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Morphological correlates of injury-induced reorganization in primate somatosensory cortex

Morphological correlates of injury-induced reorganization in primate somatosensory cortex Background: Topographic reorganization of central maps following peripheral nerve injury has been well characterized. Despite extensive documentation of these physiological changes, the underlying anatomical correlates have yet to be fully explored. In this study, we used Golgi impregnation and light microscopy to assess dendritic morphology following denervation of the glabrous hand surface in adult primates. Results: After survival durations that permit complete physiologically-defined reorganization, we find a systematic change in the dendritic arborization pattern of both layer II/III pyramidal and layer IV spiny stellate cells in the contralateral hand region of area 3b, compared to unaffected cortical areas. In general, our analyses indicate a progressive expansion of distal regions of the dendritic arbor with no appreciable changes proximally. This pattern of distal dendritic elaboration occurs for both basilar and apical dendrites. Conclusions: These observations are consistent with the notion that latent inputs gain expression in reorganized cortex after nerve injury via their influence through contacts with more distally located termination sites. following peripheral nerve injury in adult primates. On Background The ability of the nervous system to modify its output in the foundation of these observations, great strides have accordance with experiential demands is a central tenet of been made in understanding the mechanisms [3-9] and neuronal plasticity. For many years, the view of critical extent [10-13] of this phenomenon. These findings have periods permeated our beliefs; almost dictating that plas- generalized beyond sensory systems and collectively have ticity beyond such epochs was, at best, minimal. The sem- been interpreted as reflective of fundamental properties of inal experiments of Merzenich, Kaas and colleagues [1,2] the nervous system. have proved instrumental in moving the field beyond this restrictive mindset by showing that the central representa- While physiological techniques are frequently used to tion of the skin surface is subject to dramatic modification characterize topographic (re)organization of central Page 1 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 maps, the underlying anatomical correlates have not been neurons (9/9, p < .01; see Fig. 2b). For apical dendrites, thoroughly investigated. Using intracellular injection there are 63.1% more intersections in distal portions of techniques, thalamic axons have been reported to inner- the arbors of deprived cells relative to controls (15/16, p vate a much broader sector of cortex than necessary to rep- < .01; see Fig. 2c). Finally, the average length of the distal resent typical receptive field size, suggesting the existence apical dendrites of deprived pyramidal cells is 37.4% of "latent" inputs [14,15]. Disinhibition is a strong candi- greater than in controls (14/16, p < .01; see Fig. 2d). date as the primary mechanism during the immediate phase of somatotopic reorganization following nerve Layer IV spiny stellate cells injury [16-18]. While unmasking of latent inputs may A largely comparable set of outcomes were found for account for a portion of the overall reorganization [19], spiny stellate cells in layer IV. For the distal sectors of basi- modification of central maps is neither complete immedi- lar dendrites, there are 66.7% more intersections in arbors ately following nerve injury [1,20-22] nor dependent on a of deprived relative to control neurons (9/9, p < .01; see single mechanism [20,22-25]. Moreover, topographic Fig. 3a). Similarly, the overall average length of distal basi- reorganization appears to be permanent in nature [26], lar dendrites is 92.4% longer in deprived stellate cells while at least some neurochemical changes have shown to compared to controls (9/9, p < .01; see Fig. 3b). For the be relatively transient [6,18]. Together, these observations distal apical dendritic arbors, deprived stellate cells have, suggest that alterations in the underlying anatomical con- on average, 25.5% more intersections than are found in nectivity might provide a stable platform for the mainte- control neurons (11/12, p < .01; see Fig. 3c). Conversely, nance of modified somatotopy. while the distal apical dendrites of deprived neurons are 20.5% longer than controls, on average, this difference is In this study, we report our examination of neurons in not statistically significant (8/12, p > .10; see Fig. 3d). two cortical layers; spiny stellate cells in layer IV, as this is Differential effects of deprivation on basilar versus apical the primary input target of