Brain Research, 565 (1991) 218-224 © 1991 Elsevier Science Publishers B.V. All rights reserved. 0006-8993/91/$03.50 ADONIS 000689939117184P
218
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Short-term expansion of receptive fields in rat primary somatosensory cortex after hindpaw digit denervation Jennifer A. Byrne and Michael B. Calford Vision, Touch and Hearing Research Centre and Department of Physiology and Pharmacology, The University of Queensland, Qld. 4072 (Australia) (Accepted 9 July 1991)
Key words: Plasticity; Somatosensory cortex; Amputation; Local anesthesia
The immediate effect of changing the driving cutaneous input to locations within primary somatosensory cortex (St) was examined by denervating one or more digits of the rat hindpaw by amputation or local anesthesia. When all or part of a receptive field of a cluster of neurons was dencrvated, it was found that the cortical location recorded from gained responsiveness to cutaneous stimulation of hindpaw areas bordering the denervated region. In 22 of the 29 animals studied this expansion took place within 5 min of the denervation.
INTRODUCTION
It has been shown repeatedly that the representation in primary s,~matosensory cortex (SI) of adult mammals is capable of functional plasticity induced by various peripheral denervations 2.~'t~'22.2.~'z~-27.2'~''~. Whereas the details of plasticity reported in these experitoents differ considerably, it is clear that the area of the cortical representation is a primary determinant of the extent and type of change that will be observed. Thus, amputation of one finger of an owl monkey was found after a few weeks to have produced a topographic expansion of the representation of adjacent fingers and palm over the entire area that originally coded for the amputated finger; amputation of two fingers left an unresponsive area 27. Similar limits were found on the extent of reorganization in the hindlimb representation of rats following section of the sciatic nerve 35, where reorganization appears limited to 0.5-1.0 mm across cortex, in general the total reutilization of denervated cortex, in the form of an expanded and topographic representation of adjacent intact areas, is limited to experiments where the cortical representation of the denervated region is within this limit. Previous work from this laboratory 2'3 has shown that for such small denervatio~s the physiological basis for further reorganization is the rapid unmasking of existing inputs from cutaneous regions adjacent to the denervation. Within a few minutes of the denervation of tbe
thumb in flying foxes s cortical neurons for which the receptive field (RF) was initially restricted to the denerrated region show sensitivity to stimulation of adjacent regions; loci where neural sensitivity initially extended onto the denervated region show expanded RFs. The phenomenon of rapid unmasking of new or expanded receptive fields following denervation has not been widely studied. The short-term changes following large denervations have been reported for the S! median nerve representation in owl and squirrel monkeys 2s'2~', sciatic and saphenous nerve representations in rat a'~, and digit representations in raccoon 2~'2~'32. However, the shortterm effects of small peripheral denervations on the representation in SI cortex have been reported only for the thumb representation in flying foxes T M and the digit representation in macaque monkeys 4. There is a need to extend the basic descriptive information available on this phenomenon, in particular, keeping within the limits of a small denervation, it is necessary to examine the effects of variation in denervation extent in absolute terms and in terms of the RF under study. The hindpaw representation of rats was chosen for study because published maps of this representation ~ show that the entire representation occupies a cortical surface area around 1 mm 2, Denervation of toes represents a small denervation and was expected to lead to functional reorganization rather than unresponsive zones in affected cortex.
Corre~pomh, nce: M.B. Calford, Vision, Touch and Hearing Research Centre, The University of Queensland, Old. 40"/2, Australia.
219 MATERIALS AND METHODS Experiments were performed on 29 adult male Wistar rats (270500 g) aged between 12 and 17 weeks. The day prior to experimentation the animals were given an intram:lscular iniection of 1 mg/kg dexamethasone phosphate (Dexadreson, lntervet (Aust.), Pty Ltd). Animals were anesthetized with an intramuscular injection of 35 mg/kg ketamine hydrochloride (Ketamine Injection, Jurex, Aust.) and 5 mg/kg xylazine (Rompun, Bayer, Aust. Ltd), Supplementary injections of the ketamine/xylazine mix were given during the experiment to the level required to abolish pedal reflexes. Animals were held in a stereotaxic frame and the right somatosensory cortex was exposed and covered with silicone oil. The cortical area occupied by the hindpaw representation (approximately 1 mm 2) was found in all animals to lie somewhere between 1.5 and 4.0 mm lateral of the midline, and 0.5 mm rostral and 3.0 mm caudal of Bregma. In each animal, a basic map of the hindpaw representation was derived. Recordings were made using tungsten-in-glass electrodes with tip dimensions (approximately 20 × 10/~m) such that recordings were made extracellularly from small clusters of clearly identified neurons. Activity recorded by the electrode was amplified (Grass PI5D), displayed on a digital oscilloscope (OS4100, Gould) and fed into an audioamplifier and speaker. At each electrode penetration site, the cutaneous RF was delineated by lightly stimulating the hindpaw and hindlimb with a small brush. The hindpaw was immobilized during stimulation, so as not to stimulate joint receptors. A receptive field (RF) was defined as the discrete area of skin the stimulation of which resulted in increased activity at the particular cortical location such that a boundary could be delineated with confidence. This criterion meant that RFs in this study included areas of skin where stimulation resulted in less-than-maximal cortical excitation. Thus RFs in this study were larger than those which would have been delineated had threshold stimuli been used (see ref. 14). After mapping the hindpaw representation, the electrode was held at a single location in cortex where the RF was confined to the distal hindpaw. Provided the RF was stabile for 30 min the body region to which neurons at this location were sensitive was partially or completely denervated. Amputations were used to permanently alter peripheral input and ranged in extent from a single toe to 4 toes. Temporary denervations were made using a local anesthetic (lignocain¢ hydrochloride, Apex Laboratories Pry Ltd, Aust.). When a single toe was selected for local anesthesia, subcutaneous injections of 0.1 mg (5 ~1 of 2%) lignocaine were delivered to the toe's dors~d, ventral, lateral and medial sides approximately 2 mm from its base, if the RF did not extend along the toe's dorsal surface, the dorsal injection was omitted, in all experiments, timing commenced once the initial manipulation had been performed, and the nature and time course of RF changes were described. When the denervation was temporary, the time taken for the return of cutaneous responsiveness to the locally anesthetized region, as seen through the cortical recording, was also recorded. The electrode remained at the same cortical location for between 22 and 134 min. Only one cortical sitc per animal was studied with denervation.
