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Transcript
Brain Research 769 Ž1997. 256–262
Research report
Denervation-induced sprouting of intact peripheral afferents into the cuneate
nucleus of adult rats
D.R. Sengelaub
a,b
, N. Muja a , A.C. Mills c , W.A. Myers a , J.D. Churchill
a,b
, P.E. Garraghty
a,b,)
a
Department of Psychology, Indiana UniÕersity, Bloomington, IN 47405, USA
Program in Neural Science, Indiana UniÕersity, Bloomington, IN 47405, USA
Department of Biology, Middle Tennessee State UniÕersity, Murfreesboro, TN 37132, USA
b
c
Accepted 28 May 1997
Abstract
In adult monkeys with dorsal rhizotomies extending from the second cervical ŽC 2 . to the fifth thoracic ŽT5 . vertebrae, cortex deprived
of its normal inputs regained responsiveness to inputs conveyed by intact peripheral afferents from the face wT.P. Pons, P.E. Garraghty,
A.K. Ommaya, J.H. Kaas, E. Taub, M. Mishkin, Massive reorganization of the primary somatosensory cortex after peripheral sensory
deafferentation, Science 252 Ž1991. 1857–1860x. It has been suggested that the extent of this massive topographic reorganization may be
due to the establishment of novel connections between intact afferents and neurons denervated after dorsal rhizotomy wP.E. Garraghty,
D.P. Hanes, S.L. Florence, J.H. Kaas, Pattern of peripheral deafferentation predicts reorganizational limits in adult primate somatosensory
cortex, Somatosens. Motor Res. 11 Ž1994. 109–117x. Using adult rats with comparably extensive dorsal rhizotomies, we employed
anatomical tracing techniques to address this possibility. Subcutaneous hindpaw injections of horseradish peroxidase conjugated to either
wheat germ agglutinin or cholera toxin subunit B revealed aberrant expansions of gracile projections into the cuneate and, in one case,
external cuneate nucleus within three months of the deafferentation. It seems plausible that such modest sprouting of ascending
projections at the level of the brainstem may form functional connections which, through divergence, ultimately drive a larger population
of neurons in cortex. This new growth may well account for both the substantial cortical reorganization observed in the ‘Silver Spring
monkeys’ wT.P. Pons, P.E. Garraghty, A.K. Ommaya, J.H. Kaas, E. Taub, M. Mishkin, Massive reorganization of the primary
somatosensory cortex after peripheral sensory deafferentation, Science 252 Ž1991. 1857–1860x and the ‘referred sensation’ phenomena
Žsee J.P. Donoghue, Plasticity of adult sensorimotor representations, Curr. Opin. Neurobiol., 5 Ž1995. 749–754 for review. reported to
follow proximal limb amputations in humans. q 1997 Elsevier Science B.V.
Keywords: Dorsal rhizotomy; Brainstem; Gracile nucleus; Sprouting; Deafferentation
1. Introduction
In 1991, Pons et al. w17x reported a reorganization of
somatosensory cortex in adult macaques with complete
deafferentations of the arm, hand, and upper trunk that was
as much as an order of magnitude greater than cortical
reorganizations found after peripheral injuries w3,12–14x.
In the so-called ‘Silver Spring monkeys’, a circumscribed
portion of the representation of the face was found to have
expanded in excess of 10 mm medially, apparently across
the entire deprived region of somatosensory cortex.
)
Corresponding author. Department of Psychology, Indiana University, Bloomington, IN 47405, USA. Fax: q1 Ž812. 855-4520; E-mail:
[email protected]
0006-8993r97r$17.00 q 1997 Elsevier Science B.V. All rights reserved.
PII S 0 0 0 6 - 8 9 9 3 Ž 9 7 . 0 0 7 0 8 - 7
Unlike topographic changes seen after peripheral nerve
damage w2,12,13x, the extent of the topographic reorganization found in the Silver Spring Monkey was sufficiently
large that it could not be readily accounted for based on
the maximal sizes of thalamocortical axonal arbors w7,19x.
