Relationship between dendritic pruning and behavioral recovery following sensorimotor cortex lesions

doi:10.1016/S0166-4328(98)00030-8

Behavioural Brain Research

Volume 97, Issues 1–2, 1 December 1998, Pages 89-98

https://doi.org/10.1016/S0166-4328(98)00030-8 Get rights and content

Abstract

A unilateral injury to the forelimb area of the sensorimotor cortex results in an increase in dendritic arborization in the contralateral homotopic cortex which is followed by a pruning back of these dendritic arbors. The increase in arborization is due to an increase in the use of the unimpaired forelimb for postural-motor support; whereas, the dendritic pruning is related, in time, to the return to more symmetrical limb use, but is not prevented by the maintenance of asymmetrical limb use. Dendritic pruning can be prevented by administering an NMDA receptor antagonist (such as MK801 or ethanol) during the pruning phase. This manipulation also coincides with the chronic reinstatement of behavioral deficits. The purpose of this study was to see whether removing the antagonism of the NMDA receptor results in the eventual return of dendritic pruning and behavioral recovery. Therefore, MK801 was administered to lesioned animals starting at post-lesion day 18. One group received MK801 injections until day 60 (Lesion+MK60) and another lesioned group received MK801 until day 30 after which the injections were changed to saline until day 60 (Lesion+MK30). Lesion+MK60 animals showed a prevention of dendritic pruning as well as a chronic reinstatement of forelimb deficits. Lesion+MK30 animals also showed a prevention of dendritic pruning, however, they showed behavioral recovery. These findings suggest that pruning of dendritic arbors may not be directly related to behavioral recovery.

Introduction

Over the years an increasing number of studies have shown that neural plasticity can occur in the adult brain under a variety of different conditions: changes in environment 15, 45, learning 5, 6, 14, deafferentation 10, 24, 33, 34, 35, 39and neural injury [25]. Recently, our laboratory has also shown neural plasticity in adult animals in response to neural injury. Unilateral injury (via an electrolytic lesion) to the forelimb representation area of the sensorimotor cortex (FL-SMC) results in an increase in dendritic arborization of layer V pyramidal neurons of the contralateral, homotopic cortex which is maximal at day 18 post-lesion [21]. This morphological event is linked to the behavioral over-reliance of the animal on the unimpaired forelimb for support during postural-motor behaviors 21, 27, 29, 30. Dendritic growth is followed by a subsequent decrease or a ‘pruning’ back of dendrites to pre-injury levels which occurs between days 18 and 45–60 post-lesion 21, 22, 23, 27, 30. Although the dendritic pruning is temporally related to a reduction in asymmetrical limb-use, it does not appear to be driven simply by a return to more symmetrical limb use. When animals with a FL-SMC lesion are forced to continue to use only the ipsilateral forelimb during the pruning phase (by immobilizing the contralateral forelimb with a plaster of paris cast), the normal course of neuromorphological changes remains unaltered. That is, the pruning occurs despite an ‘artificial’ prolongation of behavioral asymmetry [22].

Dendritic pruning is sensitive to pharmacological manipulation. The NMDA receptor antagonist MK801 [27]or ethanol [30]administered during the pruning period in rats with a unilateral FL-SMC lesion, prevented the elimination of dendritic arbors of cortical layer V pyramidal cells in the contralateral, homotopic area of the cortex (examined at post-lesion day 45). In unlesioned animals, MK801 or ethanol administration did not result in behavioral deficits nor did it affect the morphology of layer V pyramidal neurons 27, 30. These studies also revealed that blocking dendritic pruning was associated with the reinstatement of severe impairments in placing behaviors and measures of postural motor asymmetries which did not recover to sham levels (when measured during the 45 days post-lesion) as did lesioned animals that did not receive the drug.

It is unknown whether blockade of the NMDA receptor via MK801 for a limited amount of time during the pruning period is sufficient to cause chronic changes in dendritic morphology and behavioral function. This study was designed to determine whether a brief administration of MK801 during the early pruning period (days 18–30), was sufficient to permanently maintain the increase in dendritic arborization and impaired behavioral function. Or, on the other hand, would this transient pharmacological blockade result in eventual dendritic pruning and behavioral recovery once the drug administration ceased and the animals allowed to survive for another 30 days. The design of this study also provided a means by which to examine the relationship between dendritic pruning and recovery of function following injury.

Section snippets

Subjects

Fifty-two male, hooded Long-Evans rats weighing between 400 and 600 g were used. Rats were individually housed in clear Plexiglas cages with wire bottoms and maintained on a 12:12 h light/dark cycle. Food and water was available ad libitum. Animals were tamed by gentle handling for at least 5 min/day for 3–4 weeks prior to surgery and behavioral testing.

Surgical procedures

A unilateral injury to the forelimb representation area of the sensorimotor cortex (FL-SMC) 17, 37was performed as described previously 21, 22,

Lesion volume

MK801 did not affect the size of the lesion as demonstrated by stereological estimates of volume using Cavalieri’s principle. No significant differences in the volume of remaining tissue were seen between lesion+MK60, lesion+MK30, lesion+(−)MK and lesion+vehicle groups (F(3,26)=0.727, P=0.545). The mean volume (±S.D.) of remaining tissue for each group was: lesion+MK60=145.8 (6.4); lesion+MK30=147.11 (6.6); lesion+(−)MK=145.5 (3.1); and lesion+vehicle=149.8 (6.5). Therefore, the behavioral

Summary

Kozlowski et. al., 1994 found that a 30-day regimen of the NMDA antagonist, MK801, beginning at Day 18 post-lesion (when dendritic arbor growth was maximal), blocked dendritic pruning. Likewise, in the present study, MK801 administered to lesioned animals during the dendritic pruning phase (days 18–60, lesion+MK60), maintained the increase in dendritic arborization in the contralateral, homotopic cortex when measured at day 60 post-lesion. In lesioned animals that received MK801 between days 18

Acknowledgements

This study was supported by NS 23964, AA07471, and the Texas Advanced Research Program. The authors would like to thank Debra James, J. Leigh Humm, Jeff Gotts, Rebecca Cody, Alycia Halliday and Rueben Gonzales for their help with the experiments and Theresa Jones, Stefan Lee and Mayumi Prins for their critical reading of this manuscript.

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Relationship between dendritic pruning and behavioral recovery following sensorimotor cortex lesions

Abstract

Introduction

Section snippets

Subjects

Surgical procedures

Lesion volume

Summary

Acknowledgements

Euro J Pharm

Exp Neurol

Dev Brain Res

Neuroscience

Neuropsychologia

Exp Neurol

Neurosci Lett

Exp Neurol

Brain Res

Behav Brain Res

Brain Res

Brain Res

J Neurosci Methods

Brain Res

Brain Res Rev

Mech Aging Dev

Neuroscience

Neurosci Lett

Brain Res

Exp Neurol

Behav Brain Res

Neurobiol Learn Mem

Trends Psychol Sci

Brain Res

The role of NMDA receptors in synaptic integration and the organizaton of motor patterns