EXPERIMENTAL

N’RUROLOGY

116,40-51

(19%)

Recovery of Function after Spinal Cord Hemisection in Newborn and Adult Rats: Differential Effects on Reflex and Locomotor Function ELLEN KUNKEL-BAGDEN, HAI-NING DAI, AND BARBARA S. BREGMAN ~e~rt~nt

of Anatomy and CeLl Siology, Georgetown University S&oaf of Medicine, W~~~~~a~

injury before the mature pattern of locomotion has developed results in a different motor strategy than after injury in the adult. The observation that locomotor patterns and motor strategies differ between newborn and adult operates suggests that the mechanisms underlying the recovery also must differ. 0 is92 Academic PWS, I~C.

It is often assumed that the response of the immature nervous system to injury is more robust and exhibits greater anatomical reorganization and greater recovery of function than in the adult. In the present experiments the extent of recovery of function after spinal cord injury at birth or at maturity was assessed. We used a series of quantitative tests of motor behavior to measure reflex responses and triggered movements and to examine different components of locomotion. Rats received a midthoracic “over-hemiseetion” at birth or as adults. The neonatal operates were allowed to mature and the adult operates were allowed to recover. The animals were trained to walk on a treadmill and to cross runways of varying difficulty. The animals were tested for reflex responses and triggered movements, videotaped while crossing the runways, and footprinted while walking on the treadmill. The adult operates had greater deficits in the reflex responses than the neonatal operates. The adult operates lost the contact placing response and had a decreased hopping response in the ipsilateral limb, while these responses were not impaired in the neonatal operates. Although the contact placing response in the neonatal operates was spared, a greater stimulus was necessary to induce the response than in control animals. In contrast, the neonatal operates had greater deficits in locomotion. Footprint analysis revealed that the animals’ base of support was significantly greater after the neonatal injury than after the adult injury, and deficits in limb rotation were larger in the neonatal operates than in the adult operates. Both groups crossed the grid with a similar number of steps but the adult operates made significantly more errors with the hindlimb ipsilateral to the lesion than the contralateral one, while the neonatal operates made an equivalent number of errors with both limbs. The neonatal operates took longer to execute the climb test and used a different movement pattern than the adult operates. The neonatal operates had a different locomotor pattern than the adult operates. Despite greater recovery of reflex responses after spinal cord injury at birth, the pattern of locomotion exhibits greater de&its when compared with the same lesion in the adult. Just as the anatomical consequences of injury to the developing nervous system are not uniform, similarly, the behavioral consequences are also not uniform. Spinal cord 0014-4886192 Copyright

$3.00 0 1992 by Academic Press, Al1 rights of reproduction in any form

INTRODUCTION

The response of the immature spinal cord to injury often exhibits a greater amount of anatomical reorganization than the same injury in the adult (6,7,10-13,27). Rerouting of late-developing pathways and a more robust axonal sprouting after neonatal lesions than observed after lesion in the adult contribute to this enhanced anatomical plasticity in the developing animal (&lo-14,27,28,52,59,62,66). Although it is generally assumed that the immature spinal cord responds to injury with greater anatomical plasticity, in fact, the response of particular spinal cord pathways varies. Concomitant with greater anatomical plasticity of some pathways, in other pathways the immature neurons are more vulnerable to injury (10,13,15,45,54). For example, injury to the immature rubrospinal pathway results in massive retrograde cell death of axotomized red nucleus neurons, while injury to the mature pathway results in neuronal atrophy and increased gliosis within the nucleus but little cell loss (15, 44, 54). Similarly, dorsal root axons are capable of robust sprouting after injury to the immature spinal cord but exhibit more restricted growth in the adult after injury (9,18,27,28,31, 32, 42,51, 61, 63). The unique response of a particular pathway to spinal cord damage may reflect the relative maturity of that pathway at the time of the damage (9, 10). Different spinal cord pathways are at different relative stages of development at birth in the rat and many continue to develop postnatally. The fibers of the corticospinal pathway, a late-developing pathway, enter and make synaptic contact within the spinal cord during the first 2 weeks postnatally (14,29, 33). Other pathways such as the rubrospinal, raphe-spinal and dorsal root projections are present at birth, but continue to mature post40

Inc. reserved.

