the sprouting of saphenous nerve terminals in the spinal cord following early postnatal sciatic...

THE JOURNAL OF COMPARATIVE NEUROLOGY 240~407-413 (1985)

The Sprouting of Saphenous Nerve Terminals in the Spinal Cord Following Early Postnatal Sciatic Nerve Section in

the Rat

MARIA FITZGERALD Cerebral Functions Research Group, Department of Anatomy, University College

London, London WClE 6BT, United Kingdom

ABSTRACT Transganglionic labelling of the saphenous nerve in rats with WGA-

HRP revealed the central distribution of its terminals in the lumbar dorsal horn. The terminal field was clearly defined and consistent in rats aged between day 6 and day 90. If, however, the sciatic nerve was sectioned on day 1 of postnatal life, the saphenous terminal field expanded to occupy twice the normal area (measured between the L2 and L4 boundaries). The spread was caudal, medial, and lateral into areas normally occupied by sciatic nerve terminals. This sprouting was very weak if the sciatic nerve was sectioned later in postnatal life, on day 5, and nonexistent if sectioning took place on day 10. Crushing the sciatic nerve on day 1 also triggered the effect but the spread of the terminal field was less than that produced by section of the sciatic nerve. There was no evidence of sprouting from the contralateral intact sciatic nerve. The results demonstrate the necessity of intact afferent input during a critical period of neonatal life in order to maintain the precise somatotopic termination pattern of dorsal root afferents.

Key words: development, plasticity, peripheral nerve, dorsal horn

Peripheral afferent fibres terminate in the dorsal horn of the spinal cord in a strict somatotopic pattern. The central terminals of a given peripheral nerve are found in a dis- crete region of the dorsal horn bordering, but not overlap- ping, the central termination region of an adjacent peripheral nerve (Koeber and Brown, '82; Swett and Woolf, '85). This precise pattern is reflected to a considerable de- gree in the receptive field properties of second-order dorsal horn cells in the region of the terminals so that the repre- sentation of the sensory body map is maintained. This type of topical termination pattern is also seen in other sensory systems, e.g., the retinotopic terminations in the visual system.

The question of how these precise connections are made during development and to what extent they are influenced by the available peripheral input is one that has interested neurobiologists for some time (see Jacobson, '78). In many areas of the nervous system, excess diffuse connections between afFerents and target cells are made initially and these are then selectively pruned and eliminated to form the final precise pattern (see Hopkins and Brown, '84). An example is in the establishing of the retinotopic map to the

0 1985 ALAN R. LISS, INC.

lateral geniculate nucleus, superior colliculus, and visual cortex (Rakic, '77; and see Wiesel, '82). Dorsal root afferents do not appear to develop in this way, however. Careful HFtP labelling of peripheral nerves both pre- and postnatally shows that the precise termination pattern seen in the adult is present from the time the connections are formed (Smith, '83; Fitzgerald and Swett, '83).

In systems where initially diffuse connections are reduced to precise ones, the patterns are apparently established by competition between neighbouring inputs. Activity patterns in both the afferents and the postsynaptic target cells contribute to the final connectivity. The mechanisms in- volved have been demonstrated by removal or inactivation of selected inputs early in development and by observing the resultant distortion in afferent termination pattern. Such experiments have demonstrated the potential plasticity in the developing nervous system which allows intact afferent terminals to spread their terminal field in the

Accepted May 22,1985.

408

absence of their neighbours (see Hopkins and Brown, '84, for review).

The aim of the experiments reported here was to examine the role of neighbouring peripheral nerve afferents on the establishment of the precise somatotopic primary afferent map observed in the dorsal horn. To test this, the effect of cutting or crushing the sciatic nerve in neonatal rats has been examined on the central terminal dorsal horn map of the neighbouring saphenous nerve. In adult rats such peripheral nerve damage has no effect on the distribution of surrounding nerve terminals of intact nerves (Seltzer and Devor, '84) in the dorsal horn. Some sprouting of dorsal root afferents does occur following dorsal root or spinal cord lesions in neonates (Stelzner et al., '79; Hulsebosch and Coggeshall, '831, but the question of whether the established somatotopic terminal map can be distorted by dis- crete peripheral lesions has not been previously examined.