thalamocortical axons; and pyramidal neurons in layer II/III, as supragranular dendrites changes have been shown to precede somatotopic modi- Deprivation of a specific region of somatosensory cortex fication in the granular cell layer [27]. We predicted that by nerve transection clearly had a detectable effect on the dendritic arborization in the affected areas would be distal portions of both the basilar and apical dendrites of altered following peripheral nerve injury, providing an both layer II/III pyramidal cells and layer IV spiny stellate anatomical correlate of the functional changes. If the ana- cells. The data also support the contention that the basilar tomical correlates of physiologically-defined changes can dendrites of both cell types were more profoundly be readily observed, our understanding of the mecha- affected by deprivation than were their apical dendrites. nisms underlying such changes would be greatly The magnitudes of the deprivation effects are more pro- enhanced. nounced in basilar than in apical dendrites (see Fig. 4; Mann-Whitney = 0; p < .01). Results Figure 1 presents typical Golgi-filled layer II/III pyramidal Discussion (Fig. 1A) and layer IV spiny stellate cells (Fig. 1B). Figures General observations 1C (pyramidal) and 1D (stellate) are corresponding In the present experiments, we investigated whether changes in dendritic morphology of neurons in deprived reconstructions of the same two cell types. Our initial inspection of the data revealed considerable heterogeneity somatosensory cortex are correlated with the well-docu- as one moved from proximal to distal regions of the den- mented topographic reorganization that follows periph- dritic arbor. With regards to the proximal halves of the eral nerve injury in adult primates. Our general findings arbors, we observed no statistically significant differences were that in deprived cortical areas, dendritic arbors were between deprived and control groups for either basilar or expanded distally, while being unaffected proximally. apical dendrites. This pattern was found for both the basilar and apical dendrites of layer IV spiny stellate and layer II/III pyrami- Layer II/III pyramidal neurons dal neurons, though the effects were more pronounced for We found a greater number of intersections in the distal the basilar dendritic arbors, a difference that is consistent halves of dendritic arbors of pyramidal cells in deprived with previous reports [28]. Measures of dendritic length relative to control cortex. For basilar dendrites, there is a and the frequency of intersections, both well accepted 92.0% increase in the number of intersections in the distal metrics of dendritic arborization, yielded generally similar arbors of deprived cells relative to control cells (9/9, p < patterns of observations. These anatomical changes could .01; see Fig. 2a). Likewise, we find an 89.5% increase in well provide the means by which the functional changes total basilar dendritic length in the distal sectors of in map topography proceed. Alternatively, they could deprived cortical pyramidal cells, compared to control reflect generic neural responses to deprivation per se, and Page 2 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 Photom Figure 1 icrographs and reconstructions of Golgi-filled neurons Photomicrographs and reconstructions of Golgi-filled neurons. a: A typical layer II/III pyramidal cell used in the analy- sis of dendritic arborization. b: A typical layer IV spiny stellate cell. c,d: Reconstructions of a pyramidal and a stellate cell. Scale bar = 50 µm. Page 3 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 Dendritic arborization Figure 2 pattern in the distal sectors of layer II/III pyramidal cells Dendritic arborization pattern in the distal sectors of layer II/III pyramidal cells. The figure depicts the extent of arborization as a function of distance from the cell body using a Sholl ring analysis. On average, basilar dendrites in deprived cortex are both more complex (increased number of intersections; Fig 2a) and longer (dendritic length; Fig 2b) than those from controls. Likewise, apical dendrites in deprived cortex are also more complex (intersections; Fig 2c) and longer (length; Fig 2d), compared to controls. All effects were statistically significant. have little or nothing to do with the functional cannot be equally effective in conveying suprathreshold reorganization. receptive field information to the cortex, and that changes in synaptic efficacy could sustain the topographic plastic- Does nerve injury-induced reorganization reflect the ity that follows peripheral nerve injury [14,30]. Our strengthening of normally latent inputs? observations of subthreshold, latent inputs to the cortex Previous research has shown that the spread of thalamo- [3], and the emergence of their expression when