LX. 20007

RECOVERY

OF

FUNCTION

natally (6, 8, 9, 42, 17, 50, 66). Coincident temporally with this anatomical maturation within the spinal cord is the maturation of many spinal cord reflexes and locomotion itself. The immature form of locomotion that the animals use at birth matures into the adult pattern postnatally (l&40,41,53). Therefore, both the anatomical and the functional development of locomotion take place postnatally. The greater anatomical plasticity in the young animal after spinal cord injury is thought to be associated with greater functional recovery, and the sparing of some motor functions after a lesion to the developing spinal cord is referred to as the infant lesion effect (lo-13,X, 56, 65). For example, reflex responses such as contact placing develop after a lesion to the immature spinal cord but are lost after injury in the mature animal (lo12, 53, 60). The development of contact placing is dependent upon the anatomical reorganization of the corticospinal pathway in the young animal after lesions at birth (10,13). Transection of the spinal cord in neonatal rats results in greater recovery of function than in older rats (60,64). A similar sparing of function after neonatal transection is seen in cats (20,56). The local development of the spinal cord continues in the absence of supraspinal control in the neonatal animal. In contrast, spinal cord injury in the older group, in which motor behavior is already under supraspinal control, results in loss of locomotor function. As the animal matures the spinal circuitry may become dependent upon descending influences. Furthermore, the spinal neurons caudal to the lesion may show altered development when deprived of descending input. Although descending control is removed permanently, there is some recovery of segmental locomotor function after transection of the spinal cord in adult animals (2) through alterations in the segmental circuitry caudal to the lesion. After partial lesions there are obviously fewer permanent deficits and greater recovery of function than after complete damage. After partial lesions of the spinal cord, reorganization of the remaining descending pathways, in addition to the reorganization of segmental circuitry, may also contribute to the recovery of function. After spinal cord damage in newborn and adult cats, Bregman and Goldberger (10,12) showed greater recovery of function in the neonatal operates in most, but not all, of the motor behavior examined. The cat spinal cord, however, is relatively developed at birth. The rat spinal cord is less developed at birth, and in keeping with the general hypothesis that earlier lesions lead to more sparing and recovery of function, the rat may be expected to show greater differences between adult and neonatal operates. In the present study we used quantitative and qualitative methods to assess reflex and locomotor function (40, 41). Previously the methods were used to demonstrate recovery of motor function after spinal cord injury at birth in the presence of fetal spinal

AFTER

SPINAL

CORD

INJURY

41

cord transplants (41). The methods test for specific reflex responses and motor functions and are sensitive to subtle differences in the pattern of locomotion and individual limb function. We compared the reflex and locomotor function of rats which received a spinal cord “over-hemisection” at birth with that of animals which received the same lesion as adults. Both the neonatal and adult operates were tested as adults. Thus, we have assessed the chronic status of motor behavior in each instance: the neonatal operates have matured and the adult operates have recovered fully from the initial effects of the lesion. We sought to determine if the consequences of spinal cord injury at birth on motor function in the rat were less severe than the same lesion sustained at maturity and to determine if the behavioral consequences of injury are uniform across a variety of behavioral tasks. METHODS

Spinal

Cord Lesions

Neonate. Sprague-Dawley rat pups (48 h postnatal, N = 23) were anesthetized by hypothermia. Under a dissecting microscope, the spinal cord was exposed by partial laminectomy at T5-T6. The dura was opened and iridectomy scissors were used to sever both dorsal columns plus the right lateral and ventral funiculus (over-hemisection). The site of the hemisection was covered with durafilm. The muscle and skin were sutured in layers and the wound was covered with a cyanoacrylate monomer (Nexaband liquid). Animals were warmed, received prophylactic injections of antibiotics (bicillin, Wyeth laboratories), and returned to their mothers. Unoperated control littermates (N = 13) were used and housed with the lesioned animals (10 pups per litter). At 4 weeks of age the animals were weaned and males and females were separated and housed 3-5 per cage in the animal care facilities under a 10114 h light/dark cycle. At 8 weeks of age the animals were trained and behavioral testing begun. In an early group of animals in this study, only some of the behavioral tests were examined. Thus, the number of animals used for each behavioral test varies. Adult. Male Sprague-Dawley rats (150-200 g, N = 30) were trained on the battery of locomotor tests prior to surgery, and measurements of their presurgical locomotor behavior were recorded. When training and presurgical testing was complete (after 3 weeks) the animals were anesthetized with chloral hydrate (400 mgl kg) and a right “over-hemisection” was performed as describedabove (N = 18). Sham-operatedanimals (laminectomy only, N = 7) and normal animals (N = 5) served as controls. Since the performance of the shamtreated animals was identical to that of the control group, these two groups were combinedin all data analy-

42

KUNKEL-BAGDEN,

sis. The animals were returned to the animal facilities and allowed to recover for 4 weeks. Thus, these studies assess a stable pattern of motor behavior in the adult operates after they have recovered fully from the initial effects of the lesion. At the end of the recovery period the rats were retrained and behavioral testing was begun again. The additional training was necessary to ensure optimal behavioral performance. Three adult lesioned animals damaged their hindlimbs and were eliminated from the study. Tests of Reflex Function Placing. The ability of the animals to place the hindlimb onto a surface for support in response to proprioceptive and to contact stimuli was recorded. The normal placing response involves flexion of the limb to clear the edge of the surface and subsequent extension and placement of the foot onto the surface. The contact stimulus was measured by a force transducer and recorded with a Grass polygraph. Each hindlimb was tested in both the forward (dorsal surface stimulated) and the lateral direction (lateral surface stimulated). The presence or absence of the placing response after each stimulus was recorded. The percentage of contact or proprioceptive stimuli that induced a placing response was determined. Hopping. The monopedal hopping response was tested in the lateral direction for the left and right hindlimb using a treadmill (9 m/min). The animals were held gently with all limbs restrained except the one being tested. The hopping response was induced by the movement of the treadmill which displaced the animal’s hindlimb, so that the animal was no longer over its base of support. In response to this displacement, the animal lifts the limb and replaces it under its center of gravity for support. The excursion of the limb (distance) was recorded by inking the footpad and measuring the distance between prints. Behavioral Training