METHODS Wistar rat pups of both sexes aged 1, 5, or 10 days were

anaesthetized with ether. Under sterile conditions the sciatic nerve was exposed in the back of the knee and either cut and ligated or crushed for 3 seconds with jeweller's forceps. The muscle and skin were then sutured; the pups were allowed to recover from the anaesthesia and were returned to their mothers.

At various times from 4 to 90 days after the operations the rat pups were reanaesthetised with 20 mgkg Nembu- tal. Again, using sterile procedures, the saphenous nerves on one or both sides were exposed in the medial thigh. The nerve was cut at knee level, dissected free of the surrounding tissue, and a length of 2-5 mm was isolated by dripping low-melting-point wax around it. When set, a small pool containing the exposed tip of the saphenous nerve was made in the wax. The nerve ending was then soaked in a 5% solution of WGA-HRP (horseradish peroxidase conju- gated with wheat germ agglutinin) for 2 hours. After this it was carefully rinsed with saline solution, the wax was removed, and the wound was closed. On recovery from the anaesthetic the pups were returned to their mother, or if weaned, returned to their cage. Pups less than 2 weeks old were perfused after 24 hours and older pups after 48 hours. They were perfused with 1.25% glutaraldehyde and 1.0% formaldehyde in 0.1 M phosphate buffer at O'C, and then with the buffer containing 10% sucrose also at 0°C. The lumbar cord was removed, the segments were identified by tracing back to the sciatic nerve, and the segment junctions were marked with vertical pins. The cord was stored for not more than 48 hours in 10% sucrose in 0.1 M phosphate buffer at 0°C. Transverse frozen 50-pm sections were cut and one in two was saved for pups less than 2 weeks old and one in three for older pups. The sections were then stained for HRP labelling by the TMB method described by Mesulam ('82) and counterstained with neutral red.

The sections were inspected, using light- and darkfield microscopy, for HRP labelling in the dorsal horn of the spinal cord. The pattern of label in consecutive sections was plotted out using a camera lucida. This was simplified by considering lamina 2 from the medial to the lateral edge of the dorsal horn as a straight line and marking the position of the label along it. This is illustrated in Figure 1. It does not, of course, take into account the lateral bend of the dorsal horn at lamina I1 but since the saphenous nerve label is always medially placed this is a reasonable approx- imation. The overall distribution of label through the seg-

d

M. FITLGERALD

a b d +

Fig. 1. Diagram to illustrate the method used to measure the afferent terminal field area in the dorsal horn. Right: measurements of the position of the HRP reaction product (in black) in lamina I1 were made in serial 50- ym transverse sections of the spinal cord through from L2 to L4. Left: these measurements were then lined up to form a horizontal map of the dorsal horn through lamina I1 with the terminal field area plotted on it.

ments was then reconstructed from this series of transverse lines as a horizontal map of the spinal cord viewed as if from above (Fig. 1). The area of this reconstructed flat sheet of gray matter taken up by saphenous nerve terminals in lamina 2 between the L4L5 and L1L2 junctions was measured using a computerized area-measuring program and was expressed as a percentage of the total sheet of gray matter.

RESULTS Transganglionically transported WGA-HRP was ob-

served in dorsal root afferent fibres in the dorsal horn 24- 48 hours after application to the saphenous nerve. As far as is possible to detect using light microscopy, both axons and terminals contained label. The reaction product was heavily concentrated in laminae I and I1 of the dorsal horn; the label in laminae 111-V was faint or absent. This preferential labelling of terminals in superficial laminae has been reported previously using this method (Brushart and Mesulam, '80; Woolf and Swett, '84; Seltzer and Devor, '84). The distribution of reaction product following WGA-HRP labelling of the saphenous nerve was examined in three different experiment groups: (1) control, unoperated rats (n = 51, (2) rats with unilateral sciatic nerve section at various times after birth (n = l), and (3) rats with unilateral sciatic nerve crush at birth (n = 6).

Normal saphenous nerve terminal distribution The normal pattern of saphenous nerve terminals in the

spinal cord was mapped with HRP in five rats: two aged 6 days and three aged 28-30 days. The distribution of terminals was exactly as previously described for the adult rat (Swett and Woolf, '85), as shown in Fig. 2A (left side). The area extended from caudal to the L3L4 junction to the L1/ L2 junction. It consisted of a long, narrow strip of label with well-defined borders positioned somewhat medially in the dorsal horn. As has been shown previously for the sciatic nerve (Fitzgerald and Swett, '831, there was no change in the terminal field area with increasing age of the animal.