of the initial RF, and according to the size of the denervation (1 toe; 2-4 toes). Across these conditions the consistent finding of this study was that shortly after denervation the cortical neurons became responsive to stimulation at previously ineffective sites, either adjacent to the boundary of the denervation or to regions extending from remaining portions of the initial RF. In all experiments new responsiveness was found (longest latency of 41 min); in 22 of the 29 experiments this occurred within 5 min of the denervation.
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RESULTS
The immediate effects of peripheral denervation of some part of the hindpaw on the receptive field of multiunit activity at a single position in SI cortex was studied in 29 adult rats. The denervation, either by amputation or local anesthesia, removed all of the initial RF in 8 experiments and part of the initial RF ill the others. Aside from variation in the method of denervation, experiments also varied according to the size and location
Fig. 1. Examples of the effect of digit amputation on the receptive fields (RFs) of cortical units where some of the original field remains intact. Receptive fields are drawn on dorsal and ventral outlines of the hindpaw. The original RF is shown uppermost in each panel followed by examples of the RF at various times after amputation. In this and other figures the earliest time after denervation illustrated is that at which the RF was first seen to expand. Once expanded the new RFs in these two cases remained fairly stable.
220
Denervation by amputation of digits in 13 experiments a small and rapid denervation was achieved by the amputation of one or more hindlimb digits. In all cases, the original RF of the units under study extended onto, or was contained within, the amputated region. When the amputation did not remove the entire RF, as was the case in 6 experiments, new responsiveness arose from skin areas continuous with regions of the RF not removed by the amputation. Thus the remaining R F was said to have expanded (Fig. 1). This expansion was noted after a short period (median = 2 min) during which responses were elicited only in the remaining region of the initial RE in the other 11 experiments, the amputation removed the entire RF and therefore all of observable excitatory cutaneous input to the locus apparent prior to amputation. New responsiveness which appeared in these experiments therefore formed new RFs, which in all cases were continuous with the amputation wound (Fig. 2). After an initial RF change was noted, the size and position of the new or expanded RF was closely monitored over time. in 5 cases, expanded or new RFs which were initially noted did not change in size or position over the subsequent 30-60 min of recording (e.g. Figs. la and 2a,b). In 4 cases, there was further expansion of the new RF in the 10 min following its first appearance; thereafter the RF was stable. However, in 4 of the cases, expanded or new RFs shrank back partially after the maximum RF was observed (e.g. Fig. 2d), and in two of these cases RFs were observed to fluctuate towards and away from the amputation wound. Retraction from maximum RF extent was most apparent in two experiments in which components on the dorsal hindpaw disa l)peared around lO rain after they were first noted (e.g. Fig 2d). Marked fluctuations were noted in one experimt'nt (Fig. 3), in which the amputation of 4 toes had ini,.ially induced a rapid expansion of the remaining RF ~,ver the entire hindpaw and distal dorsal hindlimb. However the RF shrank back 30 min after the amputation ,~as performed, such that the ventral RF component was that which remained immediately after the amputation, and the dorsal component had totally disappeared. Subsequently there was further expansion of the ventral component.
in)~:,:i,-~ in all cases. In no case, judging from the cortica; ~'eeordir~g, did anesthesia spread to other toes or the foot. Within a period varying from 30 s to 7 min, the remaining RF expanded. In evaluating the RF changes subsequent to the initial expansion it is necessary to take into consideration the duration of local anesthesia. For the majority of experiments in which a denervated toe regained esthesia, as judged by the responsiveness of the
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Denervation by local anesthesia Temporary denervation, with a local anesthetic, was produced in 16 experiments in which a single toe was anesthetized. The initial changes to the RF of the cortical neurons under study were indistinguishable from the experiments using denervation by amputation. When a single toe was anesthetized the loss of that area from the RF was rapid, occurring within 1 min of
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Fig. 2, Examples of the expression of new responsiveness of cortical neurons after the original RF was completely removed, in all cases the new RF extended from the amputation wound and was continuous. Retraction of the RF from the maximal expansion was found in the experiments shown in c and d.