domi- cortical arbors is much broader than necessary for the nant inputs are attenuated [31] lend support for this idea. expression of typical receptive field size in primary soma- Moreover, these presumptive latent inputs are largely pre- tosensory cortex [14,15]. Because of this disparity vented from gaining expression in cortex when NMDA between the grain of the cortical topographic map [29] glutamatergic receptors are blocked [20,23]. Such a block- and the far more extensive thalamocortical anatomy, we ade could prevent reorganization by preventing changes have suggested that all parts of thalamocortical arbors in the strength of existing synapses [e.g., [32]], by Page 4 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 Dendritic arborization Figure 3 pattern in the distal sectors of layer II/III stellate cells Dendritic arborization pattern in the distal sectors of layer II/III stellate cells. The figure depicts the extent of arborization as a function of distance from the cell body using a Sholl ring analysis. On average, basilar dendrites in deprived cortex are both more complex (increased number of intersections; Fig 3a) and longer (dendritic length; Fig 3b) than those from controls. Likewise, apical dendrites in deprived cortex are also more complex (intersections; Fig 3c) and longer (length; Fig 3d), compared to controls. All effects were statistically significant. interfering with neurite outgrowth [33], or both. In any IV spiny stellate cells act primarily as intracolumnar signal event, such latent inputs become evident only when the processors; while pyramidal cells integrate both horizon- normally expressed, dominant inputs are somehow weak- tal and top-down information [39]. Supragranular layers ened – via pharmacological disinhibition [16,18,34], appear to be particularly fertile to altered stimulation nerve injury [19,35], or use-dependency [36-38]. The data patterns as cortical reorganization occurs initially in the reported here are consistent with this notion, and suggest outermost layers of cortex, followed later by changes in that distal sectors of the dendritic arbor may be selectively the granular cell layer [27]. Measures of astrocytic recruit- innervated by these latent inputs. ment mirror this outside-to-inside temporal progression of experience-dependent reorganization as well [40]. The Our observations that distal regions of apical dendrites, selective elaboration of distal regions of the dendritic which clearly reside in upper cortical layers, are modified arbor is also consistent with data that implicate intracorti- come as no surprise. Previous work has shown that layer cal pathways as playing a major role in cortical Page 5 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 [44]. The reliability of progressively distal changes inde- pendent of dendritic location (apical or basilar) is cer- tainly consistent with this idea. While these possibilities are not mutually exclusive, and certainly not all-inclusive, we believe that expansion of the distal arbor reported here is reflective of the altered activation pattern following nerve injury and serves as a long-term trace of this modi- fied stimulation pattern. Conclusions Considering the range of survival durations following nerve injury in the current study, the observation of mod- ifications to both layer IV spiny stellate and layer II/III pyramidal neurons was not unexpected. While this broad survival range may have "smeared" our snapshot with respect to the temporal integration of anatomical changes, Co Figure 4 mparison of basilar vs. apical effects for all cells analyzed our intention was simply to determine whether Comparison of basilar vs. apical effects for all cells morphological changes were occurring at any point analyzed. The figure illustrates that for both cell types during the reorganization process. Our data clearly indi- (pyramidal and stellate) and metric of dendritic arborization cate that the anatomy in affected cortical areas is subject (intersections and length), the magnitude of the effect was to modification and that the morphological changes reliably larger for basilar dendrites than for apical dendrites. observed may be related to the functional reorganization revealed electrophysiologically. We have begun experi- ments to better refine the temporal window in which these changes become evident. reorganization [41,42], though, clearly, the contribution In sum, we have shown that just as the functional respon- of bottom-up processes cannot be discounted [12]. siveness of the mature primate nervous system is suscepti- ble to change, so is the underlying anatomy. Our Is reorganization a secondary consequence of other observations that the anatomical changes appear to be mechanisms/processes? either potentiated in, or possibly restricted to, distal While morphological changes may be less