The apparent insufficiency of existing anatomical connections to account for the extensive rhizotomy-induced reorganization suggested that novel connections may well have
been established. Rausell et al. w18x suggested that relay
neurons in the ventroposterior medial nucleus ŽVPM. might
have sprouted novel connections onto denervated cells in
the ventroposterior lateral nucleus ŽVPL., and that the
trigeminal receptive fields represented in VPM were then
conveyed to ‘VPL cortex’ over this new pathway. We
found it more plausible to imagine that new growth had
indeed occurred, but that it involved the sprouting of
D.R. Sengelaub et al.r Brain Research 769 (1997) 256–262
primary peripheral afferents at the level of the brainstem
since vacated synaptic sites no doubt existed in the denervated cuneate nucleus Žsee Fig. 6B,C.. It seemed reasonable to hypothesize that modest sprouting at the level of
the brainstem could, through divergence, innervate a larger
population of neurons in the thalamus which could consequently drive an even larger population of neurons in the
cortex.
To evaluate the hypothesis that intact afferents may
form novel connections with denervated targets in the
brainstem, we have performed unilateral dorsal rhizotomies in adult rats as extensive as those in the monkeys
studied by Pons et al. w17x. Our results provide evidence
for denervation-induced, sprouting of intact peripheral afferents into the denervated cuneate nucleus of adult rats. A
preliminary report of some of these data has appeared
elsewhere w6x.
2. Materials and methods
Thirteen adult, Sprague–Dawley rats weighing between
200 and 360 g underwent unilateral rhizotomy of the
dorsal roots projecting to the left cuneate nucleus. Animals
were deeply anesthetized with an intramuscular Ži.m.. injection of ketamine HCl ŽKetaset, 80 mgrkg. and xylazine
ŽRompun, 10 mgrkg.. Supplemental doses were administered as needed in order to maintain a surgical level of
anesthesia. Their backs were shaved and prepared for
surgery with alternate scrubbings of Betadine and alcohol.
The animals were placed on a heating pad to maintain
normal body temperature and ophthalmic ointment was
applied to prevent corneal desiccation. A skin incision was
made along the dorsal midline from the base of the skull to
the mid-spinal level. The layers of muscle overlying the
spinal column were incised and retracted. Under microscopic view, fine rongeurs were used to perform partial
laminectomies from the second cervical to the fourth or
fifth thoracic vertebrae thereby exposing the spinal cord.
The dura encasing the spinal cord was incised and reflected to expose the dorsal roots for avulsion. After dorsal
root transection, Gelfilm and a pledget of Gelfoam ŽUpjohn. were placed over the exposed cord for protection and
support. The overlying musculature was then sutured in
layers and the skin wound was sutured shut. Postoperatively, the rats received i.m. injections of dexamethasone
Ž0.8 mgrkg., Dopram Ž8 mgrkg., penicillin ŽAmbi-Pen,
120 000 unitsrkg., and lactated ringers solution with 5%
dextrose Ž5% body weightrh of surgery, s.c... A bolus of
penicillin was administered daily for 3 days. Recovery
from these procedures was generally uneventful, though in
2 of the 13 rats, some autotomy was observed.
After survival durations ranging from 58 to 304 days,
the rats were anesthetized with ether. Horseradish peroxidase conjugated with either: Ž1. cholera toxin subunit B
Ž1% B-HRP, Sigma.; Ž2. wheat germ agglutinin Ž2%
257
WGA-HRP, type VI, Sigma.; or Ž3. a combination of both
was dissolved in distilled water and injected subcutaneously into several bilaterally matched areas of the animals hindpaws Ž n s 5; and face, n s 2 of these 5., or into
the hindpaw on the deafferented side Ž n s 8. using a
Hamilton microsyringe. One additional normal control rat
received unilateral hindpaw injections of tracer. There are,
thus, 13 cases of hindlimb injections ipsilateral to a denervated cuneate nucleus, and 6 cases with hindlimb injections ipsilateral to an intact cuneate nucleus.