221 cortical neurons under study, the period of effective denervation averaged 25 min (range 6-55 min). However, in one experiment the toe did not regain esthesia (Fig. 4c), and in two experiments stimulation of the dorsal surface of the toe remained ineffective. Of the 13 experiments in which esthesia was regained there were no cases in which the RF returned to precisely the same boundaries as before anesthesia; in one case the RF remained expanded (Fig. 4a), in two cases final RFs were smaller than the original, in 5 experiments the final RF was marginally larger than the original and in 4 experiments the final RF, although smaller than reached at maximal expansion, was clearly larger than the original (Fig. 4b). The interpretation of some of these experiments is complicated, however, by the possibility that recording ceased before the RF had stabilized. In most experiments shrinking of the expanded RF was first noted at or shortly after the denervated toe regained esthesia, but in 3 cases shrinkage commenced earlier. Fluctuation of the RF during shrinkage occurred in 4 cases. These were minor compared to some of the fluctuations found after amputation (Fig. 3) and there was a clear trend toward a smaller RE
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The period before RF expansion In these experiments there was a variable period following denervation bef,.~re RF expansion. A frequency
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Fig. 3. Time course of rapid expansion and subsequent partial retraction of a very large RF produced by amputation of 4 digits which left some of the initial RF intact. At 5 rain after amputation the RF extended over most of the dorsal hindlimb. This experiment is notable for the large fluctuations in the size of the RE
Fig. 4. Experiments in which subcutaneous injection of a local anesthetic was used to denervate part of the RF of cortical neurons. in general RFs expanded soon after injection and shrank after the digit regained esthesia. Most RFs did not return to the original boundaries remaining either slightly enlarged, as in the examph; in b, or slightly contracted compared to the original field, in two cases the RF remained expanded as in a. In one case the digit dit r,~ot regain esthesia as judged by the cortical response (c).
222
partial RF denervation IB total RF denervation '3
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t0 20 30 40 Latent period to expansion ot RF (rain)
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Fig. 5. Frequency, histogram of the latent period before a new, or expanded, RF was noted after digit dencrvation. The distribution from experiments in which part of the RF of the cortical neurons under study remained intact is stippled. Where the denervation removed the entire RF the histogram bins are filled. ]'he two distributions are significantly different (P < 0.003).
histogram of these periods is presented in Fig. 5. The data can be formed into 6 non-mutually exclusive groups for analysis by the Student's t-test. Testing partial denervation of an RF (.~ = 3.0 win, n - 21) against total denervation of an RF (~" = 13.5 min, n = 8 ) r e v e a l e d a significant difference (t2~ = 3.3, P < 0.003). The other tests were not significant: local anesthesia (~" ffi 3.0 min, n = 16) against amputation (~ - 9.5 min, n = 13) and single toe denervation (~" ffi 4.0 min, n ffi 21) against multiple toe denervation (.~ -- 11.0 min, n = 2t). Thus, the latent period is shorter for denervations that remove part of an RF than for those that remove the entire RF. Sample sizes are too small to allow full testing of intera~tion effects across these 3 conditions, but it is clear that the analysis is influenced by the combination of local anesthesia, single toe denervation and partial denervation conditions which often apply together (15 cases in the sample of 29). DISCUSSION The immediate effect of removing the peripheral innervation of neurons within SI was examined by amputating or locally anesthetizing areas of the rat hindpaw. The responses of multiunits in SI that had RFs overlapping, or contained within, the denervated region were monitored with a stationary electrode. In all cf the animals studied the units studied in S! gained responsiveness to body regions outside the limits of the intitial RFs. The denervafions were thus small when compared to those of other studies in which large denervations left unresponsive areas of S133"3"~, o r responsiveness not normally found in S123'32, Areas of new sensitivity, or expanded RFs, were always continuous with the original
RF or extended from the denervation boundary. In almost all of the denervation-induced changes to RFs studied there was a delay in the expression of the new or expanded field. Where local anesthesia was used to denervate, some of this delay may be due to a period before the onset of full anesthesia, but similar initial delays were also found with amputation, and the comparison between these treatments did not show a significant difference. The delay, or latent period, was longer for denervations which removed an entire RF. The present experiments do not allow any determination of the site of expression of expanded RFs. However, the apparently new responsiveness revealed after a small denervation indicates that there are functional connections to loci in Sl that are not normally expressed. These connections are unmasked by the removal of some of the effective input to a locus (i.e. the RF). Whereas this unmasking could take place at other levels of the somatosensory pathway, anatomical 17'24 and electrical stimulation 31 studies of thalamocorticai arborizations and experiments with cortical iontophoresis of the GABA Areceptor anatagonist bicuculline ~'~!,t8 clearly indicate that existing connectivity within SI is sufficient to account for new and expanded receptive fields following a small denervation. Recent work from this laboratory has shown that blocking of only C-fiber activity in the radial nerve of cat or flying fox mimics the unmasking of larger RFs of SI neurons seen with complete denervation ~. This result provides a partial explanation for the phenomena observed following a small denervation, in that it identifies a primary source of drive for the masking inhibition as C-fiber ttctivity. However, it does not explain the delays prior to the expression of expanded RFs following denervation in the present study. Similar delays were found after local anesthetic denervation of a digit in flying foxes 5. However, in this species, the receptive field almost always continued to expand for a further 5-10 min; again there is no obvious explanation for this effect. It is noteworthy that the period of delay to expansion of RFs was not significantly different for denervation by amputation or local anesthetic, Overall the results from the studies of short-term effects of small denervations (this study and refs. 2-6) are consistent with the new or expanded RF effect being a consequence of unmasking of existing and viable connections from the newly responsive regions to somatosensory cortex. In the context of the hypothesis that C-fibers from the region of the RF provide a source of activity for inhibitory interneuron circuits that normally mask much of the potential excitatory drive to cortical neurons, the delay in the unmasking effects of small denervations may be significant. A problem raised by the C-fiber blocking expe~i,'ncnt is