The area taken up by the saphenous nerve label was measured and taken as a percentage of the total area of

CENTRAL SPROUTING AFTER NEONATAL NERVE INJURY 409

A r - - - - - - - - -1

L2

L3

250pm

/ - - - - - - - - \

Fig. 2. A. The distribution of saphenous nerve terminals in lamina 11 of the rat dorsal horn. WGA-HRP was taken up by the saphenous nerve 48 hours before perfusion on day 24. The distribution of HRP reaction product was mapped out in a horizontal plane from serial transverse (50-pm) sections. The black outline represents the medial and lateral boundaries of the lamina II gray matter. The central straight vertical line represents the midline. Segment boundaries are indicated. The stippled area represents the HRP-filled saphenous nerve terminal region. Left: the control area from

lamina 11 between the L1A2 junction and the L4A5 junction (see Methods). The mean value obtained for the five control maps was 19.2 f 1.1% (f S.E.). This is in very good agreement with the value obtained in adult rats by Swett and Woolf (‘85).

Saphenous nerve terminal distribution following neonatal sciatic nerve section

In nine animals the sciatic nerve was sectioned on one side on day 1 of life. At various times after this (day 6 (n = 3), day 28-30 (n = 3), and day 90 (n = 3)) the saphenous nerve on the same side was labelled with WGA-HRP and the saphenous terminal field in the dorsal horn mapped.

The distribution of label was found in all cases to be larger than that of control animals. The most noticeable change on first inspection was a medial spread of label such

an untreated rat. Right the area after the sciatic nerve was sectioned on day 1. B. Darkfield micrographs of 50-pm transverse sections through the mid-L3 dorsal horn showing saphenous nerve terminals. Only the dorsal quadrant is shown. Bright granular HRP reaction product can be seen in laminae I and 11 of the dorsal horn marking the position of the saphenous nerve terminal region. Scale = 100 pm. Top: a control, untreated rat. Bot- tom: the same area of cord but in a rat whose sciatic nerve had been sectioned on day 1.

that throughout much of the longitudinal distribution, terminal labelling reached right up to the medial edge of the dorsal horn. On reconstruction of the full area of label, it was clear that the area had also spread laterally into the central part of the dorsal horn and caudally, to end well into the L4 segment. This is illustrated in Figure 2A,B. There did not appear t o be a significant rostra1 spread of label. In individual transverse sections it could be seen that the dorsoventral distribution of label was unaltered. The edges of the saphenous terminal field were not as sharp as in control material but the borders of the labelling were still clear and easy to measure (Fig. 2B). The extent of the spread of the saphenous terminal field was as great in the day 6 rats as in the older rats. The mean value of the terminal field area was 39.7 + 1.1% of the total L2-L4 lamina II area (n = 9). This is over twice the control value. Considerable spread of central saphenous nerve terminals

410 M. FITZGERALD

into the sciatic nerve terminal region had therefore oc- curred following neonatal sciatic nerve section.

Critical period for sciatic nerve section It has been shown previously that such a spread of nearby

afferent terminals does not occur following sciatic nerve section in adult rats (Seltzer and Devor, '84). Here we tested at what age after birth sciatic nerve section ceases to trigger this spread. Sciatic nerve section was carried out on day 4 (n = 2), day 5 (n = 2), and day 10 (n = 2) and death was on days 28-32. Nerve section on day 4 still resulted in significant sprouting (mean terminal field area was 29.2%) although less than after day 1 section. If the section was performed on day 5, the effect was very small and not significant (mean terminal field was 21.3%; see Fig. 3). In rats whose sciatic nerve was sectioned on day 10 there was no spread of the saphenous terminal field at all on the treated side.

Contralateral terminal fields In two rats the sciatic nerve was sectioned on day 1 of

life, and then the contralateral sciatic nerve was labelled with WGA-HRP 48 hours before perfusion on day 24 (Fig. 4). The results show that the terminal field of the sciatic nerve on the opposite side to the section is completely normal. The area occupied was U-shaped, medially positioned,

Fig. 4. The distribution of the sciatic nerve terminals in lamina I1 of the dorsal horn of a day 24 rat. The sciatic nerve on the other side had been cut on day 1 of postnatal life.