Three days were allowed for the anatomical tracerŽs. to
be transported anterogradely to the central nervous system.
At that time, the rats were administered a lethal overdose
of urethane Ž0.5 mgrml, i.p.. and perfused transcardially
through the ascending aorta at normal blood pressure with
physiological saline followed by a cold mixture of 1%
paraformaldehyde and 1.25% glutaraldehyde. The brainstems were then carefully extracted and postfixed for 5 h
in the same fixate and transferred to 0.1 M phosphate
buffer ŽpH 7.4. containing 10% sucrose overnight at 48C.
The tissue was embedded in gelatin and sectioned coronally or, in 4 of the experimental cases, horizontally, at 40
mm on a freezing microtome. Sections were cut into cold
phosphate buffer ŽpH 7.4. and processed histochemically,
according to Mesulam’s w15x protocol, with tetramethylbenzidine ŽTMB, Sigma. as the chromagen. In some cases,
alternate sections were counterstained with 1.0% Neutral
red. The sections were mounted on gelatinized slides and
allowed to dry overnight. The tissue was dehydrated in
increasing concentrations of alcohol, cleared in a series of
xylenes, and coverslipped with Permount.
Camera lucida reconstructions of the anatomical location of the labeling were done under darkfield at 10 =
magnification. Terminal label was reconstructed in brightfield at 100 = magnification with an oil immersion objective. Nuclear boundaries were defined using the atlas of
Paxinos and Watson w16x.
Additional quantitative measurements were made. First,
we counted the number of instances of terminal label in
the cuneate nucleus after hindlimb tracer injection. Clearly
separated patches of terminal label within and across sections were counted as single instances of aberrant terminations. Second, the mean area of the aberrant terminal label
was calculated by taking the average of the areas of
minimal convex polygons drawn to include all of the
aberrant terminal label in each section of each case.
3. Results
Phenotypically, the success of the surgery was evidenced by a complete lack of use of the deafferented
forelimb in locomotion Že.g., see w24x.. Interestingly, the
deafferented forelimb was used in stereotypical bilateral
grooming and feeding behaviors suggesting that forelimb
use in these behaviors requires no afferent feedback from
258
D.R. Sengelaub et al.r Brain Research 769 (1997) 256–262
the forelimb for their initiation and maintenance Žthough it
is possible that stimulation of the head and face by the
deafferented forelimb provides inputs that could shape the
stereotypical forelimb behavior..
Tissue reacted for HRP using TMB revealed aberrant
sprouting of intact gracile projections into denervated
cuneate nuclei in 12 of the 13 subjects within 2 months of
the deafferentation. Fig. 1A,B shows low- and high-power
micrographs of coronally sectioned tissue taken from one
case. A serial reconstruction of the terminal label Žacross 3
sections. is illustrated in Fig. 2. As can be seen, there is an
unambiguous expansion of label into the cuneate nucleus
extending from the vicinity of the gracile nucleus.
Fig. 1C,D and Fig. 3 illustrate comparable data from
another subject. In this case, the brainstem was sectioned
in the horizontal plane. Again, the photomicrographs ŽFig.
1C,D. demonstrate that HRP-labeled fibers extended into
the denervated cuneate nucleus. The camera lucida reconstruction of this label is illustrated in Fig. 3. Comparable
aberrant label was found in the denervated cuneate nucleus
in 12 of the 13 subjects whether the anatomical tracer was
injected into both face and hindlimb Ž n s 2. or hindlimb
Fig. 1. Darkfield photomicrographs of HRP terminal labeling in the brainstems in two rats that had undergone dorsal rhizotomies extending from C 2 to T5 .