223 that the result implies that some C-fibers have tonic activity which when blocked leads to disinhibition. Such activity has not been observed. However, if the inhibitory influence from activity in involved fibers has an effective period of a few minutes then perhaps very low rates of tonic activity, that have not been notable in peripheral studies, may be sufficient. Donoghue et al. 9 have reported short-term changes to the outcome of microstimulation in the vibrissae region of ketamine-anesthetized adult rat primary motor cortex (MI) following section of the facial nerve. They report a delay, typically around 1 h, before stimulation gives rise to new EMG activity in the forelimb. The time course for this expression of MI output is longer than that commonly observed in the present study for the sampling of new receptive fields in SI after a small denervation (Fig. 5), but is comparable to the two longest latent periods observed in the present study (26 and 41 min) observed after amputation of 3 toes to which the RF was originally confined. Donoghue et al., while not discounting other sites, state that the most plausible explanation for their observation is the unmasking of existing connections within MI. This parallels the explanation we prefer for short-term unmasking in Sl. Details of the action or site of the masking inhibition consistent with the delay to, and gradual expression of, the new responsiveness are unknown at this stage although microiontophoresis of bicuculline shows that there is capacity to account for the phenomenon within motor cortex 2°. Very different effects to those of the presenL study have been reported following denervations to the forepaw of the adult raccoon 32. Removing single digits resuited in the unmasking of inhibitory RF,~;, whereas denervating only the ventral digital surface resulted in the unmasking of large excitatory RFs. It was suggested that different extents of topographical disruption may unmask different levels of converging excitatory and inhibitory inputs. Low levels of ongoing spontaneous activity made determination of inhibitory receptive fields impossible in the present study. However, it is difficult to draw any comparisons between the studies due to the size of the repreaentation of the digit in the raccoon (18-45 mm 2) where both ventral surface and total digit dener-
REFERENCES 1 Batuev, A.S., Alexandrov, A.A. and Scheynikov, N.A., Picrotoxin action on the receptive fields of the cat sensorimotor cortex neurons, J. Neurosci. Res., 7 (1982) 49-55. 2 Calford, M.B. and Tweedale, R., Immediate and chronic changes in responses of somatosensory cortex in adult flying-fox after digit amputation, Nature, 332 (1988) 446-448. 3 Calford, M.B. and Tweedale, R., The capacity for reorganization in adult somatosensory cortex. In M. Rowe and L. Aitkin (Eds.), Information Processing in Mammalian Auditory and
vations would be classed as large, Looking more generally at the result of immediate unmasking of expanded RFs, where we interpret the initial events following a small denervation as largely mechanical (a consequence of the removal of the source of drive for the masking inhibition), leads to the obvious question: when do the plastic changes begin? It was clear from chronic recording in the flying fox that the receptive field~ of some loci showed shrinkage 1 day after amputation 2"3. Further, in the present study there were marked differences in the receptive fields recorded before and after temporary anesthesia in about 60% of cases, suggesting that plasticity may begin within hours of denervation in ketamine-anesthetized animals. This proportion of such diff, aces was, however, quite small in the experiments with local anesthesia of digits in the flying fox 5. The species difference may reflect the somewhat capricious nature of cortical recording in rats, but could be indicative of a quicker onset of plasticity in this species. Either way, the proposed explanation of initial events following a small denervation does not discount a role for modification of synapses in shaping receptive fields. Within SI such modification has been demonstrated by 'use-dependent' changes to receptive fields s' 2~,30. Descriptions of the modular organization of the somatotopic map n-~'~'2s'34 also strongly suggest such modification, at least in developmental stages. Anatomical investigations ~9 suggest that local inhibitory circuits within cortex are imprecise, providing a substrate for a non-specific damping inhibition ~0 rather than specific inhibitory interactions. The large receptive fields seen shortly after partial denervation are consistent with the predicted outcome of the disruption of such circuitry. The plastic events which follow this initial disruption to produce small receptive fields 2 and somatotopy 27 would, however, appear to be indicative of synaptic modification.
Acknowledgements. This work was supported by grants from the National Health and Medical Research Council of Australia and a Commonwealth Special Research Centres Award to the Vision, Touch and Hearing Research Centre. We thank Leah Krubitzer for her help in preparing the manuscript,
Tactile Systems, Liss, New York, 1990, pp. 221-236. 4 Calford, M.B. and Tweedale, R., lnterhemispheric transfer of plasticity in the cerebral cortex, Science, 249 (1990) 805-807. 5 Calford, M.B. and Tweedale, R., Acute changes in cutaneous receptive fields in primary somatosensory cortex following digit denervation in adult flying fox, J. Neurophysiol., 65 (1991) 178187. 6 Calford, M.B. and Tweedale, R., C-fibres provide a source of masking inhibition to primary somatosensory cortex, Proc. R. Soc. Lond., 243 (lqgl) 269--275. 7 Chapin, J.K. and Lin, C.-S., Mapping the body representation