likely to regions of the dendritic arbor provide additional insight account for acute changes in somatotopy after nerve into the mechanisms involved in the physiological injury, restructuring of the underlying anatomy could well changes. Further research will be instrumental in deter- correlate with the longer-term, persistent changes in corti- mining the exact role that the underlying anatomy plays cal topographic maps. The modifications of distal den- in this complex reorganization process. dritic regions reported here may be interpreted from at least three possible, non-exclusive, perspectives. First, Methods Adult squirrel monkeys (Saimiri scireus or Saimiri boliven- expansion of the distal arbor may be a homeostatic response to a reduction in stimulation frequency/pattern sius) were socially housed with food and water available following nerve injury. Progressive elaboration of the dis- ad libitum. In six animals, the median and ulnar nerves to tal arbor might be an attempt to maintain optimal stimu- one hand were transected following the principles of ani- lation levels, and, thus, normal interneuronal trophic mal care detailed in NIH publication no. 86–23. The local relationships. The altered somatotopy could be construed institutional animal care and use committee approved all as simply the epiphenomenonal consequence of the acti- procedures prior to initiation of any experiments. Briefly, vation of a homeostatic response. Second, the elaboration monkeys were anesthetized with an intramuscular injec- of the distal arbor may be a general property of the nerv- tion of a mixture of ketamine hydrochloride (25–30 mg/ ous system, a mechanism that permits the brain to kg) and xylazine (0.5–1.0 mg/kg). Their forearms were respond in a dynamic and adaptable manner [43]. This shaved and prepared for surgery with alternate scrubbings supposes that the functional changes in cortex that follow of povidone-iodine and alcohol. Under sterile conditions nerve injury are adaptive, and that has not been convinc- an incision was made along the midline of the ventral ingly demonstrated. Third, the observation that changes forearm, the median and ulnar nerves were located by occur distally may simply reflect the fact that areas rela- blunt dissection and cut about midway between the tively distant to the soma are more vulnerable/susceptible elbow and wrist. The epineural sheath of the proximal to changes, regardless of the adaptability of such changes stump was retracted 0.5–1.0 cm, and the exposed nerve Page 6 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 avulsed. The empty epineural sheath was re-extended, design of study: DRS participated in design of study: PEG folded back upon itself and ligated. The nerve stumps participated in design of study, conducted statistical were repositioned and the incision closed with sutures. analyses, conceived and coordinated the study. All Post-surgically, all subjects received penicillin, dopram authors read and approved the final manuscript. hydrochloride, and dexamethasone injections. Subjects were permitted to recover for a period of time previously Acknowledgments Supported by National Institutes of Health Grant NS37348 (PEG). We shown sufficient to permit complete reorganization of the thank E.E. Garman and L.L. Arnold for technical assistance. hand representation in cortical area 3b (3–52 months, mean = 15.3). Two additional subjects served as naïve References controls. 1. Merzenich MM, Kaas JH, Wall JT, Sur M, Nelson RJ, Felleman DJ: Pro- gression of change following median nerve section in the cor- Following electrophysiological mapping of the affected tical representation of the hand in areas 3b and 1 in adult owl and squirrel monkeys. Neuroscience 1983, 10:639-665. cortical areas, animals were overdosed and perfused tran- 2. Merzenich MM, Kaas JH, Nelson RJ, Sur M, Felleman D: Topo- scardially with 0.9% saline. Brains were extracted and graphic reorganization of somatosensory cortical areas 3b and 1 in adult monkeys following restricted deafferentation. immersed in a modified Golgi–Cox solution for 11 days, Neuroscience 1983, 8:33-55. thereafter dehydrated and embedded in celloidin. Tissue 3. 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Merzenich MM, Nelson RJ, Stryker MP, Cynader MS, Schoppmann A, Zook JM: Somatosensory cortical map changes following digit Publish with Bio Med Central and every amputation in adult monkeys. The Journal of Comparative scientist can read your work free of charge Neurology 1984, 224:591-605. 36. Fuchs JL, Salazar E: Effects of whisker trimming on GABAa "BioMed Central will be the most significant development for receptor binding in the barrel cortex of developing and adult disseminating the results of biomedical researc h in our lifetime." rats. Journal of Comparative Neurology 1998, 395:209-216. Sir Paul Nurse, Cancer Research UK 37. Recanzone GH, Merzenich MM, Jenkins WM: Frequency discrimi- nation training engaging a restricted skin surface results in Your research papers will be: an emergence of a cutaneous response zone in cortical area available free of charge to the entire biomedical community 3a. Journal of Neurophysiology 1992, 67:1057-1070. 38. 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Morphological correlates of injury-induced reorganization in primate somatosensory cortex