In both cases, the anatomical tracer was injected into the hindlimb ipsilateral to the deafferentation. A: coronal section showing label in the gracile nucleus
Žopen arrow. and the anomalous labeling in the cuneate nucleus Žsolid arrow.. Medial is to the right, dorsal to the top. B: higher magnification
photomicrograph of anomalous labeling shown in A. C: horizontal section showing labeling in the gracile nucleus Žopen arrow. and anomalous labeling in
the cuneate nucleus Žsolid arrow.. Medial is to the right, rostral to the top. D: higher magnification photomicrograph of the anomalous labeling shown in C.
Scale bars Žin A,C. s 250 mm; Žin B,D. s 100 mm.
D.R. Sengelaub et al.r Brain Research 769 (1997) 256–262
259
Fig. 2. Camera lucida reconstruction of terminal label illustrated in Fig. 1A,B. This label was serially reconstructed across three 50-mm sections. The
labeling in the cuneate nucleus clearly appears to extend from the gracile nucleus. AP, area postrema; A2, A2 noradrenergic cells.
alone Ž n s 11.. It is, therefore, probable, that the cuneate
label in all cases derived from the hindlimb injection sites.
While not illustrated, we saw no such innervation of the
cuneate nucleus by gracile fibers in any of the 5 rats in
which matched injections of anatomical tracer were made
contralateral to the rhizotomy, nor was any cuneate labeling detected in the one normal control rat. Thus, the
histological label found in the cuneate nucleus ipsilateral
to the rhizotomy in 12 of the 13 rhizotomized subjects is
apparently not characteristic of typical hindlimb projections to the brainstem, but, rather reflects opportunistic
Fig. 3. Camera lucida reconstruction of the terminal label illustrated in
Fig. 1C, D. Extensive labeling is again evident in the cuneate nucleus.
Fig. 4. Histograms representing the mean Ž"S.E.M.. areal extent of the
aberrant terminal label in the cuneate nucleus ipsilateral to the dorsal
rhizotomies after the injection of anatomical tracer into the ipsilateral
hindpaw. The left-hand bar is for coronally sectioned material; the
right-hand bar is for horizontally sectioned material. Control data are not
represented as there were no instances of such label in any of those cases.
260
D.R. Sengelaub et al.r Brain Research 769 (1997) 256–262
Fig. 5. Histograms representing the mean Ž"S.E.M.. number of discrete
patches of terminal label in the cuneate nucleus ipsilateral to the dorsal
rhizotomies after the injection of anatomical tracer into the ipsilateral
hindpaw. The left-hand bar is for coronally sectioned material; the
right-hand bar is for horizontally sectioned material. Control data are not
represented as there were no instances of such label in any of those cases.
expansion of intact afferents into the denervated nucleus
Ž x 2 s 13.45, P - 0.005..
Fig. 4 presents the mean area of HRP label in the
cuneate nucleus after hindlimb tracer injection. The data
presented are the means from the coronally and horizontally sectioned brainstems of the rhizotomized animals.
The 6 control cuneate nuclei are not represented here as
we detected no aberrant terminal label in any of these
animals, leaving them with a mean and standard error of 0
Žall control cases were sectioned coronally.. The difference
between the coronally and horizontally sectioned cases is
an artifact of the plane of section. That is, the cuneate
nucleus extends over a larger area in the horizontal than in
the coronal plane. Fig. 5 presents the average number of
clearly separated sites of aberrant terminal label in the
coronally and horizontally sectioned brainstems, and, as is
evident, there was no difference.
