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Department of Anatomy and Neurobiology, Medical College of Ohio, Toledo, Ohio 43614
Submitted 24 January 2003; accepted in final form 27 May 2003
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ABSTRACT |
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80% stump-only sites. These results indicate age-dependent differences in receptive-field reorganization of the forelimb-stump representation, which may reflect the spatiotemporal development of SI. Results from cobalt chloride inactivation of the SI vibrissae region and electrolesioning of the dysgranular cortex suggest that normally suppressed vibrissae inputs to the SI forelimb-stump area originate in the SI vibrissae region and synapse in the dysgranular cortex. |
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INTRODUCTION |
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-amino butyric acid (GABAA+B) are pharmacologically blocked (Lane et al. 1997
). Electrolytic lesioning of the SI hindlimb representation in neonatal amputees drastically reduced the number of hindlimb responsive sites within the forelimb-stump region, suggesting that a majority of these hindlimb inputs originate in the SI hindlimb representation (Lane et al. 1999). A significant reduction in the number of hindlimb responsive sites also resulted from cobalt chloride (CoCl2) inactivation of the dysgranular cortex located between the hindlimb and forelimb-stump representations, suggesting that the hindlimb-to-forelimb-stump circuit includes synapses in the dysgranular zone (Stojic et al. 2001). While more than one-third of multi-unit recording sites in the SI forelimb-stump of neonatal amputees respond to hindlimb stimulation during GABA receptor blockade, it is interesting that far fewer sites respond to stimulation of other body regions such as the face (vibrissae or lower jaw), or the trunk, which have SI representations adjacent to and surrounding that of the forelimb (Chapin and Lin 1984). The reason for this is presently unclear, but it may be related to the normal progression of cortex development. Anatomical and functional evidence suggest that SI development progresses along a lateral to medial gradient (i.e., from face to forelimb to hindlimb representations) (McCandlish et al. 1989, 1993). This differential development of SI during the perinatal period could set limits on the capacity for intact cortical representations surrounding the affected forelimb-stump region to influence the receptive fields of its constituent neurons. Forelimb amputation on P0 may come at a time when the medial hindlimb representation has more potential than the lateral face regions to develop or strengthen inputs into the deafferented forelimb-stump region. The relative immaturity of medial compared with lateral portions of SI at the time of injury could promote the development of hindlimb (but not face) inputs. If the potential for intact cortical areas to "contribute" to the functional receptive-field reorganization of a deafferented zone is associated with an early developmental state of that cortical region, then an amputation performed on embryonic day (E) 16 should result in a higher number of inputs from the lateral SI representations of the facial vibrissae and lower jaw. In contrast, the mature SI of adult amputees would be expected to exhibit fewer reorganized inputs to the forelimb-stump area overall. To test this hypothesis, the SI forelimb-stump representation of adult rats that had sustained forelimb amputation on either E16, P0, or as adults was electrophysiologically mapped. The mapping was repeated during GABA receptor blockade, and the number and locations of nonstump inputs were recorded. In addition, CoCl2 was used to temporarily inactivate the SI vibrissae representation and electrolytic lesions were placed in the dysgranular cortex to test if vibrissae inputs to the forelimb-stump originate in the vibrissae field and travel intracortically through the dysgranular zone. |
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METHODS |
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Fetal forelimb amputations were carried out using methods previously described (Rhoades et al. 1993). Timed pregnant Sprague-Dawley dams were anesthetized with ether on E16. A 25-mm incision was made through the skin and muscular abdominal wall along the linea alba 5 cm above the vagina. The muscular wall was reflected and the uterine horns exteriorized. The uterine sac containing each fetus was stabilized between the blades of blunt forceps and transilluminated with a fiber-optic light source. The uterine wall and amniotic sac were pierced with a microknife, and either the left or right forelimb was excised. After limb amputation, the blade of the microknife was withdrawn, and pressure was applied to the incision site with a cotton swab to arrest leakage of the amniotic fluid. The uterine horns were then replaced into the abdominal cavity, the abdominal wall was sutured, 0.7% bupivacaine (Abbott Laboratories) was applied, and the overlying skin was sutured and stapled. Pups were allowed to come to term and survive 
60 days before electrophysiological recording.
