Denervation-induced sprouting of intact peripheral afferents into the cuneate nucleus of adult rats

doi:10.1016/S0006-8993(97)00708-7

Brain Research

Volume 769, Issue 2, 26 September 1997, Pages 256-262

https://doi.org/10.1016/S0006-8993(97)00708-7 Get rights and content

Abstract

In adult monkeys with dorsal rhizotomies extending from the second cervical (C₂) to the fifth thoracic (T₅) vertebrae, cortex deprived of its normal inputs regained responsiveness to inputs conveyed by intact peripheral afferents from the face [T.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 (1991) 1857–1860]. 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 [P.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 (1994) 109–117]. 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' [T.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 (1991) 1857–1860] and the `referred sensation' phenomena (see J.P. Donoghue, Plasticity of adult sensorimotor representations, Curr. Opin. Neurobiol., 5 (1995) 749–754 for review) reported to follow proximal limb amputations in humans.

Introduction

In 1991, Pons et al. [17]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 3, 12, 13, 14. 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.

Unlike topographic changes seen after peripheral nerve damage 2, 12, 13, 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 7, 19. 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. [18]suggested that relay neurons in the ventroposterior medial nucleus (VPM) might have sprouted novel connections onto denervated cells in the ventroposterior lateral nucleus (VPL), 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 primary peripheral afferents at the level of the brainstem since vacated synaptic sites no doubt existed in the denervated cuneate nucleus (see 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. [17]. 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 [6].

Section snippets

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 (i.m.) injection of ketamine HCl (Ketaset, 80 mg/kg) and xylazine (Rompun, 10 mg/kg). 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.

Results

Phenotypically, the success of the surgery was evidenced by a complete lack of use of the deafferented forelimb in locomotion (e.g., see [24]). 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 the forelimb for their initiation and maintenance (though it is possible that stimulation of the head and face by the deafferented forelimb provides inputs that

Discussion

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 C₂ to T₅[17]. In those animals, with denervated cuneate nuclei, electrophysiological mapping in primary somatosensory cortex revealed that the deprived zone of cortex had come to

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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The primate somatosensory neuroaxis provides an excellent model system with which to investigate adult neural plasticity. Here, we report immunohistochemical staining data for AMPA and GABA_A/B receptor subunits in the cuneate nucleus of adult squirrel monkeys 1 and 5 months after median nerve compression. This method of nerve injury allowed the investigation of the way in which patterns of receptor correlates change during peripheral nerve regeneration. These results are compared to cortical data collected within the same animals. As observed in the cortex, the pattern of subunit staining in the brainstem 1 month after nerve compression suggests that the sensory deprived nucleus enters a state of reorganization. That is, the expression of GluR2/3 AMPA receptor subunits is significantly increased, while GABA α1 and GABA_BR1b receptor subunits are significantly decreased. Five months after nerve injury, the pattern of subunit expression is again very similar to that observed in the infragranular layers of cortex. At this later time we observe a significant increase in GluR2/3 and GABA_BR1a, with no change in GABA_Aα1, and a significant decrease in GABA_BR1b. Together these results suggest that during reorganization and recovery from injury the brainstem and cortex are governed by homogeneous mechanisms of plasticity.
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Injuries to the peripheral nerves result in partial or total loss of motor, sensory, and autonomic functions in the denervated segments of the body due to the interruption of axons, degeneration of distal nerve fibers, and eventual death of axotomized neurons. Functional deficits caused by nerve injuries can be compensated by reinnervation of denervated targets by regenerating injured axons or by collateral branching of undamaged axons, and remodeling of nervous system circuitry related to the lost functions. Plasticity of central connections may compensate functionally for the lack of adequate target reinnervation; however, plasticity has limited effects on disturbed sensory localization or fine motor control after injuries, and may even result in maladaptive changes, such as neuropathic pain and hyperreflexia. After axotomy, neurons shift from a transmitter to a regenerative phenotype, activating molecular pathways that promote neuronal survival and axonal regeneration. Peripheral nerve injuries also induce a cascade of events, at the molecular, cellular, and system levels, initiated by the injury and progressing throughout plastic changes at the spinal cord, brainstem nuclei, thalamus, and brain cortex. Mechanisms involved in these changes include neurochemical changes, functional alterations of excitatory and inhibitory synaptic connections, sprouting of new connections, and reorganization of sensory and motor central maps. An important direction for research is the development of therapeutic strategies that enhance axonal regeneration, promote selective target reinnervation, and are also able to modulate central nervous system reorganization, amplifying positive adaptive changes that improve functional recovery and also reducing undesirable effects.

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Research reportDenervation-induced sprouting of intact peripheral afferents into the cuneate nucleus of adult rats

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Curr. Opin. Neurobiol.

Neurosci. Lett.

Neuroscience

Neuroscience

Neuroscience

Pattern of peripheral deafferentation predicts reorganizational limits in adult primate somatosensory cortex

Somatosens. Motor Res.

Large-scale functional reorganization in adult monkey cortex after peripheral nerve injury

Proc. Natl. Acad. Sci. USA

NMDA receptors and plasticity in adult primate somatosensory cortex

J. Comp. Neurol.

Sprouting of intact afferents into the denervated cuneate nucleus of adult rats after dorsal rhizotomy

Soc. Neurosci. Abstr.

Morphology of single intracellularly stained axons terminating in area 3b of macaque monkeys

J. Comp. Neurol.

Central projections of the sciatic, saphenous, median, and ulnar nerves of the rat demonstrated by transganglionic transport of choleragenoid-HRP (B-HRP) and wheat germ agglutinin-HRP (WGA-HRP)

J. Comp. Neurol.

Research report
Denervation-induced sprouting of intact peripheral afferents into the cuneate nucleus of adult rats