Animals were trained to cross the runways, climb the platform, and walk on the treadmill for a water reward. During the &day training period, animals received water (12 ml/day) only after each runway crossing or while walking at the speed of the treadmill. Once the rats were trained, they were allowed free access to additional water at the end of the testing session for 15 min daily. Animal weights were monitored and all animals received supplemental water if weight loss in any animal was noted. After training for 5 days on each of the tests all animals were able to perform the tasks. All the animals were trained and tested by observers unaware of the animal’s surgical treatment. All animals were trained and tested under similar conditions. The size of the animals at the time of test-

DAI, AND BREGMAN

ing, however, differed between the two groups. The mean weight of the neonate animals was 431 g, while the mean weight of the adult animals was 583 g. Individual comparisons were made between the lesioned animals and control animals of the same size within each group. The training of the animals in the adult group also differed somewhat from the animals in the neonate group. The adult animals were trained and tested (3 weeks) before surgery to obtain data on their preoperative performance, while the neonate animals obviously could not be trained preoperatively. The training sessions (5 days) included several days for the animals to learn the task, followed by several additional days to ensure that the animals’ performance was consistent and to the animals’ maximum ability. The spinal cord surgery interfered with the animals’ ability to perform the tests, and therefore it was necessary for all animals to be trained again after surgery. Although the adult operates were trained before surgery during the 3-week preoperative testing session, additional training after surgery was necessary to ensure consistent performance. Locomotion

The methods used were identical to those used in our previous studies and are explained in detail elsewhere (41). Grid. The animals were trained to cross a grid runway 180 cm long with 50 X 50-mm holes. After 5 days of training the animals were videotaped while crossing the runway for an additional 5 days (4 crossings/day). The number of forelimb steps to cross the runway and the number of hindlimb errors (footfalls through the grid holes) were determined from slow motion analysis of the videotapes. Footprints. Animals were trained for 5 days to walk at the speed of the treadmill (11 m/min). The animals fore- and hindpaws were inked and the footprints were recorded on paper covering the treadmill (41). The base of support (the distance between the central pads of the hindfeet), stride length, and individual hindlimb rotation were measured. Climbing test. Animals were trained to climb onto a platform (illustrated in Fig. 1) for a water reward. The hindlimb placed on the platform first was noted. Animals were tested for 3 consecutive days with three trials each day. analysis of the data Statistical analysis. Statistical was performed using the Dynastat Professional (Dynamic Microsystems, Incorporated, Washington, D.C.) statistical software package for multiple analysis of variance. The influence of age of the animal at the time of the lesion on performance of each of the tests was analyzed with a two factor ANOVA (age X lesion). Individual comparisons were made with Tukeys protected t tests (only upon observing a significant age X lesion interaction). Differences between the left and right

RECOVElRY

OF

FUNCTION

AFTER

SPINAL

FIG. 1. Animals were trained to climb onto the platform for a water reward. places 1them onto the surface. This rapid axial movement is disrupted in animals

hindlimbs were assessed with a three factor ANOVA (age X lesion X hindlimb). Lesion Analysis

At the completion of behavioral testing the animals were deeply anesthetized (chloral hydrate 1000 mg/kg, ip) and perfused intracar~ally with 0.9% saline followed by 4% paraformaldehyde in 0.1 h4 phosphate buffer at pH 7.4. Serial transverse l&pm cryostat sections were stained with cresyl violet. A microprojector and a Zeiss microscope were used to reconstruct the lesion site. At the maximum transverse extent of the lesion, the extent of damage was qualitatively compared between animals. The rostral/caudal extent of the lesion was calculated from the lesion reconst~ctions.

CORD

43

INJURY

A normal animal after a hemisection.

lifts

both

hindlimbs

simultaneously

and

column on the left and the entire right side except a very small portion of the ventral funiculus. Animals with lesions outside these limits were eliminated. In the neonatally lesioned group 14 of 23 animals met the lesion criteria for inclusion in the behavioral analysis. Of the 15 adult lesioned animals initially prepared, 8 met all of the lesion criteria for inclusion in the behavioral analysis. Representative transverse sections at the maximum site of the lesion from an adult (b) and a neonatal (a) oper-

RESULTS Spinal Cord Lesions

Lesions were defined as being within maximum and minimum limits (Fig. 2). The maximum lesion included was the entire right side of the cord plus on the left the dorsal column, portions of dorsolateral funiculus, intervening gray matter, and a small portion of the ventral funiculus. Minimum lesions included loss of the dorsal

Maximum

Minimum

FIG. 2. The maximum and minimum transverse extent of the lesion for animals included in the behavioral analysis are illustrated on standard diagrams of the cord. See text for explanation of criteria used to determine maximum and minimum limits of the lesion.