Neonatal amputations were carried out using methods previously described (Lane et al. 1995). P0 rat pups (<12 h old) were anesthetized by hypothermia until immobile. The left forelimb was amputated using iridectomy scissors at a point distal to the shoulder. After amputation, the brachial artery was sealed by electrocautery. The stump was infiltrated with 0.7% bupivacaine and the skin closed with cyanoacrylate adhesive. The pups were rewarmed, returned to their mothers, and allowed to reach 60 days of age before recording.
Adult amputations were performed on rats 60 days old. The rat was anesthetized with 100 mg/kg ketamine hydrochloride (Fort Dodge Laboratories) and 20 mg/kg xylazine (Bayer Corporation) administered intraperitoneally. A circular skin incision was made at the mid-region of the upper arm. The brachial nerve and associated vessels were isolated, ligated, and cut 5 mm distal to the brachial plexus. The humerus was exposed and sectioned at mid-shaft. Distal attachments of adjacent muscles were freed and sutured together over the cut end of the humerus. The region was infiltrated with 0.5% bupivacaine and the skin was sutured and stapled. Rats were allowed to recover and were used in recording experiments after 60 days from the date of surgery.
Recordings from SI and GABA receptor blockade
Rats were anesthetized with 60 mg/kg ketamine and 15 mg/kg xylazine administered intraperitoneally and prepared for recordings as previously described (Lane et al. 1995, 1997, 1999). Investigators were blinded as to the time of injury until each experiment was completed. The trachea was cannulated, and the animal was placed in a stereotaxic head holder and ventilated mechanically. A midsagittal incision was made, the cisterna magna was opened to drain cerebral spinal fluid, and a craniotomy was performed over the cerebral cortex contralateral to the amputated forelimb. The dura and arachnoid were incised and reflected. Warm culture medium (Neurobasal medium, Gibco-BRL) was applied to the cortical surface to prevent desiccation. The surface of the cortex was photographed and magnified (20x) to mark the placement of recording electrode penetrations during mapping. Light anesthesia was maintained throughout the recording session by intramuscular injection of 1 g/kg urethane (Sigma). Unit clusters were recorded with varnish coated tungsten electrodes (Z = 0.9–1.3 M
, at 1 kHz). Electrode penetrations were spaced 250–300 µm apart, and multi-unit activity was recorded at depths between 600 and 800 µm below the pial surface (the approximate depth of lamina IV). Tactile stimuli to the stump, whisker pad, lower jaw, trunk, or hindpaw were delivered with a blunt probe and used to map cutaneous receptive fields of neuron clusters within the forelimb-stump representation. Evoked responses were considered significant if at least nine action potentials were elicited in response to a train of 10 light taps delivered to the body surface at a frequency of 3 Hz. After the initial mapping was completed, a 30-µl solution containing 50 µM bicuculline methiodide (BMI) and 50 µM saclofen (SAC; both supplied by Research Biochemicals International) was applied to the surface of the cortex as previously described (Lane et al. 1997). The forelimb-stump region was remapped 10–15 min later. The antagonists are effective by 10 min after application and continue to be effective at blocking GABA receptor activity for 30 min (Stojic et al. 2000). Additional 30-µl applications were employed if needed; neuronal bursting activity was used to monitor the level of receptor antagonism. All recording sites were retested during GABA receptor blockade (GRB). The percentage of sites responsive to stump-only, stump/hindlimb, stump/face (vibrissae and/or lower jaw), stump/hindlimb/face, and stump/trunk were determined under both conditions. Spontaneous and evoked bursting activity was increased during GRB; receptive-field mapping was facilitated by delivering tactile stimuli between periods of bursting. Response latencies to electrical stimulation (0.1-ms duration, ranging from 2.5 to 10 V) of the infraorbital nerve were measured in the SI vibrissae representation and also in the SI forelimb-stump region during GRB. Response latencies to electrical stimulation of the brachial plexus (on the amputated side) were also recorded in the forelimb-stump region. Latency values were defined on oscilloscope traces as the time between the beginning of the stimulation artifact and the beginning of the cortical response. After completion of the second map, small electrolytic lesions (2-s duration, 5 V) were made to mark the location of the forelimb-stump representation for tissue processing. After the recording session, the animal was given a lethal dose of carbon dioxide and perfused with heparinized saline followed by 4% paraformaldehyde dissolved in sodium phosphate buffer (pH 7.4). The brain was allowed to postfix overnight before the cortex was removed, flattened, and tangentially cut into 50-µm sections on a freezing microtome. Tissue sections were processed for cytochrome oxidase (CO) (Wong-Riley 1979), and evaluated microscopically.