ological recording in somatosensory cortex suggests that
the new connections are functional to a limited extent, as
evidenced by an apparent expansion of hindlimb responsiveness into ‘cuneate’ cortex w6x. A comparable outcome
has been reported for rats that had undergone neonatal
forelimb amputation w10x. In those animals, the expansion
of gracile fibers into the cuneate nucleus was extensive,
but there was minimal invasion of the forelimb region in
cortex by hindlimb inputs. The major difference between
forelimb amputation and C 2 –T5 rhizotomies is that many
normal inputs to the cuneate nucleus remain after amputation. Lane et al. w10x suggested that the aberrant inputs to
the cuneate, which could drive activity in that nucleus,
were functionally suppressed at the level of the thalamus
or cortex. Such suppression might be less likely following
extensive rhizotomies where the aberrant inputs are not
intermingled with a larger set of ‘normal’ inputs. The
incomplete invasion of the forelimbrupper trunk cortex in
the rhizotomized rats relative to the apparently complete
occupation of deprived cortex by inputs from the face in
the Silver Spring Monkeys might be due to the substantial
differences in postsurgical survival durations, or, alternatively, simply to species differences.
It should be noted that small projections from gracile
fasciculus fibers into the cuneate nucleus have been reported in normal rats w8,9,11,20,21x, though not consistently. For example, LaMotte et al. w9x reported a termination from the hindlimb in the cuneate nucleus in only one
of 16 rats following the labelling of either the saphenous
or sciatic nerve. Thus, it is possible that the aberrant label
in the cuneate nucleus in the present rats reflects an
expansion in a previously existing projection. In any event,
label was present in 12 of the 13 experimental animals in
the cuneate ipsilateral to the rhizotomies, but was not
observed in the 5 rats in which matched injections were
placed in the hindlimb contralateral to the deafferentation
or in the one control rat.
4. Discussion
4.1. Is sprouting confined to intact peripheral afferents?
In the present experiments, we have evaluated the hypothesis that aberrant growth of intact peripheral sensory
afferents might follow extensive deafferentation. This hypothesis was derived from observations in adult macaque
monkeys that had survived for a number of years after
dorsal rhizotomies extending from C 2 to T5 w17x. In those
animals, with denervated cuneate nuclei, electrophysiological mapping in primary somatosensory cortex revealed that
the deprived zone of cortex had come to represent skin
surfaces innervated by the trigeminal nerve w17x. The most
parsimonious ‘explanation’ seemed to be that intact
trigeminal fibers had formed sprouts into the denervated
cuneate nucleus, and that these sprouted trigeminal afferents then used the ‘cuneate circuitry’ to relay their receptive fields to the deprived cortex w2x. The present results
demonstrate clearly that new growth is possible within the
adult mammalian brainstem, and preliminary electrophysi-
This aberrant growth at the level of the brainstem in
rhizotomized rats in no way precludes the existence of
sprouting at the level of the thalamus, a possibility suggested by Rausell et al. w18x. They reported that the
cuneate nuclei ipsilateral to the dorsal rhizotomies were
severely shrunken, and hypothesized that this was due, at
least in part, to cell loss. This appearance of a cuneate cell
loss led them to suggest that VPM relay neurons whose
axons course to the cortex through the VPL might have
formed sprouts onto VPL neurons denervated by the loss
of cuneate cells. These novel VPM connections with VPL
neurons could then serve to relay trigeminal receptive
fields to the ‘cuneate region’ of somatosensory cortex,
providing the anatomical underpinnings for the electrophysiological data of Pons et al. w17x.
We see no apparent shrinkage of the cuneate nuclei in
D.R. Sengelaub et al.r Brain Research 769 (1997) 256–262
rats with equivalently extensive rhizotomies, but hasten to
add that the postsurgical survival times in these rats were
substantially shorter than those of the Silver Spring Monkeys Ž10–12 years.. It is certainly possible that comparable
reductions in cuneate nucleus volumes would also follow
more protracted survivals in the rats, but in the absence of
neuronal counts the issue of cell loss must remain unresolved. Obviously, if one assumes no species differences,
aberrant sprouting could occur at both brainstem and thalamic levels, but we would argue for the more parsimonious
account of sprouting only at the level of the brainstem as a
small expansion of intact afferents at that level could,
through diverging projections, come to activate a large
region of the cortex. In either case Žsprouting in brainstem
and thalamus or brainstem alone., the present results
demonstrate clearly that intact peripheral afferents can
form novel connections central to the spinal cord in adult
rats after extensive dorsal rhizotomies.