44

KUNKEL-BAGDEN,

DAI,

AND

BREGMAN

a FIG. 3. Photomicrographs of transverse sections at the maximum extent of the lesion a representative neonatal operate (a) and adult operate (b). The lesion included the entire left side. The lateral funiculus (LF) andventral horn (VH) are indicated on the left. Gliosis, operates, but is not present in the neonatal operates. Bar = 1 mm.

ate are illustrated in Fig. 3. The “over-hemisection” lesion results in greater damage on one side (referred to, for convenience, as the ipsilateral limb). The difference in size between the representative sections reflects the larger size of the adult operates (mean weight = 583 f 20 g) compared to the neonatal operates (mean weight = 431 +- 23 g). Qualitative examination of the lesion sites revealed that there was no systematic difference in the transverse extent of the lesion between the two groups. The rostrocaudal extent of the lesion was, however, longer after a spinal cord lesion at birth compared to a lesion in the adult. The length of the lesion site of the neonatally lesioned animals was twice as long as that of the adult lesioned animals (ADULT = 4 +- 1.2 mm, NEONATE = 8 f 1.6 mm). Reflex Responses Monopedal hopping. The hopping response was permanently impaired in the adult operates, but not in the

taken from serial sections through the lesion site of right side of the cord and the dorsal column on the indicated by the arrowheads, is evident in the adult

neonatal operates. Qualitatively, the hopping response in the adult operate was characterized by an increased threshold to elicit the response. In the neonatal operates, the displacement to elicit the response was similar to that observed in control littermates, although the execution of the response in the neonatal operates displayed hypermetric flexion. Quantitative analysis indicated that there was a significant decrease in the distance the adult lesioned animals hopped with the limb ipsilateral to the lesion compared to control animals (Fig. 4). Two-way ANOVA showed a significant interaction between age and lesion (F,,, = 10.4, P c 0.01) in right hindlimb hopping. Comparisons of the groups indicated a significant decrease in the distance the adult lesioned animals hopped with the limb ipsilateral to the lesion (right) compared to control animals (Fig. 4; CON = 63.6 f 1.7 mm, HX = 54.8 1?11.9 mm; P < 0.01). There was no change in the distance the adult lesioned animals hopped with the limb contralateral to the lesion (left)

RECOVERY 80

OF

FUNCTION

T

AFTER

SPINAL

CORD

45

INJURY

z 100 g 5 ‘& 80

70-c

z! ?j 0

60

E 5

40

Y ;

20

4 R

30CON

HX

CON

I-IX

m CON ES3 HX

0

FLFL

FLFL

LEFT RIGHT IST

NEONATE

ADULT

FIG. 4. The mean (+SEM) distance the animals hop with their right hindlimb. The distance traversed by the hindlimb during a hopping response was not altered by a neonatal hemisection (CON, N = 6; HX, N = 6). Hemisection in the adult animals impaired this response. The adult animals after a hemisection hopped a significantly shorter distance than the control animals (CON, N = 12; HX, N = 8). Asterisk indicates means which are significantly different (P < 0.01).

compared to control (CON = 70.5 f 2.8 mm; HX = 67.4 -t 4.2 mm). The hopping response in the neonatal operates was similar to the control animals with both hind limbs (Fig. 4; ipsilateral: CON = 59.2 + 3.4 mm, HX = 64.6 f 1.8 mm; contralateral: CON = 58.1+- 2.2 mm, HX = 64.7 f 1.8 mm). Placing responses. Proprioceptive placing responses were impaired and recovered in both neonatal and adult operates. Contact placing responses develop postnatally; thus, they were not present at the time the neonatal spinal cord lesion was made. The development of contact placing responses has been associated with the maturation of the corticospinal pathway (1, 13, 19). Contact placing responses were spared in all of the animals which received a spinal cord lesion at birth. Contact placing was abolished in animals following spinal cord lesion in the adult as in previous studies (1,13,19). In most of the adult operates, contact placing failed to recover, but in a few adult lesioned animals contact placing responses could be elicited. These animals were the ones with the largest lesions, involving the contralatera1 lateral funiculus. This may represent the release of spinal stepping from descending inhibition. In adult cats, contact placing is abolished by spinal cord hemisection, but reappears after a subsequent lesion to the contralateral side of the spinal cord (Helgren and Goldberger, unpublished results). The percentage of animals within each group that had contact placing responses for each direction is illustrated in Fig. 5. A contact placing response was considered present when the animal responded to greater than 30% of the light contact stimuli with a placing response. In control animals, contact placing responses were almost always present with both hindlimbs and in both