CoCl2 inactivation, electrolytic lesioning, area measurements, and data analysis
A 30 mM solution of CoCl2 (Sigma) dissolved in saline was injected at 10–12 sites (1–3 µl/site) in the SI vibrissae representation. Inactivation of the region was confirmed by monitoring spontaneous and evoked activity in three to four sites within the vibrissae field. When the vibrissae representation was inactivated, and with GRB maintained, all stump/vibrissae sites were retested. After 30–45 min, spontaneous and evoked activity in the vibrissae region returned to normal, and stump/vibrissae sites were tested again 1 h after CoCl2 injections. The dysgranular cortex between the SI vibrissae and forelimb-stump representations was lesioned by making multiple electrode penetrations 100–150 µm apart to a depth of 1 mm while maintaining a constant 5 V DC current. GRB was maintained and stump/vibrissae sites were tested once again. Area measurements were attained by tracing the perimeter of the SI forelimb-stump representation (defined electrophysiologically before GRB) from the enlarged cortical photographs on a digitizing tablet (Wacom).
Multi-unit recording sites in the SI forelimb-stump were characterized before and during GRB. Sites were defined during mapping as responsive either to stimulation of the stump-only, stump/hindlimb, stump/face (vibrissae and/or lower jaw), stump/hindlimb/face, or stump/trunk. The resulting frequency data were evaluated by one-way ANOVA to test for differences in the frequency of different receptive fields, before and during GRB. The accepted level of significance was P < 0.05. Separate ANOVAs were used to assess receptive-field differences with respect to age of the animal at the time of amputation, before and during GRB, and to test for receptive-field differences under conditions of CoCl2 blockade and dysgranular lesioning. When the ANOVA showed significant differences between groups, a Bonferroni multiple-comparison test was performed to identify experimental groups with significantly different means. Response latencies were compared using the Student's t-test for independent samples. Area measurements were analyzed by the nonparametric Kruskal-Wallis ANOVA (P < 0.05) and the Mann Whitney U test.
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RESULTS |
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Cutaneous receptive fields of 1,601 multi-unit recording sites from 23 amputated rats (amputation on E16: n = 11; P0: n = 6; adult: n = 6) were evaluated in this study before and during GRB. Figure 1 shows electrophysiological maps of the SI forelimb-stump representation in three representative animals before and during GRB along with corresponding CO-stained tissue sections labeled to indicate the relative locations of somatotopic representations in layer IV of SI. Initial mapping in all animals revealed that on average 80% of forelimb-stump sites were responsive only to stimulation of the stump. Of the remaining sites, 3% were unresponsive, and the others were additionally responsive to one of the nonstump regions tested ("split receptive-field sites"). These split receptive-field sites were usually located within 300 µm of the SI forelimb-stump perimeter and indicate that overlap in representational borders is detectable by extracellular recording. The number of split receptive-field sites noted prior to GRB was somewhat higher in this study than in previous studies (Lane et al. 1997, 1999), which found 5% of sites to be hindlimb responsive and noted but did not quantify other sites that were responsive to vibrissae stimulation. The higher percentage of split receptive-field sites recorded prior to GRB in the current study may be related to differences in electrode properties, different times of injury, and/or the careful assessment of multiple cutaneous regions in the current study compared with a previous focus on predominant hindlimb receptive-field sites in neonatal amputees. GRB resulted in significant increases in the number of split receptive-field sites within the SI forelimb-stump in fetal and neonatal but not adult amputees. Stump/face sites were predominant in fetal amputees while stump/hindlimb sites were predominant in neonatal amputees (Fig. 1). The electrophysiological effect of GRB is demonstrated in Fig. 2, which shows recordings from microelectrodes placed centrally in the forelimb-stump representation and left undisturbed while GABA antagonists were applied. Before GRB, multi-unit activity at all recording sites shown could only be evoked by cutaneous stimulation of the stump as was typical for most forelimb-stump sites. During GRB, the recording site in the E16 amputee also responded to cutaneous stimulation of the vibrissae, whereas that in the P0 amputee also responded to hindlimb stimulation. A significant percentage of sites (22%) in E16 amputees responded to both the face and the hindlimb during GRB. Tracings from the adult amputee showed no change in stimulus-evoked activity, but there was an increase in spontaneous activity. Increased spontaneous activity was a consistent effect of GRB in all animals (Fig. 2).