224 in the SI cortex of anesthetized and awake rats, J. Comp. Neurol., 229 (1984) 199-213. 8 Clark, S.A., Allard, T., Jenkins, W,M. and Merzenich, M.M., Receptive fields in the body-surface map in adult cortex defined by temporally correlated inputs, Nature, 332 (1988) 444-445. 9 Donoghue, J,P., Suner, S. and Sanes, J.N., Dynamic organization of primary motor cortex output to target muscles in adult rats. ll. Rapid reorganization following motor nerve !esior~s, Exp. Brain Res,. 79 (1990) 492-503. 10 Dykes, R.W., Parallel processing of somatoscnsoon informat,~on: a theory, Brain Rex. Rev., 6 (1983) 47-115. 11 Dykes, R.W., Landon, P., Metherate, R. and Hicks, T.E, Functional role of GABA in cat primary somatosensory cortex: shaping receptive fields of cortical neurons, J. Neurophysiol., 52 (1984) 1066-1093. 12 Favorov, O. and Whitsel, B.L., Spatial organization of the peripheral input to area 1 cell columns. I. The detection of "segregates', Brain Rex. Rev.. 113 (1988) 25-42. 13 Favorov, O. and Whitsel, B.L., Spatial organization of the peripheral input to area ! cell columns. !!. The forelimb representation achieved by a mosaic of segregates, Brain Res. Rev.. 13 (1988) 43-56. 14 Favorov, O.V. and Diamond, M.E., Demonstration of discrete place-defined columns - segregates - in the cat SI, J. Comp. Neurol., 298 (1990) 97-112. 15 Favorov, O.V., Diamond. M.E. and Whitscl, B.L., Evidence for a mosaic representation of the body surface in area 3b of the somatic cortex of cat, Proc. Natl. Acad. Sci. U.S.A., 84 (1987) 6606-6610. 16 Franck, J.l., Functional reorganization of cat somatic sensorymotor cortex (SMi) after selective dorsal root rhizotomies, Brain Re,search, 186 (1980) 458-462. 17 Garraghty, P.E. and Sur, M., Morphology of single intracellularly stained axons terminating in area 3b of macaque monkeys. J. Comp. Neurol.. 294 (19u0) 583-593, 18 Hicks, T.P. and Dykes, R.W., Receptive fluid size for certain neurons in primary somatosenso~y cortex is determined by GABA.mediatcd intracortical inhibition, Brain Research, 274 (1983) 160-164, 19 Houser, C.R. Vaughn, J.E., Hendry, S.H,C., Jones, E.G, and Peters, A,, GABA neurons in the cerebral cortex, In E,G, Jones and A. Peters {Eds.), Cerebral Cortex, Vol. 2. Fum'tlomll Propertie,~' of Cortical Cell,s'. Plenum, New York, 1984, pp. 63~ 89. 20 Jacobs, K,M, and Donoghue, J,P., Reshaping the cortical motor map by unmasking latent intrucortical connections, Science, 251 (1991) 944-947. 21 Jenkins, W.M., Merzcnich, M.M., Ochs, M.T., Allard, 1". and Guic-Roblcs, E., Functional reorganization of primary soma. tosensory cortex in adult owl monkeys after behaviorally controlled tactile stimulation, J. Neurophysiol., 63 (1990) 82-104. 22 Kalaska, J. and Pomeranz, B., Chronic paw dencrvation causes an age-dependent appearance of novel responses from forearm
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BRES 17184
Short-term expansion of receptive fields in rat primary somatosensory cortex after hindpaw digit denervation Jennifer A. Byrne and Michael B. Calford Vision, Touch and Hearing Research Centre and Department of Physiology and Pharmacology, The University of Queensland, Qld. 4072 (Australia) (Accepted 9 July 1991)
Key words: Plasticity; Somatosensory cortex; Amputation; Local anesthesia
The immediate effect of changing the driving cutaneous input to locations within primary somatosensory cortex (St) was examined by denervating one or more digits of the rat hindpaw by amputation or local anesthesia. When all or part of a receptive field of a cluster of neurons was dencrvated, it was found that the cortical location recorded from gained responsiveness to cutaneous stimulation of hindpaw areas bordering the denervated region. In 22 of the 29 animals studied this expansion took place within 5 min of the denervation.
INTRODUCTION
It has been shown repeatedly that the representation in primary s,~matosensory cortex (SI) of adult mammals is capable of functional plasticity induced by various peripheral denervations 2.~'t~'22.2.~'z~-27.2'~''~. Whereas the details of plasticity reported in these experitoents differ considerably, it is clear that the area of the cortical representation is a primary determinant of the extent and type of change that will be observed. Thus, amputation of one finger of an owl monkey was found after a few weeks to have produced a topographic expansion of the representation of adjacent fingers and palm over the entire area that originally coded for the amputated finger; amputation of two fingers left an unresponsive area 27. Similar limits were found on the extent of reorganization in the hindlimb representation of rats following section of the sciatic nerve 35, where reorganization appears limited to 0.5-1.0 mm across cortex, in general the total reutilization of denervated cortex, in the form of an expanded and topographic representation of adjacent intact areas, is limited to experiments where the cortical representation of the denervated region is within this limit. Previous work from this laboratory 2'3 has shown that for such small denervatio~s the physiological basis for further reorganization is the rapid unmasking of existing inputs from cutaneous regions adjacent to the denervation. Within a few minutes of the denervation of tbe
thumb in flying foxes s cortical neurons for which the receptive field (RF) was initially restricted to the denerrated region show sensitivity to stimulation of adjacent regions; loci where neural sensitivity initially extended onto the denervated region show expanded RFs. The phenomenon of rapid unmasking of new or expanded receptive fields following denervation has not been widely studied. The short-term changes following large denervations have been reported for the S! median nerve representation in owl and squirrel monkeys 2s'2~', sciatic and saphenous nerve representations in rat a'~, and digit representations in raccoon 2~'2~'32. However, the shortterm effects of small peripheral denervations on the representation in SI cortex have been reported only for the thumb representation in flying foxes T M and the digit representation in macaque monkeys 4. There is a need to extend the basic descriptive information available on this phenomenon, in particular, keeping within the limits of a small denervation, it is necessary to examine the effects of variation in denervation extent in absolute terms and in terms of the RF under study. The hindpaw representation of rats was chosen for study because published maps of this representation ~ show that the entire representation occupies a cortical surface area around 1 mm 2, Denervation of toes represents a small denervation and was expected to lead to functional reorganization rather than unresponsive zones in affected cortex.