FLFL RIGHT

FLFL

LEFT RIGHT LEFT RIGHT

ADULT

NEONATE

FIG. 5. Contact placing response. Percentage of animals in each treatment group that had contact placing responses in either the forward (F) or lateral (L) directions with the left or right hindlimb. The neonatal operates (HX, N = 9; CON, N = 7) developed contact placing responses. Placing responses with the left limb in the forward direction developed in all the animals, and in the lateral direction in most of the animals. Fewer animals developed placing responses with the right limb in either direction. Only a few placing responses could be elicited in the adult operates (HX, N = 8; CON, N = 11).

forward and lateral directions. In the neonatal operates, greater sparing of contact placing responses was seen in the left hindlimb than in the right (Fig. 5). The occasional appearance of contact placing responses in the adult displayed no limb or directional prominence. Although contact placing was spared following neonatal spinal cord lesion, the response was not normal. The mean force (grams) necessary to induce the contact placing response in neonatal lesioned animals was greater than that in the control group (Table 1; F7,40 = 8.1, P < 0.0001). It was difficult to quantify the force necessary to induce contact placing in the adult, since there were so few responses. When all of the placing responses from the adult lesioned animals were combined, however, the mean force to induce a contact placing response in the adult appeared similar to that in control animals (5.9 g ADULT HX; 5.6 g CON).

TABLE Force

(in

1

Grams) Necessary to Elicit Placing ResDonses

Contact

CON Left Forward Lateral

2.6 f 0.1 2.2 I!z 0.2

HX Right 2.4 3~ 0.2 2.9 + 0.4

Left

Right

4.0 k 0.4* 4.8 iz 0.4*

4.8 f 0.6* -

Note. Values shown are means + SEM of neonatal placing responses in Fig. 5. * Significantly different than control (P < 0.01).

operates

with

46

KUNKEL-BAGDEN,

DAI,

AND

BREGMAN

200 lGEl

160--

CON HX

T 5

160--

ti f Iii E

140-120-looCON

HX

NEONATE

CON

NEONATE

HX

LEFT

ADULT

FIG. 6. Stride length. Mean (+SEM) distance between consecutive right hindlimb footprints. Similar measurements were obtained with the left hindlimb (data not shown). Hemisection decreased the stride length similarly in the neonatal and adult operates. Analysis of variance indicated a significant effect of the lesion (Fi,37 = 25.1, P < 0.0001 indicated by the asterisks) and an effect of age on stride length (F,,, = 37.7, P < 0.0001). Stride length increases with animal size; the difference in stride length between the control animals of both groups reflects the larger size of the adult animals at the time of testing.

Locomotion Footprint analysis. Although locomotion is initially impaired after spinal cord injury in the adult, both overground and treadmill locomotion recover. Some quantitative deficits in the pattern of locomotion persist permanently, however. Locomotion develops postnatally in the rat. Locomotion develops after spinal cord injury at birth, but permanent quantitative deficits in locomotion persist. The pattern of locomotion was more similar to normal in adult lesioned rats than in those lesioned at birth. In both neonate and adult operates, there was a permanent significant decrease in stride length (Fig. 6) and an increase in contralateral limb rotation (Fig. 7). In the neonatal operates, but not in the adult operates, there were bilateral deficits in limb rotation and a significant increase in base of support (Fig. 8). The hemisection decreased the stride length similarly in both the neonate and adult operates (Fig. 6; Fl,37 = 26.7, P < 0.0001). Limb rotation was also altered by the hemisection in both the neonatal and adult operates. The neonatal operates rotated their ipsilateral (right) limb more medially than the control animals (Fig. 7; CON = 96”, HX = 89’, P < 0.05) and their contralateral (left) more laterally (CON = 98”, NEONATE HX = 105”, P < 0.01). In animals which received a hemisection as adults only contralateral (left) limb rotation was significantly different compared to the control group (Fig. 7; CON = 97”, HX = 103”, P < 0.0001). Hemisection in the neonate animals resulted in a significant increase in the animals’ base of support (Fig. 8; HX = 48 f 2.3 mm, CON = 37 f 2.4 mm, P < 0.01) similar to previous re-

ADULT

NEONATE

ADULT

RIGHT

FIG. ‘7. Individual limb rotation. Mean (+SEM) measurements of right (ipsilateral) and left (contralateral) hindlimh rotation. Both the neonatal and the adult operates rotated their left limb more laterally than the control animals (P < 0.01; ADULT: CON, N = 12; HX, N = 7; NEONATE: CON, N = 13; HX, N = 9). The neonatal operates rotated their right foot more medially than the control animals (P < 0.01).