-7 and extended from iust rostra1 to the L5h6 iunction to the L2L3 border, as has been described previo;sly (Swett and Woolf, '85). The saphenous nerve field normally "slots" into the space between the two arms of the U. Since the sciatic terminal field occupies a more caudal position than the saphenous nerve the area occupied was calculated as a percentage of the lamina I1 area between the L5L6 border and the L2h1 border. The mean value obtained was 49.6%, which agrees exactly with previous reports (Fitzgerald and Swett, '83; Swett and Woolf, '85). Clearly no spread of contralateral terminals occurs into the sectioned sciatic terminal field.

Sciatic nerve crush In six rats, the sciatic nerve on one side was crushed on

day 1. The saphenous nerves were then labelled with WGA- HRP before perfusion on day 6 (n = 3) and day 21 (n = 3). Considerable spread of the terminal field was seen in the dorsal horn, similar in pattern to that following complete section of the sciatic nerve (Fig. 5A,B). The spread was the same in the 6-day-old and 21-day-old rats, but was less extensive in all directions than that following sciatic nerve section. The mean area occupied by the saphenous nerve terminals was 30.5 1.3% (n = 6) of the total L2-L4 lamina II gray matter.

DISCUSSION The results confrm that the central saphenous nerve I 250pm terminals lie in a medial strip in the L2-L4 segments of

L - - - - - - - - I the spinal cord (Devor and Claman, '80) and occupy 19% of the available area in that reson (Swett and Woolf, '85). -

Fig. 3. The distribution of saphenous nerve terminals in lamina I1 of the dorsal horn of the spinal cord. The WGA-HRP label was applied to the saphenous nerve 48 hours before perfusion on day 28. Left: the control untreated side. Right the contralateral, treated side. The sciatic nerve ha;

The terminal labelling was concentrated in lamina 11 of the dorsal horn. mis appears to be a feature of WGA-mp labelling Of (Brushart and Mesu1am3 root

been sectioned on day 5 of postnatal life. '80; Woolf and Swett, '84). It may indicate preferential


A -i

transport by cutaneous C fibres which terminate exclu- sively in lamina I1 (Light and Perl, '79).

The precise termination pattern of saphenous nerve afferents was completely disrupted following early neonatal section of the sciatic nerve. The sciatic nerve innervates the lateral area of the hindlimb skin adjacent to the medial region innervated by the saphenous (Devor et al., '79). The central terminal fields are also adjacent. The terminal field of the sciatic nerve in the spinal cord forms a large U-shape spreading from L2 to L5 (Devor and Claman, '80; Fitzgerald and Swett, '83; Swett and Woolf, '851, and the saphenous nerve field slots exactly into the gap left between the two rostral arms of the sciatic U-shape (Devor and Claman, '80; Swett and Woolf, '85). Transection of the sciatic nerve at birth resulted in expansion of the area normally occupied by the saphenous nerve in a caudal, medial, and lateral direction, into regions normally occupied by terminals of the superficial peroneal, tibial, and sural nerves respec- tively (Swett and Woolf, '85). The absence of spread in a rostral direction shows that the expansion of the saphenous territory was specific and confined to those regions where the original afferent input was missing. The expansion did not fill the whole sciatic field but if one assumes that other adjacent peripheral nerves, e.g., from thigh and back skin (Devor and Claman, '80), expand comparably then the sciatic nerve field could be fully occupied by terminals from adjacent nerves.

The lack of overlap between terminal fields of cutaneous nerves in control material (Fitzgerald and Swett, '83) sug- gests that this expansion is not a result of failure to elimi- nate excessive neonatal connections but rather a result of sprouting of saphenous nerve terminals into the sciatic nerve territory. Although initially forming very precise connections (Killackey and Belford, '79; Smith, '83) dorsal root afferents are apparently capable of growing into inap- propriate target areas if the sites are vacated. The sprouting is triggered by crushing as well as cutting a nerve and is established at least 5 days after the nerve injury. The phenomenon has a "critical period" that does not extend beyond the first 4 days of life. Peripheral nerve section in adults does not produce sprouting of central nerve terminals (Stelzner and Devor, '84). In fact, recent evidence dem- onstrates that even dorsal root section in adults fails to produce sprouting (Rodin et al. '83). It does, however, occur following root section or hemisection in neonates (Kerr, '75; Stelzner et al., '79; Hulsebosch and Coggeshall, '83). Plas- ticity of connections is a feature of the developing nervous system and has been well described in, e.g., the hippocam- pus (Lynch et al., '73), the visual system (Weisel, '821, and the whisker sensory system (van der Loos and Woolsey, '73). Particularly relevant to the present study is the report that in neonatal hamsters, infraorbital nerve section results in redistribution of the mandibular nerve terminal field in the brainstem (Rhoades et al., '83).

