured animals they were 16, 63 and 21 %, respectively. As the proportions of cell types are not altered by treatment but are not equivalent (smaller percentages in the LT/HT categories) we have analysed the following data collectively. We have confirmed that the following results are also true for the WDR subtype when analysed separately. However, due to the small proportions in the LT and HT categories we cannot make specific statements about these classes of cells.
Spontaneous activity, that is the resting background level of spike activity in the absence of stimulation, was also not significantly altered by either treatment, being 15.8 ± 4.4 spikes min-1 in P21 controls, 20.1 ± 4.8 spikes min-1 in neonatal carrageenan animals and 18.8 ± 5.4 spikes min-1 in neonatally skin injured animals.
Effect of neonatal injury on responses to mechanical skin stimulation
The mechanical thresholds of individual dorsal horn neurons were measured by applying graded, calibrated von Frey hairs (vFh) to the centre of dorsal horn neuron receptive fields. Neither treatment significantly altered mechanical vFh thresholds of dorsal horn neurons at 3 weeks, P21 (Fig. 1A and B) or at 6 weeks, P42 (data not shown). Response magnitudes, or number of spikes fired to threshold or suprathreshold mechanical vFh stimulation were also not significantly different in each group at 3 weeks old, P21 (Fig. 1C and D) or at 6 weeks, P42 (data not shown).
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Figure 1. The effect of hindpaw carrageenan inflammation (A and C) and plantar skin injury (B and D) at birth upon the response properties of dorsal horn cells to natural skin stimulation at 3 weeks (P21) A and B, mean ± S.E.M. mechanical von Frey hair (vFh) cutaneous thresholds of cells in control and treated rats. C and D, mean ± S.E.M. response amplitudes to suprathreshold mechanical (vFh) stimulation of the receptive fields, measured as the number of spikes in a 12 s period from stimulus application, in control and treated rats. | ||
Effect of neonatal injury on dorsal horn neuron receptive field size
The receptive field size was mapped (see Methods) on the plantar surface of the hindpaw and calculated as a percentage of the total plantar hindpaw surface area. Figure 2A shows that neonatal carrageenan did not significantly alter receptive field size at 3 weeks old. However, this was not the case following neonatal skin injury. Three weeks after neonatal skin injury, the receptive fields were 2.5 times larger than controls (P21 controls: 16 ± 2.5 %; P21 neonatally injured: 39 ± 4.1 %, P < 0.0001, unpaired t test, Fig. 2B). This effect continued into adulthood. At 6 weeks, P42, receptive field sizes in neonatally injured animals were still 2.2 times larger than controls (P42 controls: 17 ± 3.0 %; P42 neonatally injured: 37 ± 5.5 %, P = 0.003, unpaired t test, Fig. 2C).
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Figure 2. The effect of hindpaw carrageenan inflammation (A) and plantar skin injury (B and C) at birth upon the receptive field size of dorsal horn cells at 3 weeks, P21 (A and B) and 6 weeks, P42 (C) A and B, mean ± S.E.M. cutaneous receptive field areas, expressed as percentage of total area of the plantar surface, of dorsal horn cells in control and treated rats at 3 weeks, P21. C, mean ± S.E.M. cutaneous receptive field areas of dorsal horn cells in control and neonatally injured rats at 6 weeks, P42. The diagram illustrates typical receptive field expansions seen in neonatally injured rats. | ||
Effect of neonatal injury on electrically evoked responses
The amplitude of the responses evoked by electrical stimulation was not altered by either neonatal carrageenan or injury at all ages tested. This is shown in Fig. 3A and B for the A fibre-evoked response, and in Fig. 3C and D for the C fibre-evoked response at P21. The percentage of cells with C fibre-evoked responses, was unaffected by neonatal injury. At P21, C fibre responses were recorded in 27 % of cells in control animals, 21 % in neonatal carrageenan animals and 36 % in neonatally injured animals. The percentage of cells showing 'wind-up' to repeated stimulation was less than 10 % in all groups. A fibre-induced sensitisation (build-up in background activity during repetitive A fibre stimulation) was not significantly affected by neonatal carrageenan treatment (P = 0.7, Mann-Whitney test) or neonatal skin injury (P = 0.3, Mann-Whitney at ~P21; P = 0.2, Mann-Whitney at ~P42).