ports (41). In contrast, the base of support in adult lesioned animals was not significantly different than the control animals (Fig. 8; HX = 42 + 2.9, CON = 41 f 1.2). Four animals of the fourteen neonatal operates developed a pattern of locomotion completely different than the other animals. The base of support was very narrow (30.5 + 5.2 mm) and both limbs rotated medially (left: 86.1” f 3.6”; right: 88.6” f 3.6”). These animals were not included in the data presented. This pattern was not seen in any of the adult operates. Grid. The control animals crossed the grid rapidly and made only a few errors (footfalls through the grid 60 Y &

T

CON

HX

NEONATE

CON

HX

ADULT

FIG. 8. Base of support. Mean (+SEM) distance between the hindlimbs for each group. The base of support was significantly larger in animals with a neonatal hemisection than in control animals (P < 0.01; NEONATE: CON, N = 13; HX, N = 9). The base of support in the adult group was similar in the control animals and animals with a hemisection (ADULT: CON, N = 12; HX, N = 7). Asterisk indicates a significant difference between the means (P c 0.01).

RECOVERY

OF

FUNCTION

AFTER

SPINAL

25-r

CORD

47

INJURY

100 1

& K -

80

II

60

L

0

t .A’ .

t

5

2

M

CON

HX

CON

HX

FIG. 9. Grid: Steps to cross. The mean (+SEM) number of steps the animals took to cross the grid runway. Animals with a hemisection in both groups took significantly more steps to cross the grid runway (F,,, = 56.0, P < 0.0001 indicated by the asterisks).

holes) while crossing. Both neonatal and adult operates took longer to cross the grid than the control animals and made many errors while crossing the grid. After the hemisection both the neonatal and adult operates took significantly more steps to cross the grid than the control animals (Fig. 9; Fl,43 = 56.4, P < 0.0001; NEONATE: HX = 20 steps vs CON = 14 steps; ADULT: HX = 17 steps vs CON = 12 steps). Both the neonatal and adult lesioned animals made errors with their hindlimbs while crossing the grid (Fig. 10). A three-way ANOVA with hin~imbs, lesion, and age as factors indicated interac-

D IPSILATERAL lS9l CONTRALATERAL

I

10

0123456789 ERRORS

/CROSSING

A BOTH

ADULT

11

(180chi)

FIG. 10. Grid: Errors. The mean (+SEM) number of errors (footfalls into the grid holes) by the hindlimb ipsilateral (solid bars) and contralateral (hatched bars) to the lesion of each of the groups. The adult operates (N = 8) made significantly more errors than the neonatal operates (N = 14) with the ipsilateral hindlimb (P < 0.01, indicated by one asterisk; CON: NEONATE, N = 13; ADULT, N = 12). The adult operates made significantly more errors with the ipsilateral limb than the contralateral (P < 0.01, indicated by two asterisks). The neonatal operates made a similar number of errors with both hindlimbs.

‘.

..

.+.

..

;:?,

‘_

'. ., “A

“..

201 0

NEONATE

..t

‘.

_’ .*_-.:. .._.

40

i

;’ -.

+

‘8::. LEFT

:: : . j .

I 80

NEONATE

HX

ADULT HX CONTROL

RIGHT

FIG. 11. Climb. Mean percentage of the trials that the animals in each group placed either both hindlimbs onto the platform simultaneously or placed the left or right hindlimb onto the platform first. The control animals from each group placed both hindlimbs simultaneously onto the platform. The adult hemisected animals (N = 5) were able to place both limbs onto the platform simultaneously, similar to the control animals (N = lZ), but also placed their left limb onto the platform first in many of the trials. The animals that received a hemisection as neonates (N = 6) never placed both limbs onto the platform simultaneously like the control animals (N = 6), and usually placed their left hindlimb onto the platform first.

tions between lesion and hindlimb (F1,86 = 11.7, P < 0.001) and age and hindlimb (Fl,8, = 6.6, P < 0.05). The neonatal lesioned animals made many errors with both the right and left hindlimbs compared to the control animals (Fig. 10; ipsilateral: HX = 6, CON = 0.4; contralateral: HX = 5, CON = 0.2). The adult lesioned animals made significantly more errors with their ipsilateral hin~imb than their contralateral hin~imb (Fig. 10; P < 0.01; ipsilateral HX = 9; contralateral HX = 4). Post hoc comparisons also indicated that the adult lesioned animals also made significantly more errors with their ipsilateral limb than the neonatally lesioned animals (P < 0.01). The total number of hindlimb errors made (ipsilatera1 plus contralateral) was similar for the neonatal and adult operates (NEONATE: 10.4 +- 1.1 and ADULT: 12.7 -1- 2.3), but the neonatal operates took a greater number of steps to cross than the adult operates. CZinb. The control animals climbed onto the platform by lifting both hin~imbs together from the suspended position with a rapid movement of their hips, so that both limbs landed almost simultaneously. Qualitatively, after a hemisection the adult lesioned animals either climbed onto the platform in a manner similar to the control animals using both hips to lift their hindlimbs onto the platform (N = 5) or they were unable to climb onto the platform (N = 3). In contrast, the animals that received the neonatal spinal cord hemisection used their individual hindlimbs rather than their hips to pull themselves onto the platform (N = 6) or they were unable to lift themselves up onto the platform (N = 1). The quantitative analysis of which limb was placed onto the platform first is presented in Fig. 11. The adult le-