The trigger for afferent sprouting in neonates is not clear. Immature neurons are well known to die as a result of severance from their peripheral field (see Lieberman, '74) and the section of the sciatic nerve on day 1 performed here would have resulted in considerable cell death in the dorsal root ganglia (DRG) as well as of motoneurones (Aldskogius and Riding, '83; Riding et al., '83). Infraorbital nerve section in hamsters at birth results in 80% C fibre and 75% A fibre loss (Math et al., '83) and Schmalbruch ('84) estimates that myelinated sensory afferent loss following sciatic nerve section in newborn rats is about two-thirds. The wroutine:

Fig. 5. A. The distribution of saphenous nerve terminals in lamina I1 of the dorsal horn of a 6-day-old rat pup. Left the control, untreated side. Right the sciatic nerve had been crushed on day 1 of postnatal life. B: A darkfield microPraDh of a 50-om transverse section through mid-L3 on the - . treated side. Scale = 50 fim. _ _ _..__. ._. _ ~ _ . _ _ . -. -

4r2 M. FITZGERALD

of nearby intact dorsal root afferents may therefore be triggered by the degeneration of sciatic nerve afferents and the release of unoccupied terminal regions in the dorsal horn. In addition there must be particularly favourable conditions in the neonate. Peripheral nerve section in adults causes, over months and years, atrophy and cell death in the DRG (Aldskogius and Arvidsson, '78; Janig and Mc- Lachlan, '84) and yet no afferent sprouting occurs (Devor and Claman, '80). The peripheral terminals of cutaneous af€erents also sprout in neonates after nerve section (Jack- son and Diamond, '83, '84) and high-threshold fibres maintain this ability throughout adult life (Devor et al., '79). It seems likely then, that the key to sprouting lies in the environment of the terminals and the considerable differ- ence in the CNS environment in immature and adult animals. DeafFerentation in neonates leads to more rapid and complete vacation of receptor sites with little retention of remnants and more importantly, little invasion of glia (Bakay and Westrum, '84). The environment may also be affected by the activity of dorsal horn neurons. The imme- diate postnatal period is a time when dorsal root afferents are elaborating their final termination patterns (Ramon y Cajal, '09; Scheibel and Scheibel, '68; Smith, '83; Fitzgerald and Gibson, '84) and more importantly, some of their target cells, the interneurones in lamina 11, are still maturing (Bicknell and Beal, '84), thus creating changing activity patterns in dorsal horn neurons (Fitzgerald, '85). The stim- ulus may also be chemical. Recently a neuronotrophic activity has been found in extracts of chick, rat, and human cord that peaks postnatally and is specific for sensory nerves (Lindsay and Peters, '84). Such a factor may be responsible for the sprouting observed here. If so, it is somehow able to override the normally very precise signals for separate nerve terminal fields that exist in the uninjured control animal.

The question remains as to what this sprouting of intact central terminals in response to peripheral nerve section in the neonate means to the developing animal. Do the sprouted terminals actually form physiologically function- ing synapses? If so, does the spread of adjacent input com- pensate for the denervated region? How does this affect sensory mapping in the CNS and reflex behaviour? In adult rat, peripheral nerve section while producing no central sprouting does result in changes in functional organization of dorsal horn cells and increased sensitivity of nearby deafTerented regions (Devor and Wall, '81; Markus et al., '84). The mechanism is thought to involve removal of inhib- itory processes in the dorsal horn (Wall, '85). It appears then that two different forms of plasticity can be induced by peripheral nerve injury depending on the age at which it occurs.

ACKNOWLEDGMENTS I am indebted to P. Ainsworth for her skilled histology

and to C.J. Woolf and P.D. Wall and S.B. McMahon for useful discussion and advice. The work was supported by the M.R.C.

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