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Biomedicine; Neurosciences; Neurobiology; Animal Models
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Abstract

Background: Topographic reorganization of central maps following peripheral nerve injury has been well characterized. Despite extensive documentation of these physiological changes, the underlying anatomical correlates have yet to be fully explored. In this study, we used Golgi impregnation and light microscopy to assess dendritic morphology following denervation of the glabrous hand surface in adult primates. Results: After survival durations that permit complete physiologically-defined reorganization, we find a systematic change in the dendritic arborization pattern of both layer II/III pyramidal and layer IV spiny stellate cells in the contralateral hand region of area 3b, compared to unaffected cortical areas. In general, our analyses indicate a progressive expansion of distal regions of the dendritic arbor with no appreciable changes proximally. This pattern of distal dendritic elaboration occurs for both basilar and apical dendrites. Conclusions: These observations are consistent with the notion that latent inputs gain expression in reorganized cortex after nerve injury via their influence through contacts with more distally located termination sites. following peripheral nerve injury in adult primates. On Background The ability of the nervous system to modify its output in the foundation of these observations, great strides have accordance with experiential demands is a central tenet of been made in understanding the mechanisms [3-9] and neuronal plasticity. For many years, the view of critical extent [10-13] of this phenomenon. These findings have periods permeated our beliefs; almost dictating that plas- generalized beyond sensory systems and collectively have ticity beyond such epochs was, at best, minimal. The sem- been interpreted as reflective of fundamental properties of inal experiments of Merzenich, Kaas and colleagues [1,2] the nervous system. have proved instrumental in moving the field beyond this restrictive mindset by showing that the central representa- While physiological techniques are frequently used to tion of the skin surface is subject to dramatic modification characterize topographic (re)organization of central Page 1 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 maps, the underlying anatomical correlates have not been neurons (9/9, p < .01; see Fig. 2b). For apical dendrites, thoroughly investigated. Using intracellular injection there are 63.1% more intersections in distal portions of techniques, thalamic axons have been reported to inner- the arbors of deprived cells relative to controls (15/16, p vate a much broader sector of cortex than necessary to rep- < .01; see Fig. 2c). Finally, the average length of the distal resent typical receptive field size, suggesting the existence apical dendrites of deprived pyramidal cells is 37.4% of "latent" inputs [14,15]. Disinhibition is a strong candi- greater than in controls (14/16, p < .01; see Fig. 2d). date as the primary mechanism during the immediate phase of somatotopic reorganization following nerve Layer IV spiny stellate cells injury [16-18]. While unmasking of latent inputs may A largely comparable set of outcomes were found for account for a portion of the overall reorganization [19], spiny stellate cells in layer IV. For the distal sectors of basi- modification of central maps is neither complete immedi- lar dendrites, there are 66.7% more intersections in arbors ately following nerve injury [1,20-22] nor dependent on a of deprived relative to control neurons (9/9, p < .01; see single mechanism [20,22-25]. Moreover, topographic Fig. 3a). Similarly, the overall average length of distal basi- reorganization appears to be permanent in nature [26], lar dendrites is 92.4% longer in deprived stellate cells while at least some neurochemical changes have shown to compared to controls (9/9, p < .01; see Fig. 3b). For the be relatively transient [6,18]. Together, these observations distal apical dendritic arbors, deprived stellate cells have, suggest that alterations in the underlying anatomical con- on average, 25.5% more intersections than are found in nectivity might provide a stable platform for the mainte- control neurons (11/12, p < .01; see Fig. 