48

KUNKEL-BAGDEN,

sioned animals were able to place both hindlimbs together onto the platform simultaneously (32% both limbs) similar to the control animals (79% both limbs), but also frequently placed the left limb on first (47% left limb). The neonatal operates placed either the left (63%) first or right (33%) first but not both together (4%). All the animals that received a spinal cord hemisection took longer to place their limbs onto the platform compared to the control animals (F1,25 = 6.6, P < 0.05; NEONATE: HX = 3.6 -t 1.8, CON = 0.7 + 0.1; ADULT: HX = 1.7 f 0.3, CON = 0.7 f 0.03). DISCUSSION

An “infant lesion effect” has often been observed following CNS lesions during development. The results of CNS damage at birth are often less severe than following similar injury in the adult (4,10-13,36,37,53,56-58, 60,65). Some investigators, however, have failed to observe an infant lesion effect and found deficits equal in adult operates and neonatal operates (22,34,35,48,49, 53) or even that the neonatal operates had greater deficits (13,38,39,57). In the current study we found that the behavioral consequences of early CNS lesions are not uniform. Although the neonatal operates had fewer deficits in reflex function than the animals injured as adults, in the tests of locomotion, greater deficits were evident in the neonatal operates than in the adult operates. One major finding of this study is the observation that both the basic locomotor pattern and the motor strategy used to accomplish more complex motor tasks differ between newborn and adult operates. This suggests that the mechanisms underlying the recovery also must differ. Differences between adult operates and neonatal operates may be explained by the stage of development of the behavior at the time of the lesion. At birth, locomotion in the rat is immature (40, 53). Spinal cord injury in the adult interrupts the descending control of locomotor patterns which have already developed. Spinal cord injury at birth, in contrast, interrupts the descending control of locomotor patterns during their development. Spinal cord injury at birth may prevent the development of the adult pattern and the immature locomotor pattern may persist, or a novel pattern of locomotion may develop. Deficits in the neonatal operates may reflect arrested development. For example, in the current study, a normal pattern of locomotion failed to develop in the animals lesioned at birth, and our results suggest that characteristics of the immature pattern persist. Footprint analysis at 2 weeks of age indicates that both control animals and animals which received a spinal cord hemisection at birth have a similar locomotor pattern, characterized by a wide base of support and a large amount of lateral limb rotation (Kunkel-Bagden and Bregman, unpublished results). As the normal ani-

DAI, AND BREGMAN

ma1 matures, both the base of support and the limb rotation decrease ((40,41) and current study). As the animals with a neonatal spinal cord lesion mature, however, a locomotor pattern with a wide base of support and large amount of limb rotation persists ((40,41) and current study), suggesting that the immature pattern persists after spinal cord damage at birth. More complex motor function, such as locomotion (and presumably the spinal pattern generator for locomotion) are immature at birth. They may require normal descending input for their maturation. The descending and afferent pathways remaining after spinal cord hemisection at birth are not sufficient for their maturation. When the spinal cord injury occurs in the adult animal, after the mature form of locomotion has already developed, deficits in locomotion are apparent initially after the injury. However, a locomotor pattern similar, but not identical, to that of the control animals subsequently recovers. The more normal pattern of locomotion which recovers after spinal cord hemisection in the adult may reflect the mature function of the spinal pattern generator (30) for locomotion under the control of remaining descending and afferent control. Previous studies have demonstrated that after spinal cord deafferentation in cats, the ipsilateral descending pathways mediate recovery of locomotion, but the recovery is characterized by abnormal kinematic locomotor patterns (23,24). When one dorsal root is spared, however, the normal kinematic motor pattern recovers, and in this case, the spared root and not the descending pathways is responsible for maintaining the recovery of function. Thus, different pathways mediate different patterns of motor behavior. One would predict, in the current study, that the kinematic pattern of limb usage also differs between newborn and adult operates, if different pathways mediate recovery in the adult and development in the neonate. The anatomical projections to the spinal cord are also immature at birth. Different spinally projecting pathways are at different relative stages of their development at birth, thus the response of different pathways to the lesion will not be uniform (9). The differences in the behavioral consequences of injury in the current study may reflect these differences in the anatomical response of particular pathways to lesions at birth. For example, corticospinal fibers have not yet reached midthoracic levels of the spinal cord at birth. Spinal cord injury at birth interrupts the terrain over which these axons would grow, but does not damage them directly. These late-growing axons are able to grow around the site of a spinal cord over-hemisection to reach normal targets (5, 10, 13, 14, 59). In contrast, brain stem-spinal pathways such as rubrospinal, coeruleospinal, and raphespinal axons are axotomized by spinal cord damage at birth and undergo massive retrograde cell loss (6-10,13,15,21,54). It seems likely that