4.2. How do the present obserÕations relate to preÕiously
reported data from animals with peripheral injury?
Numerous experiments investigating the consequences
of peripheral injuries have been performed in adults representing a variety of species Žsee w1,4x for reviews.. While
there has existed Žfor some. a tacit belief that common
mechanisms are operating after sensory loss arising from
differing manipulations, the present results together with
previous observations Že.g., w2,3,5,12–14x. suggest that
different mechanisms are operating after peripheral nerve
injuries and rhizotomy. So, for example, the transection of
a peripheral nerve deafferents the autonomous innervation
zone of that nerve, but leaves the brainstem nucleus receiving inputs conveyed by that nerve at least largely intact
ŽFig. 6A.. This fact has been demonstrated in experiments
employing electrical stimulation of the median, ulnar, and
radial nerves in monkeys w22,23x. In these experiments a
261
‘cryptic’ radial nerve somatosensory evoked potential to
‘median nerve cortex’ grows progressively following median nerve transection, mirroring the largely dorsum skin
invasion of median nerve cortex that is reported in microelectrode mapping experiments w5,12,13x. Even after the
radial nerve SEP has gained in strength Žpresumably reflecting the reorganization., electrical stimulation of the
proximal median nerve stump still evokes an SEP that is
comparable to that found prior to the nerve injury w23x.
Thus, the central projections of the median nerve are
minimally affected by transection at the mid-forearm level.
Alternatively, when sensory loss is accomplished by
transections proximal to the dorsal root ganglia Ži.e., rhizotomy., brainstem synaptic sites are necessarily vacated.
With dorsal rhizotomies as extensive as those employed in
the present experiments and in the ‘Silver Spring monkeys’, relay neurons in the cuneate nucleus are permanently disconnected from their ascending inputs ŽFig. 6B.,
permitting an expansion of intact afferents into the denervated cuneate nucleus ŽFig. 6C.. Moreover, in contrast to
the present results, there is no evidence of intact afferent
expansion in the cuneate nucleus of adult monkeys after
combined median and ulnar nerve transection and subsequent reorganization ŽS.L. Florence, P.E. Garraghty, unpublished observations.. Thus, these two deafferentation
paradigms differ fundamentally with regard to their central
consequences, and, apparently, their central effects. In the
present experiments Žand, possibly, in the ‘Silver Spring
monkeys’., intact afferents form aberrant sprouts into the
denervated cuneate nucleus ŽFig. 6C., presumably because
molecular signals associated with denervation induce collateral growth from the neighboring population of centrally
projecting fibers. While it has been previously suggested
that the topographical ‘reorganizations’ that follow peripheral nerve injury arise from changes in previously existing
anatomical circuitry w4x, the present results suggest that
previously existing anatomy may account for little, if any,
Fig. 6. Schematic illustrations of the central consequences of peripheral nerve transection ŽA. and dorsal rhizotomies extending from C 2 to T5 ŽB,C.. A:
peripheral nerve transection. Dashed lines distal to the cut signify degeneration. The central projections of the affected dorsal root ganglion cells are largely
unaffected. B: dorsal rhizotomy. Dashed lines signify degeneration. The central processes of dorsal root ganglion cells are affected. C: synaptic sites in the
cuneate nucleus are vacated by the dorsal rhizotomies. Intact afferents from the hindlimb can then form sprouts into the denervated cuneate nucleus.
262
D.R. Sengelaub et al.r Brain Research 769 (1997) 256–262
of the central topographic changes that follow more extensive, and more proximal deafferentations.
Acknowledgements
This project was supported in whole or in part by
B.R.S.G. Grant RR7031-27 from the Biomedical Research
Support Program, Division of Research Resources, National Institutes of Health.
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