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Cutaneous receptive-fields of SI forelimb-stump recording sites are shown before and during GRB in Fig. 3. On average, in E16 amputees (n = 7), 34% of forelimb-stump recording sites were stump/face, 10% stump/hindlimb, and 22% stump/hindlimb/face responsive during GRB. In P0 amputees (n = 6), 10% of sites were stump/face, 39% stump/hindlimb, and 5% stump/hindlimb/face responsive during GRB. In adult amputees (n = 6), GRB did not result in significant receptive-field changes of SI forelimb-stump neurons: 10% of sites were stump/face, 5% stump/hindlimb, 0% stump/hindlimb/face, whereas 80% of recording sites assessed were stump-only responsive before and during GRB (Fig. 3D). E16 amputees exhibited a significant increase in the percentage of split receptive-field sites responsive to stump/face (34%) and stump/hindlimb/face (22%) during GRB, when compared with preblock conditions (11%, P < 0.001 and 0%, P < 0.01, respectively). The frequency of stump/face sites in E16 amputees during GRB (34%) is significantly greater than the frequency of stump/face sites recorded under the same conditions in P0 (10%; P < 0.001) or adult (9%; P < 0.001) amputated rats. Likewise, the frequency of stump/hindlimb/face sites in E16 amputees during GRB (22%) was significantly higher than that found in the P0 (4%; P < 0.05) and adult (0%; P < 0.01) amputated rats. In contrast, P0 amputees had a significantly (P < 0.001) higher frequency of stump/hindlimb sites during GRB (39%) as compared with before (9%). This 39% frequency of stump/hindlimb sites during GRB in P0 amputees was also greater than that found in E16 (10%) and adult (5%) amputees during GRB (P < 0.001 for both). Grouping double and triple field sites together to attain total percentages indicates that 56% of SI forelimb-stump sites in E16 amputees during GRB exhibit a face response, while significantly fewer sites (P < 0.05) exhibit a hindlimb response (32%). In P0 amputees during GRB, only 15% of sites exhibit a face, while 44% exhibit a hindlimb response (P < 0.05). The 56% total face responsive sites in E16 amputees is significantly (P < 0.001) higher than that in P0 amputees (15%); and the 32% total hindlimb responsive sites in E16 amputees is significantly lower (P < 0.05) than that in P0 amputees (44%). In all age groups, the frequency of stump/trunk sites was 5% before and during GRB.
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The area of the SI forelimb-stump representation (defined electrophysiologically before GRB) was found to be significantly smaller (P < 0.01, 1-way ANOVA) in adult amputees compared with fetal or neonatal amputees. Average areas of this representation were 5.50 + 1.43 (SD) mm2 in E16 amputees (n = 7), 6.01 + 0.60 mm2 in P0 amputees (n = 6), and 3.10 + 1.04 mm2 in adult amputees (n = 6). This is consistent with recent evidence that the area of the physiologically and histochemically defined SI forelimb-stump is significantly smaller in adult compared with normal or neonatally amputated rats (Bowlus et al. 2003).