RECOVERY

OF FUNCTION

AFTER

this cell loss could contribute to permanent impairments after injury at birth. The dorsal root projections to the spinal cord are relatively mature at birth (21), survive axotomy of their central process (9,16,31), and sprout in response to injury at birth or in adulthood (25, 28, 32,42, 47). A similar spinal cord injury in the adult interrupts the descending pathways, and they fail to regrow beyond the lesion site. They are unlikely, therefore, to contribute to recovery of function after injury in the adult. Mature neurons do not undergo massive retrograde cell loss after axotomy; although they do not grow beyond the site of injury, they may be in a position to contribute to recovery of function indirectly by sprouting of collaterals (23-27,46). Cells remain in the adult which do not in the neonate and may contribute to recovery. This may explain why adult operates do better than neonatal operates in some tasks. For example, the rostrocaudal extent of the lesion was always greater in the neonatal operates than in the adult operates. This suggests a greater loss of propriospinal neurons in the neonatal operates. This greater loss of propriospinal neurons may contribute to the greater deficits in the neonatal operates, perhaps through a greater loss of segmental and intersegmental control of locomotion. This loss of propriospinal neurons in the neonatal operates may also contribute to the greater prevalence of bilateral impairment following lesion at birth than in the adult ((13) and current study). The greater retrograde cell loss after CNS lesions at birth may contribute to the greater behavioral deficits in some aspects of motor function. The greater preservation of both propriospinal and descending neurons after lesions in the adult may contribute to the greater recovery observed in the complex motor tasks. Usually, greater reflex recovery leads to greater recovery of more complex movement patterns (23, 24), as it does during normal development (11). In the current study, however, this appears not to be uniformly apparent. After spinal cord injury in the adult animal, the persistent deficits in reflex function are more severe than after injury at birth. For example, there are permanent deficits in the hopping response after injury in the adult, whereas after lesion at birth, performance is similar to that in control animals. This is similar to earlier studies (l&12,53), in which permanent deficits in hopping after spinal cord injury in the adult were more severe than after the same injury at birth. Lesions in the adult resulted in an increased limb displacement required to elicit the hopping response, compared to neonatal lesioned animals. After lesion at birth, the threshold to elicit a hopping response was similar to that in the normal animal, although the execution of the response was hypermetric. Another reflex that shows greater sparing in the neonatal operates is the placing response. Contact placing is a late developing response. After spinal cord hemisection at birth, low threshold placing de-

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CORD INJURY

49

velops, although the threshold for the placing response is increased compared to that in control animals. Contact placing is abolished immediately after the injury in the adult rat. Although an occasional placing response to low threshold stimulus eventually recovers in some adult lesioned animals, there is a permanent and significant impairment of low threshold placing responses. After spinal cord hemisection in cats, contact placing was spared after lesions at birth (10, 13). The spared placing response was dependent upon the anatomical rerouting of the corticospinal pathway (13). After spinal cord hemisection in adult cats, low threshold placing responses were abolished permanently. Low threshold placing is also more impaired after transection in the adult than in the neonate (56). After neonatal cortical damage at birth, the contralateral hemisphere mediates some aspects of recovery of forelimb visual and vibrissal placing responses, by way of an aberrant ipsilateral corticospinal projection (3). It is therefore likely that the partial sparing of placing seen in the neonatal rat is mediated by the growth of corticospinal axons around the lesion. In summary, despite greater recovery in reflex control after lesions at birth, compared to the adult, both the basic locomotor pattern and the motor strategy used to accomplish more complex motor tasks differ between newborn and adult operates. This suggests that the mechanisms underlying the recovery also must differ. The effect of neonatal spinal cord lesion on the development and recovery of motor function is not uniform. We suggest that the greater anatomical reorganization in some particular immature pathways may contribute to the greater recovery of individual limb responses following spinal cord injury at birth. This anatomical plasticity is unable to compensate fully, however, for the loss of descending input during development. After spinal cord injury at birth, an immature pattern of locomotion persists, despite greater recovery of individual limb movement. The more normal pattern of locomotion which recovers after spinal cord hemisection in the adult may reflect the mature function of the spinal pattern generator for locomotion under the control of remaining descending and afferent control. ACKNOWLEDGMENTS This work was supported by NIH Grants NS 27054, NS 19259, and Research Career Development Award (NS 01356) to B.S.B. and in part by a grant from the American Paralysis Association. We are extremely grateful to Dr. Michael E. Goldberger for his helpful comments and suggestions on an earlier version of this manuscript. We thank Marietta McAtee and Florence Chrusciel for their technical assistance and Laurie Tibbetts for assistance in manuscript preparation.

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Recovery of function after spinal cord hemisection in newborn and adult rats: differential effects on reflex and locomotor function.

It is often assumed that the response of the immature nervous system to injury is more robust and exhibits greater anatomical reorganization and great...
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