Corre~pomh, nce: M.B. Calford, Vision, Touch and Hearing Research Centre, The University of Queensland, Old. 40"/2, Australia.
219 MATERIALS AND METHODS Experiments were performed on 29 adult male Wistar rats (270500 g) aged between 12 and 17 weeks. The day prior to experimentation the animals were given an intram:lscular iniection of 1 mg/kg dexamethasone phosphate (Dexadreson, lntervet (Aust.), Pty Ltd). Animals were anesthetized with an intramuscular injection of 35 mg/kg ketamine hydrochloride (Ketamine Injection, Jurex, Aust.) and 5 mg/kg xylazine (Rompun, Bayer, Aust. Ltd), Supplementary injections of the ketamine/xylazine mix were given during the experiment to the level required to abolish pedal reflexes. Animals were held in a stereotaxic frame and the right somatosensory cortex was exposed and covered with silicone oil. The cortical area occupied by the hindpaw representation (approximately 1 mm 2) was found in all animals to lie somewhere between 1.5 and 4.0 mm lateral of the midline, and 0.5 mm rostral and 3.0 mm caudal of Bregma. In each animal, a basic map of the hindpaw representation was derived. Recordings were made using tungsten-in-glass electrodes with tip dimensions (approximately 20 × 10/~m) such that recordings were made extracellularly from small clusters of clearly identified neurons. Activity recorded by the electrode was amplified (Grass PI5D), displayed on a digital oscilloscope (OS4100, Gould) and fed into an audioamplifier and speaker. At each electrode penetration site, the cutaneous RF was delineated by lightly stimulating the hindpaw and hindlimb with a small brush. The hindpaw was immobilized during stimulation, so as not to stimulate joint receptors. A receptive field (RF) was defined as the discrete area of skin the stimulation of which resulted in increased activity at the particular cortical location such that a boundary could be delineated with confidence. This criterion meant that RFs in this study included areas of skin where stimulation resulted in less-than-maximal cortical excitation. Thus RFs in this study were larger than those which would have been delineated had threshold stimuli been used (see ref. 14). After mapping the hindpaw representation, the electrode was held at a single location in cortex where the RF was confined to the distal hindpaw. Provided the RF was stabile for 30 min the body region to which neurons at this location were sensitive was partially or completely denervated. Amputations were used to permanently alter peripheral input and ranged in extent from a single toe to 4 toes. Temporary denervations were made using a local anesthetic (lignocain¢ hydrochloride, Apex Laboratories Pry Ltd, Aust.). When a single toe was selected for local anesthesia, subcutaneous injections of 0.1 mg (5 ~1 of 2%) lignocaine were delivered to the toe's dors~d, ventral, lateral and medial sides approximately 2 mm from its base, if the RF did not extend along the toe's dorsal surface, the dorsal injection was omitted, in all experiments, timing commenced once the initial manipulation had been performed, and the nature and time course of RF changes were described. When the denervation was temporary, the time taken for the return of cutaneous responsiveness to the locally anesthetized region, as seen through the cortical recording, was also recorded. The electrode remained at the same cortical location for between 22 and 134 min. Only one cortical sitc per animal was studied with denervation.
of the initial RF, and according to the size of the denervation (1 toe; 2-4 toes). Across these conditions the consistent finding of this study was that shortly after denervation the cortical neurons became responsive to stimulation at previously ineffective sites, either adjacent to the boundary of the denervation or to regions extending from remaining portions of the initial RF. In all experiments new responsiveness was found (longest latency of 41 min); in 22 of the 29 experiments this occurred within 5 min of the denervation.
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RESULTS
The immediate effects of peripheral denervation of some part of the hindpaw on the receptive field of multiunit activity at a single position in SI cortex was studied in 29 adult rats. The denervation, either by amputation or local anesthesia, removed all of the initial RF in 8 experiments and part of the initial RF ill the others. Aside from variation in the method of denervation, experiments also varied according to the size and location
Fig. 1. Examples of the effect of digit amputation on the receptive fields (RFs) of cortical units where some of the original field remains intact. Receptive fields are drawn on dorsal and ventral outlines of the hindpaw. The original RF is shown uppermost in each panel followed by examples of the RF at various times after amputation. In this and other figures the earliest time after denervation illustrated is that at which the RF was first seen to expand. Once expanded the new RFs in these two cases remained fairly stable.
220
Denervation by amputation of digits in 13 experiments a small and rapid denervation was achieved by the amputation of one or more hindlimb digits. In all cases, the original RF of the units under study extended onto, or was contained within, the amputated region. When the amputation did not remove the entire RF, as was the case in 6 experiments, new responsiveness arose from skin areas continuous with regions of the RF not removed by the amputation. Thus the remaining R F was said to have expanded (Fig. 1). This expansion was noted after a short period (median = 2 min) during which responses were elicited only in the remaining region of the initial RE in the other 11 experiments, the amputation removed the entire RF and therefore all of observable excitatory cutaneous input to the locus apparent prior to amputation. New responsiveness which appeared in these experiments therefore formed new RFs, which in all cases were continuous with the amputation wound (Fig. 2). After an initial RF change was noted, the size and position of the new or expanded RF was closely monitored over time. in 5 cases, expanded or new RFs which were initially noted did not change in size or position over the subsequent 30-60 min of recording (e.g. Figs. la and 2a,b). In 4 cases, there was further expansion of the new RF in the 10 min following its first appearance; thereafter the RF was stable. However, in 4 of the cases, expanded or new RFs shrank back partially after the maximum RF was observed (e.g. Fig. 2d), and in two of these cases RFs were observed to fluctuate towards and away from the amputation wound. Retraction from maximum RF extent was most apparent in two experiments in which components on the dorsal hindpaw disa l)peared around lO rain after they were first noted (e.g. Fig 2d). Marked fluctuations were noted in one experimt'nt (Fig. 3), in which the amputation of 4 toes had ini,.ially induced a rapid expansion of the remaining RF ~,ver the entire hindpaw and distal dorsal hindlimb. However the RF shrank back 30 min after the amputation ,~as performed, such that the ventral RF component was that which remained immediately after the amputation, and the dorsal component had totally disappeared. Subsequently there was further expansion of the ventral component.