Effects of CoCl2 inactivation and dysgranular cortex lesions; response latencies
CoCl2 was used to reversibly inactivate synaptic activity in the SI vibrissae representation to test if this would reduce the number of vibrissae responsive sites in the forelimb-stump region of E16 amputees (n = 4). Figure 4 (B and C) shows vibrissae responses in forelimb-stump sites to be almost completely eliminated when CoCl2 is injected into the vibrissae region. In addition, electrolytic lesions were placed in the dysgranular cortex between the SI vibrissae and forelimb-stump representations to sever horizontal connections between these regions and to test whether this manipulation would also reduce the number of hindlimb responsive sites in E16 amputees (n = 5). Normally suppressed vibrissae responses in forelimb-stump sites are also almost completely eliminated after lesioning the dysgranular zone (Fig. 4, B and D, F and G). CO-stained sections in Fig. 4 (D and G) illustrate that the lesions border the medial aspect of the vibrissae representation, but spare the lower jaw region (4D, inset). As seen in Fig. 4 (C, D, and G), responses to stimulation of the lower jaw persisted in forelimb-stump sites when the vibrissae region was silenced and when the dysgranular zone was lesioned. Figure 5 demonstrates that the effect of CoCl2 treatment and dysgranular lesions in eliminating vibrissae receptive fields in forelimb-stump neurons is consistent for both cutaneous and electrical stimulation. Evoked responses to cutaneous vibrissae and electrical infraorbital nerve stimulation present in the SI stump recording site during GRB are lost during CoCl2 silencing, reappear after a washout period, but are again eliminated when lesions are placed in the intervening dysgranular cortex. Note also in Fig. 5 that vibrissae responses in the SI vibrissae recording site are present in all conditions except during CoCl2 silencing in this region, which also reduced the high spontaneous activity level induced by GRB. Figure 6 shows the individual and averaged effects of CoCl2 and dysgranular lesions on the expression of vibrissae responses in forelimb-stump neurons. On average, silencing the vibrissae representation selectively reduced the vibrissae component of stump/vibrissae sites from 23% (during GRB) to 2% (during GRB + CoCl2 in SI Vib; P < 0.01). Dysgranular cortex lesions also selectively reduced vibrissae responses in forelimb-stump neurons from 19% (during GRB) to 2% (during GRB + Dys ctx lesions; P < 0.01).
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Cortical responses in SI forelimb-stump recording sites that were evoked by electrical infraorbital nerve stimulation had long latencies compared with responses to this type of stimulation measured in the SI vibrissae representation. The average latency to infraorbital nerve stimulation measured in the SI forelimb-stump was 20.0 ± 2.9 (SD) ms (39 sites tested) whereas that measured in the SI vibrissae region was significantly shorter at 6.3 ± 1.37 ms (49 sites tested, P < 0.001, Student's t-test). The average latency to brachial plexus stimulation measured in the forelimb-stump region was 10.0 ± 1.6 ms (17 sites). These findings are consistent with previous work in neonatal amputees demonstrating that, during GRB, hindlimb responses in the SI forelimb-stump have long latency (26.3 ms), compared with hindlimb responses in the SI hindlimb (10.8 ms), or stump responses in the SI forelimb-stump (10.0 ms) (Lane et al. 1999).
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DISCUSSION |
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; Stojic et al. 2001). Development of the somatosensory system and sensitive time periods for reorganization
The trigeminal, forelimb, and hindlimb pathways of the dorsal column-medial lemniscal system develop sequentially in the order listed (see Killackey et al. 1990 for a review). Development of the rat neocortex has a corresponding lateral to medial progression that is demonstrable with anatomical, histochemical, and physiological techniques (McCandlish et al. 1989, 1993; Rhoades et al. 1990; Schlagger and O'Leary 1994). Evoked responses in SI of perinatal rats are first elicited by vibrissae stimulation, followed by forelimb and then hindlimb evoked responses (McCandlish et al. 1993). Our data suggest that this developmental gradient plays a role in determining the relative contributions of different SI representations to the functional reorganization of a deafferented zone. These results and the additional fact that forelimb removal in adulthood results in only very limited expression of either the face or hindlimb in the forelimb-stump representation suggest that there is a limited period during which input from a normally innervated cortical field can influence responses of cells in the deprived cortical representation. This period is approaching its end about the time of birth for the trigeminal cortical representation and occurs sometime later for the hindlimb representation. The greater proportion of face versus hindlimb expressing sites in fetal amputees suggests further that indirect inputs to the forelimb-stump field from the more mature trigeminal representation partially exclude or suppress those from the developing hindlimb representation. The mechanisms underlying the age dependence of cortical reorganization after forelimb amputation or the partial exclusion of hindlimb inputs after fetal amputation are not known.