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Figure 3. The effect of hindpaw carrageenan inflammation (A and C) and plantar skin injury (B and D) at birth upon the response properties of dorsal horn cells to electrical skin stimulation at 3 weeks (P21) A and B, mean ± S.E.M. number of spikes, evoked in the first 70 ms after the stimulus by A fibre skin stimulation, in dorsal horn cells of control and treated rats. C and D, mean ± S.E.M. number of spikes, evoked in the 200-2000 ms period after the stimulus by C fibre skin stimulation, in dorsal horn cells of control and treated rats. | ||
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DISCUSSION |
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Our results demonstrate for the first time that neonatal injury can lead to long-term changes in receptive field organisation. Neonatal skin injury, but not neonatal carrageenan inflammation, results in long-term alteration of sensory connections in the spinal cord dorsal horn of adult rats. Dorsal horn neuron receptive field size was significantly enhanced at 3 weeks (2.5-fold) and 6 weeks (2.2-fold) following skin injury at birth. All other properties analysed, that is mechanical thresholds and response amplitudes, electrically evoked responses and spontaneous activity, were all unaltered by neonatal skin injury. A variety of behavioural and pharmacological changes have previously been reported following neonatal injury in rats (see Fitzgerald & Walker, 2003 for review), but this is the first report of persistent receptive field changes in the dorsal horn of the spinal cord after such a brief peripheral tissue injury at birth.
Dorsal horn cell receptive field plasticity
Acute changes in dorsal horn cell properties, involving decreased mechanical thresholds and enlarged pinch receptive fields have been reported following both inflammation and skin incision in adult rats (Ren & Dubner, 1996; Zahn & Brennan, 1999) and are thought to contribute to injury-induced pain and primary mechanical hyperalgesia (Dubner & Ruda, 1992). In fact, a relatively brief nociceptive afferent barrage will produce an acute increase in the cutaneous receptive field size of dorsal horn neurons, amplify their responsiveness and reduce their thresholds (Woolf & King, 1990). Similar results are observed in young animals, where carrageenan inflammation causes an increased responsiveness in dorsal horn neurons (Torsney & Fitzgerald, 2002). The results here differ substantially, however, from previous reports of acute responses to tissue injury. The altered receptive fields are present in the mature 6-week-old animal, long after the injury applied at birth has healed. Neonatally injured skin heals very rapidly within a few days and 3 and 6 weeks later the original damage is completely undetectable. These changes are the result of a permanent alteration in connectivity that does not require a persistent acute noxious stimulus. Also, unlike the acute adult response to injury, the expanded receptive fields are not accompanied by a drop in dorsal horn cell threshold or increased response amplitude. The underlying mechanisms are therefore unlikely to be the same as those involved in the acute response to a noxious stimulus, such as a transient withdrawal of segmental inhibition (Sivilotti & Woolf, 1994) or a transient upregulation of neuropeptide transmitters (Beland & Fitzgerald, 2001), but involve a permanent reorganisation of synaptic connections. A further important difference is that unlike the acute response, the long-lasting expansion of receptive fields only occurs after neonatal skin injury and not after carrageenan inflammation. Changes in the dorsal horn connections have been reported following severe inflammation with high dose Freund's complete adjuvant (FCA) injections into the neonatal hindpaw. In this case, central afferent terminal fields were found to expand (Ruda et al. 2000) and increases in dorsal horn Fos expression to noxious chemical stimuli were observed (Tachibana et al. 2001). Recent data show that high dose FCA injections do in fact cause a chronic inflammation that lasts into adulthood (Walker et al. 2003). The carrageenan inflammation used in the present study causes an acute response that lasts just over a week (Alvares et al. 2000) and this is insufficient to cause prolonged central effects. Therefore it would appear that during the neonatal period actual skin/nerve terminal damage, but not acute inflammation, results in long-term central changes.
We cannot exclude the possibility that prolonged changes in dorsal horn cell properties also occur following skin injury in the adult as this has not been specifically addressed. However, following neonatal skin injury local peripheral nerve terminals show a profound sprouting response, which long outlasts the initial injury and behavioural studies show that this hyperinnervation is accompanied by a long lasting hypersensitivity (Reynolds & Fitzgerald, 1995; De Lima et al. 1999). This hyperinnervation response is greatest when skin injury is performed at birth and declines postnatally to resemble the weaker and transient response in the adult (Reynolds & Fitzgerald, 1995). Whilst this sprouting response may not directly underlie the enlarged receptive field sizes (see below) it appears that the response to skin injury in the adult is more acute.
Possible underlying mechanisms
The expansion of dorsal horn neuron receptive field size may reflect an expansion of primary afferent receptive field size in the periphery. Sprouting of cutaneous sensory terminals has been observed within the previously injured region (Reynolds & Fitzgerald, 1995; De Lima et al. 1999), some of which may be collateral sprouting from nearby intact primary afferents into the denervated region (Alvares et al. 2000), such as has been demonstrated following nerve injury (Diamond et al. 1987, 1992). Sprouting may be triggered by the upregulation of nerve growth factor and other neurotrophins in the skin, which is particularly marked following neonatal compared with adult skin injuries (Constantinou et al. 1994).