in)~:,:i,-~ in all cases. In no case, judging from the cortica; ~'eeordir~g, did anesthesia spread to other toes or the foot. Within a period varying from 30 s to 7 min, the remaining RF expanded. In evaluating the RF changes subsequent to the initial expansion it is necessary to take into consideration the duration of local anesthesia. For the majority of experiments in which a denervated toe regained esthesia, as judged by the responsiveness of the
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Denervation by local anesthesia Temporary denervation, with a local anesthetic, was produced in 16 experiments in which a single toe was anesthetized. The initial changes to the RF of the cortical neurons under study were indistinguishable from the experiments using denervation by amputation. When a single toe was anesthetized the loss of that area from the RF was rapid, occurring within 1 min of
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Fig. 2, Examples of the expression of new responsiveness of cortical neurons after the original RF was completely removed, in all cases the new RF extended from the amputation wound and was continuous. Retraction of the RF from the maximal expansion was found in the experiments shown in c and d.
221 cortical neurons under study, the period of effective denervation averaged 25 min (range 6-55 min). However, in one experiment the toe did not regain esthesia (Fig. 4c), and in two experiments stimulation of the dorsal surface of the toe remained ineffective. Of the 13 experiments in which esthesia was regained there were no cases in which the RF returned to precisely the same boundaries as before anesthesia; in one case the RF remained expanded (Fig. 4a), in two cases final RFs were smaller than the original, in 5 experiments the final RF was marginally larger than the original and in 4 experiments the final RF, although smaller than reached at maximal expansion, was clearly larger than the original (Fig. 4b). The interpretation of some of these experiments is complicated, however, by the possibility that recording ceased before the RF had stabilized. In most experiments shrinking of the expanded RF was first noted at or shortly after the denervated toe regained esthesia, but in 3 cases shrinkage commenced earlier. Fluctuation of the RF during shrinkage occurred in 4 cases. These were minor compared to some of the fluctuations found after amputation (Fig. 3) and there was a clear trend toward a smaller RE
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The period before RF expansion In these experiments there was a variable period following denervation bef,.~re RF expansion. A frequency
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Fig. 3. Time course of rapid expansion and subsequent partial retraction of a very large RF produced by amputation of 4 digits which left some of the initial RF intact. At 5 rain after amputation the RF extended over most of the dorsal hindlimb. This experiment is notable for the large fluctuations in the size of the RE
Fig. 4. Experiments in which subcutaneous injection of a local anesthetic was used to denervate part of the RF of cortical neurons. in general RFs expanded soon after injection and shrank after the digit regained esthesia. Most RFs did not return to the original boundaries remaining either slightly enlarged, as in the examph; in b, or slightly contracted compared to the original field, in two cases the RF remained expanded as in a. In one case the digit dit r,~ot regain esthesia as judged by the cortical response (c).
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partial RF denervation IB total RF denervation '3
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t0 20 30 40 Latent period to expansion ot RF (rain)
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Fig. 5. Frequency, histogram of the latent period before a new, or expanded, RF was noted after digit dencrvation. The distribution from experiments in which part of the RF of the cortical neurons under study remained intact is stippled. Where the denervation removed the entire RF the histogram bins are filled. ]'he two distributions are significantly different (P < 0.003).
histogram of these periods is presented in Fig. 5. The data can be formed into 6 non-mutually exclusive groups for analysis by the Student's t-test. Testing partial denervation of an RF (.~ = 3.0 win, n - 21) against total denervation of an RF (~" = 13.5 min, n = 8 ) r e v e a l e d a significant difference (t2~ = 3.3, P < 0.003). The other tests were not significant: local anesthesia (~" ffi 3.0 min, n = 16) against amputation (~ - 9.5 min, n = 13) and single toe denervation (~" ffi 4.0 min, n ffi 21) against multiple toe denervation (.~ -- 11.0 min, n = 2t). Thus, the latent period is shorter for denervations that remove part of an RF than for those that remove the entire RF. Sample sizes are too small to allow full testing of intera~tion effects across these 3 conditions, but it is clear that the analysis is influenced by the combination of local anesthesia, single toe denervation and partial denervation conditions which often apply together (15 cases in the sample of 29). DISCUSSION The immediate effect of removing the peripheral innervation of neurons within SI was examined by amputating or locally anesthetizing areas of the rat hindpaw. The responses of multiunits in SI that had RFs overlapping, or contained within, the denervated region were monitored with a stationary electrode. In all cf the animals studied the units studied in S! gained responsiveness to body regions outside the limits of the intitial RFs. The denervafions were thus small when compared to those of other studies in which large denervations left unresponsive areas of S133"3"~, o r responsiveness not normally found in S123'32, Areas of new sensitivity, or expanded RFs, were always continuous with the original