Sensitive or critical time periods exist during which peripheral changes may alter the structure and/or function of central somatotopic maps (Rhoades et al. 1993, 1997; Schlagger and O'Leary 1993; Van der Loos and Woolsey 1973; Waters et al. 1990; Wise and Jones 1978; Woolsey 1990). Interestingly, fetal manipulations followed by histochemical analyses of SI during the first postnatal week revealed that forelimb removal causes a 100% enlargement of the hindlimb representation, while infraorbital nerve section causes both a shrinkage of vibrissae and expansion of lower jaw representations (Killackey and Dawson 1989; Killackey et al. 1994). Consistent with previous results, our CO-stained sections of SI (in adult animals) revealed that the forelimb-stump representation in fetal and neonatal amputees was not as clearly defined as surrounding representations or as the forelimb-stump area in adult amputees (Pearson et al. 1999; Wong-Riley and Welt 1980). Critical time periods also exist during which the functional properties of thalamocortical synapses are most sensitive to peripheral alterations (Crair and Malenka 1995). The loss of afferent forelimb activity after perinatal amputation may cause a relative strengthening of trigeminal and hindlimb and weakening of forelimb, thalamocortical synapses (Jenkins et al. 1990). These changes could in turn influence the development and strengths of intracortical connections, whose plasticity persists into adulthood (Bear and Kirkwood 1993; Fox 1992, 1994; Hess et al. 1996; Huang et al. 1998; Lee et al. 1991; McCasland et al. 1992; Simons and Land 1987).
Substrates and mechanisms for intracortical plasticity
The results of this study suggest that vibrissae inputs to the SI forelimb-stump in fetal amputees originate in the SI vibrissae representation and are conveyed by a polysynaptic intracortical pathway involving the dysgranular cortex. Previous work employing lesioning of the hindlimb representation suggests that an intracortical pathway conveys long latency hindlimb inputs to the forelimb-stump region in neonatal amputees (Lane et al. 1999). Intracortical connections have been reported to play a role in the functional reorganization of cortical sensory and motor maps (Armstrong-James et al. 1994; Darian-Smith and Gilbert 1994, 1995; Das and Gilbert 1995; Doetsch et al. 1988; Florence et al. 1998; Keller and Carlson 1999; Pons et al. 1991), and "heterotypical" intracortical connections between different somatotopic representations have been found in normal and amputated animals (Chapin et al. 1987; Fabri and Burton 1991; Jones et al. 1978; Kaas et al. 1983; Koralek et al. 1990). Heterotypical intracortical connections are not significantly increased after amputation (Pearson et al. 2001; Stojic et al. 1998; but see also Florence et al. 1998), and this is consistent with the present and previous functional results implicating a polysynaptic pathway involving the dysgranular cortex as a substrate for reorganization after perinatal amputation (Lane et al. 1999; Stojic et al. 2001).
Other functional studies also support the existence of latent heterotypical connections within and across SI representations in normal and amputated animals (Ebner et al. 1997; Hickmott and Merzenich 1998; Lane et al. 1995, 1997; Li and Waters 1996; Li et al. 2002; Moore and Nelson 1998; Smits et al. 1991; Zarzecki et al. 1993), and connections between the vibrissae and forelimb representations are revealed by GABA receptor blockade after peripheral nerve transection (Jacobs and Donoghue 1991). In rat motor cortex, axon collaterals projecting into border regions also provide a substrate for synaptic plasticity of horizontal connections (Hess and Donoghue 1996; Weiss and Keller 1994). Our results suggest that forelimb amputation in the rat allows normally suppressed heterotypical connections between SI representations to be strengthened to a degree that they are suprathreshold when GABA receptors are antagonized. These circuits may be stronger in fetal and neonatal amputees because their potentiation could start at the time of injury and continue through the developmental period. In contrast, analogous circuits in adult amputees may be weakened or eliminated during development, and this loss of potential connections may explain the limited reorganization reported in these animals.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests: C. P. Pluto, Dept. of Anatomy and Neurobiology, Medical College of Ohio, 3000 Arlington Ave., Toledo, OH 43614 (E-mail cpluto{at}mco.edu).
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, onset of electrical stimulus. The horizontal time scale is 50 ms for cutaneous responses (200 ms epoch), 5 ms for electrical responses (20 ms epoch), and 2 s for spontaneous activity (8 s epoch).