3c). Conversely, nance of modified somatotopy. while the distal apical dendrites of deprived neurons are 20.5% longer than controls, on average, this difference is In this study, we report our examination of neurons in not statistically significant (8/12, p > .10; see Fig. 3d). two cortical layers; spiny stellate cells in layer IV, as this is Differential effects of deprivation on basilar versus apical the primary input target of thalamocortical axons; and pyramidal neurons in layer II/III, as supragranular dendrites changes have been shown to precede somatotopic modi- Deprivation of a specific region of somatosensory cortex fication in the granular cell layer [27]. We predicted that by nerve transection clearly had a detectable effect on the dendritic arborization in the affected areas would be distal portions of both the basilar and apical dendrites of altered following peripheral nerve injury, providing an both layer II/III pyramidal cells and layer IV spiny stellate anatomical correlate of the functional changes. If the ana- cells. The data also support the contention that the basilar tomical correlates of physiologically-defined changes can dendrites of both cell types were more profoundly be readily observed, our understanding of the mecha- affected by deprivation than were their apical dendrites. nisms underlying such changes would be greatly The magnitudes of the deprivation effects are more pro- enhanced. nounced in basilar than in apical dendrites (see Fig. 4; Mann-Whitney = 0; p < .01). Results Figure 1 presents typical Golgi-filled layer II/III pyramidal Discussion (Fig. 1A) and layer IV spiny stellate cells (Fig. 1B). Figures General observations 1C (pyramidal) and 1D (stellate) are corresponding In the present experiments, we investigated whether changes in dendritic morphology of neurons in deprived reconstructions of the same two cell types. Our initial inspection of the data revealed considerable heterogeneity somatosensory cortex are correlated with the well-docu- as one moved from proximal to distal regions of the den- mented topographic reorganization that follows periph- dritic arbor. With regards to the proximal halves of the eral nerve injury in adult primates. Our general findings arbors, we observed no statistically significant differences were that in deprived cortical areas, dendritic arbors were between deprived and control groups for either basilar or expanded distally, while being unaffected proximally. apical dendrites. This pattern was found for both the basilar and apical dendrites of layer IV spiny stellate and layer II/III pyrami- Layer II/III pyramidal neurons dal neurons, though the effects were more pronounced for We found a greater number of intersections in the distal the basilar dendritic arbors, a difference that is consistent halves of dendritic arbors of pyramidal cells in deprived with previous reports [28]. Measures of dendritic length relative to control cortex. For basilar dendrites, there is a and the frequency of intersections, both well accepted 92.0% increase in the number of intersections in the distal metrics of dendritic arborization, yielded generally similar arbors of deprived cells relative to control cells (9/9, p < patterns of observations. These anatomical changes could .01; see Fig. 2a). Likewise, we find an 89.5% increase in well provide the means by which the functional changes total basilar dendritic length in the distal sectors of in map topography proceed. Alternatively, they could deprived cortical pyramidal cells, compared to control reflect generic neural responses to deprivation per se, and Page 2 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 Photom Figure 1 icrographs and reconstructions of Golgi-filled neurons Photomicrographs and reconstructions of Golgi-filled neurons. a: A typical layer II/III pyramidal cell used in the analy- sis of dendritic arborization. b: A typical layer IV spiny stellate cell. c,d: Reconstructions of a pyramidal and a stellate cell. Scale bar = 50 µm. Page 3 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 Dendritic arborization Figure 2 pattern in the distal sectors of layer II/III pyramidal cells Dendritic arborization pattern in the distal sectors of layer II/III pyramidal cells. The figure depicts the extent of arborization as a function of distance from the cell body using a Sholl ring analysis. On average, basilar dendrites in deprived cortex are both more complex (increased number of intersections; Fig 2a) and longer (dendritic length; Fig 2b) than those from controls. Likewise, apical dendrites in deprived cortex are also more complex (intersections; Fig 2c) and longer (length; Fig 2d), compared to controls. All effects were statistically significant. have little or nothing to do with the functional cannot be equally effective in conveying suprathreshold reorganization. receptive