RF or extended from the denervation boundary. In almost all of the denervation-induced changes to RFs studied there was a delay in the expression of the new or expanded field. Where local anesthesia was used to denervate, some of this delay may be due to a period before the onset of full anesthesia, but similar initial delays were also found with amputation, and the comparison between these treatments did not show a significant difference. The delay, or latent period, was longer for denervations which removed an entire RF. The present experiments do not allow any determination of the site of expression of expanded RFs. However, the apparently new responsiveness revealed after a small denervation indicates that there are functional connections to loci in Sl that are not normally expressed. These connections are unmasked by the removal of some of the effective input to a locus (i.e. the RF). Whereas this unmasking could take place at other levels of the somatosensory pathway, anatomical 17'24 and electrical stimulation 31 studies of thalamocorticai arborizations and experiments with cortical iontophoresis of the GABA Areceptor anatagonist bicuculline ~'~!,t8 clearly indicate that existing connectivity within SI is sufficient to account for new and expanded receptive fields following a small denervation. Recent work from this laboratory has shown that blocking of only C-fiber activity in the radial nerve of cat or flying fox mimics the unmasking of larger RFs of SI neurons seen with complete denervation ~. This result provides a partial explanation for the phenomena observed following a small denervation, in that it identifies a primary source of drive for the masking inhibition as C-fiber ttctivity. However, it does not explain the delays prior to the expression of expanded RFs following denervation in the present study. Similar delays were found after local anesthetic denervation of a digit in flying foxes 5. However, in this species, the receptive field almost always continued to expand for a further 5-10 min; again there is no obvious explanation for this effect. It is noteworthy that the period of delay to expansion of RFs was not significantly different for denervation by amputation or local anesthetic, Overall the results from the studies of short-term effects of small denervations (this study and refs. 2-6) are consistent with the new or expanded RF effect being a consequence of unmasking of existing and viable connections from the newly responsive regions to somatosensory cortex. In the context of the hypothesis that C-fibers from the region of the RF provide a source of activity for inhibitory interneuron circuits that normally mask much of the potential excitatory drive to cortical neurons, the delay in the unmasking effects of small denervations may be significant. A problem raised by the C-fiber blocking expe~i,'ncnt is
223 that the result implies that some C-fibers have tonic activity which when blocked leads to disinhibition. Such activity has not been observed. However, if the inhibitory influence from activity in involved fibers has an effective period of a few minutes then perhaps very low rates of tonic activity, that have not been notable in peripheral studies, may be sufficient. Donoghue et al. 9 have reported short-term changes to the outcome of microstimulation in the vibrissae region of ketamine-anesthetized adult rat primary motor cortex (MI) following section of the facial nerve. They report a delay, typically around 1 h, before stimulation gives rise to new EMG activity in the forelimb. The time course for this expression of MI output is longer than that commonly observed in the present study for the sampling of new receptive fields in SI after a small denervation (Fig. 5), but is comparable to the two longest latent periods observed in the present study (26 and 41 min) observed after amputation of 3 toes to which the RF was originally confined. Donoghue et al., while not discounting other sites, state that the most plausible explanation for their observation is the unmasking of existing connections within MI. This parallels the explanation we prefer for short-term unmasking in Sl. Details of the action or site of the masking inhibition consistent with the delay to, and gradual expression of, the new responsiveness are unknown at this stage although microiontophoresis of bicuculline shows that there is capacity to account for the phenomenon within motor cortex 2°. Very different effects to those of the presenL study have been reported following denervations to the forepaw of the adult raccoon 32. Removing single digits resuited in the unmasking of inhibitory RF,~;, whereas denervating only the ventral digital surface resulted in the unmasking of large excitatory RFs. It was suggested that different extents of topographical disruption may unmask different levels of converging excitatory and inhibitory inputs. Low levels of ongoing spontaneous activity made determination of inhibitory receptive fields impossible in the present study. However, it is difficult to draw any comparisons between the studies due to the size of the repreaentation of the digit in the raccoon (18-45 mm 2) where both ventral surface and total digit dener-
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vations would be classed as large, Looking more generally at the result of immediate unmasking of expanded RFs, where we interpret the initial events following a small denervation as largely mechanical (a consequence of the removal of the source of drive for the masking inhibition), leads to the obvious question: when do the plastic changes begin? It was clear from chronic recording in the flying fox that the receptive field~ of some loci showed shrinkage 1 day after amputation 2"3. Further, in the present study there were marked differences in the receptive fields recorded before and after temporary anesthesia in about 60% of cases, suggesting that plasticity may begin within hours of denervation in ketamine-anesthetized animals. This proportion of such diff, aces was, however, quite small in the experiments with local anesthesia of digits in the flying fox 5. The species difference may reflect the somewhat capricious nature of cortical recording in rats, but could be indicative of a quicker onset of plasticity in this species. Either way, the proposed explanation of initial events following a small denervation does not discount a role for modification of synapses in shaping receptive fields. Within SI such modification has been demonstrated by 'use-dependent' changes to receptive fields s' 2~,30. Descriptions of the modular organization of the somatotopic map n-~'~'2s'34 also strongly suggest such modification, at least in developmental stages. Anatomical investigations ~9 suggest that local inhibitory circuits within cortex are imprecise, providing a substrate for a non-specific damping inhibition ~0 rather than specific inhibitory interactions. The large receptive fields seen shortly after partial denervation are consistent with the predicted outcome of the disruption of such circuitry. The plastic events which follow this initial disruption to produce small receptive fields 2 and somatotopy 27 would, however, appear to be indicative of synaptic modification.
Acknowledgements. This work was supported by grants from the National Health and Medical Research Council of Australia and a Commonwealth Special Research Centres Award to the Vision, Touch and Hearing Research Centre. We thank Leah Krubitzer for her help in preparing the manuscript,
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