One argument against a peripheral mechanism is the extent of the expansion of dorsal horn receptive field size relative to the size of the injured area. Peripheral hyperinnervation is restricted to the original 2 mm 2 mm (4 mm2) injured area on the plantar surface of the hindpaw (Reynolds & Fitzgerald, 1995), and therefore collateral sprouting of intact adjacent primary afferents could only be expected to increase dorsal horn neuron receptive field sizes by 18 % in a P21 pup, with an average plantar surface area of 140 mm2. This is considerably less than the 250 % increase observed following neonatal skin injury in the present study.
It seems likely that a central synaptic change has taken place in the spinal cord. Inputs that are subthreshold in controls may now be capable of activating dorsal horn neurons which are in an increased state of excitability, perhaps because of altered afferent activity, neurotransmitter release or receptor expression (Neumann et al. 1996) via increased neurotrophin levels (Ji et al. 2002), although this would also be expected to increase response amplitudes and change thresholds. Another possible central mechanism might be sprouting of central terminals of primary afferents as has been reported following neonatal nerve damage and severe inflammation (Fitzgerald, 1985; Fitzgerald et al. 1990; Shortland & Fitzgerald, 1994; Ruda et al. 2000) resulting in the formation of inappropriate functional connections with dorsal horn cells in areas far outside their normal termination area (Shortland & Fitzgerald, 1991). This is supported by the fact that long-term receptive field expansion is only triggered when the nerve terminals are frankly damaged and the skin is damaged; acute inflammation alone is not enough.
An important consideration is that receptive fields are normally large in the neonatal period and gradually decrease in size with age (Fitzgerald & Jennings, 1999; Torsney & Fitzgerald, 2002) presumably through the onset of inhibitory controls (Fitzgerald & Koltzenburg, 1986). Recently this developmental regulation of receptive field size has been shown to be activity dependent (Beggs et al. 2002) and is prevented by chronic spinal cord application of NMDA blockers over the postnatal period, in common with the experience-dependent plasticity of other sensory systems (for review see Berardi et al. 2000). It has been proposed that connections are strengthened when pre- and postsynaptic activity is correlated, with those connections that are uncorrelated being weakened and eliminated through the induction of NMDA-dependent long-term potentiation (LTP) and depression (LTD) (Feldman et al. 1999; Sanes & Yamagata, 1999). In the present study, activity in primary afferents arising from neonatal skin injury, during this critical period, may well have influenced the correlation of pre- and postsynaptic activity in the dorsal horn resulting in enhanced NMDA receptor-dependent LTP or a failure to induce NMDA receptor-dependent LTD. Therefore, the enlarged receptive fields encountered in the adult may result from a failure of the normal elimination of inappropriate excitatory synaptic connections or a failure to strengthen appropriate inhibitory synaptic connections during the postnatal period.
Implications for sensory processing
The expansion of dorsal horn neuron receptive field size at 3 and 6 weeks following skin injury at birth may provide a physiological mechanism for the prolonged behavioural hypersensitivity that follows early skin injury (Reynolds & Fitzgerald, 1995; De Lima et al. 1999). Expanded receptive fields will result in a greater number of dorsal horn neurons activated by a given stimulus. This will result in reduced spatial discrimination, increased input but also reduced thresholds of tertiary cells, such as motoneurons (Fig. 4). Expanded receptive fields can therefore contribute to an enhanced sensitivity and lower behavioural thresholds, in that previously ineffective/subthreshold input at the motoneuron or thalamic level may now be capable of evoking reflex behaviour or activating nociceptive neurons. As such, receptive field changes may underlie some of the reported prolonged behavioural and clinical effects of infant pain and injury in man (Anand, 2000; Grunau, 2002).
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Figure 4. Schematic diagram illustrating how increased receptive field size of dorsal horn neurons, through convergent inputs, can lead to lowered thresholds and increased chance of spike activity in tertiary cells such as motoneurons or higher CNS neurons | ||
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Acknowledgements
The authors thank Jacqueta Middleton for her technical support. C.T. was a Wellcome Trust Neuroscience PhD student at UCL. The work was supported by the Wellcome Trust and the Medical Research Council.
Author's present address
C. Torsney: Columbia University, Department of Physiology and Cellular Biophysics, 630 West 168th Street, BB 1106, New York, NY 10032, USA.
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