field information to the cortex, and that changes in synaptic efficacy could sustain the topographic plastic- Does nerve injury-induced reorganization reflect the ity that follows peripheral nerve injury [14,30]. Our strengthening of normally latent inputs? observations of subthreshold, latent inputs to the cortex Previous research has shown that the spread of thalamo- [3], and the emergence of their expression when domi- cortical arbors is much broader than necessary for the nant inputs are attenuated [31] lend support for this idea. expression of typical receptive field size in primary soma- Moreover, these presumptive latent inputs are largely pre- tosensory cortex [14,15]. Because of this disparity vented from gaining expression in cortex when NMDA between the grain of the cortical topographic map [29] glutamatergic receptors are blocked [20,23]. Such a block- and the far more extensive thalamocortical anatomy, we ade could prevent reorganization by preventing changes have suggested that all parts of thalamocortical arbors in the strength of existing synapses [e.g., [32]], by Page 4 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 Dendritic arborization Figure 3 pattern in the distal sectors of layer II/III stellate cells Dendritic arborization pattern in the distal sectors of layer II/III stellate cells. The figure depicts the extent of arborization as a function of distance from the cell body using a Sholl ring analysis. On average, basilar dendrites in deprived cortex are both more complex (increased number of intersections; Fig 3a) and longer (dendritic length; Fig 3b) than those from controls. Likewise, apical dendrites in deprived cortex are also more complex (intersections; Fig 3c) and longer (length; Fig 3d), compared to controls. All effects were statistically significant. interfering with neurite outgrowth [33], or both. In any IV spiny stellate cells act primarily as intracolumnar signal event, such latent inputs become evident only when the processors; while pyramidal cells integrate both horizon- normally expressed, dominant inputs are somehow weak- tal and top-down information [39]. Supragranular layers ened – via pharmacological disinhibition [16,18,34], appear to be particularly fertile to altered stimulation nerve injury [19,35], or use-dependency [36-38]. The data patterns as cortical reorganization occurs initially in the reported here are consistent with this notion, and suggest outermost layers of cortex, followed later by changes in that distal sectors of the dendritic arbor may be selectively the granular cell layer [27]. Measures of astrocytic recruit- innervated by these latent inputs. ment mirror this outside-to-inside temporal progression of experience-dependent reorganization as well [40]. The Our observations that distal regions of apical dendrites, selective elaboration of distal regions of the dendritic which clearly reside in upper cortical layers, are modified arbor is also consistent with data that implicate intracorti- come as no surprise. Previous work has shown that layer cal pathways as playing a major role in cortical Page 5 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 [44]. The reliability of progressively distal changes inde- pendent of dendritic location (apical or basilar) is cer- tainly consistent with this idea. While these possibilities are not mutually exclusive, and certainly not all-inclusive, we believe that expansion of the distal arbor reported here is reflective of the altered activation pattern following nerve injury and serves as a long-term trace of this modi- fied stimulation pattern. Conclusions Considering the range of survival durations following nerve injury in the current study, the observation of mod- ifications to both layer IV spiny stellate and layer II/III pyramidal neurons was not unexpected. While this broad survival range may have "smeared" our snapshot with respect to the temporal integration of anatomical changes, Co Figure 4 mparison of basilar vs. apical effects for all cells analyzed our intention was simply to determine whether Comparison of basilar vs. apical effects for all cells morphological changes were occurring at any point analyzed. The figure illustrates that for both cell types during the reorganization process. Our data clearly indi- (pyramidal and stellate) and metric of dendritic arborization cate that the anatomy in affected cortical areas is subject (intersections and length), the magnitude of the effect was to modification and that the morphological changes reliably larger for basilar dendrites than for apical dendrites. observed may be related to the functional reorganization revealed electrophysiologically. We have begun experi- ments to better refine the temporal window in which these changes become evident. reorganization [41,42], though, clearly, the contribution In sum, we have shown that just as the functional respon- of bottom-up processes cannot be discounted [12]. siveness of the mature primate nervous system is suscepti- ble to change, so is the underlying anatomy. Our Is reorganization a secondary consequence of other observations that the anatomical changes appear to be mechanisms/processes? either potentiated in, or possibly restricted to, distal While morphological changes may be less likely to regions of the dendritic arbor provide additional insight account for acute changes in somatotopy after nerve into the mechanisms involved in the physiological injury, restructuring of the underlying anatomy could well changes. Further research will be instrumental in deter- correlate with the longer-term, persistent changes in corti- mining the exact role that the underlying anatomy plays cal topographic maps. The modifications of distal den- in this complex reorganization process. dritic regions reported here may be interpreted from at least three possible, non-exclusive, perspectives. First, Methods Adult squirrel monkeys (Saimiri scireus or Saimiri boliven- expansion of the distal arbor may be a homeostatic response to a reduction in stimulation frequency/pattern sius) were socially housed with food and water available following nerve injury. Progressive elaboration of the dis- ad libitum. In six animals, the median and ulnar nerves to tal arbor might be an attempt to maintain optimal stimu- one hand were transected following the principles of ani- lation levels, and, thus, normal interneuronal trophic mal care detailed in NIH publication no. 86–23. The local relationships. The altered somatotopy could be construed institutional animal care and use committee approved all as simply the epiphenomenonal consequence of the acti- procedures prior to initiation of any experiments. Briefly, vation of a homeostatic response. Second, the elaboration monkeys were anesthetized with an intramuscular injec- of the distal arbor may be a general property of the nerv- tion of a mixture of ketamine hydrochloride (25–30 mg/ ous system, a mechanism that permits the brain to kg) and xylazine (0.5–1.0 mg/kg). Their forearms were respond in a dynamic and adaptable manner [43]. This shaved and prepared for surgery with alternate scrubbings supposes that the functional changes in cortex that follow of povidone-iodine and alcohol. Under sterile conditions nerve injury are adaptive, and that has not been convinc- an incision was made along the midline of the ventral ingly demonstrated. Third, the observation that changes forearm, the median and ulnar nerves were located by occur distally may simply reflect the fact that areas rela- blunt dissection and cut about midway between the tively distant to the soma are more vulnerable/susceptible elbow and wrist. The epineural sheath of the proximal to changes, regardless of the adaptability of such changes stump was retracted 0.5–1.0 cm, and the exposed nerve Page 6 of 8 (page number not for citation purposes) BMC Neuroscience 2004, 5:43 http://www.biomedcentral.com/1471-2202/5/43 avulsed. The empty epineural sheath was re-extended, design of study: DRS participated in design of study: PEG folded back upon itself and ligated. The nerve stumps participated in design of study, conducted statistical were repositioned and the incision closed with sutures. analyses, conceived and coordinated the study. All Post-surgically, all subjects received penicillin, dopram authors read and approved the final manuscript. hydrochloride, and dexamethasone injections. Subjects were permitted to recover for a period of time previously Acknowledgments Supported by National Institutes of Health Grant NS37348 (PEG). We shown sufficient to permit complete reorganization of the thank E.E. Garman and L.L. 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Merzenich MM, Nelson RJ, Stryker MP, Cynader MS, Schoppmann A, Zook JM: Somatosensory cortical map changes following digit Publish with Bio Med Central and every amputation in adult monkeys. The Journal of Comparative scientist can read your work free of charge Neurology 1984, 224:591-605. 36. Fuchs JL, Salazar E: Effects of whisker trimming on GABAa "BioMed Central will be the most significant development for receptor binding in the barrel cortex of developing and adult disseminating the results of biomedical researc h in our lifetime." rats. Journal of Comparative Neurology 1998, 395:209-216. Sir Paul Nurse, Cancer Research UK 37. Recanzone GH, Merzenich MM, Jenkins WM: Frequency discrimi- nation training engaging a restricted skin surface results in Your research papers will be: an emergence of a cutaneous response zone in cortical area available free of charge to the entire biomedical community 3a. Journal of Neurophysiology 1992, 67:1057-1070. 38. 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