Repair and Regeneration of the Nervous System, 1982
This group discussion deals with responses to injury at the neuronal level, with particular empha... more This group discussion deals with responses to injury at the neuronal level, with particular emphasis on injury induced by axotomy. It considers responses both in the axotomized neurons themselves and in surrounding or connected uninjured neurons in animals as diverse as leeches and man. The responses observed are considered in the light of what is now known about cellular mechanisms involved in the normal development and maintenance of neurons, in an attempt to distinguish which events are a consequence of disruption of a normal cellular process and which events are specifically concerned with attempts at regeneration. The aim is to understand more about those cellular mechanisms underlying regeneration and how they may be enhanced or promoted.
Repair and Regeneration of the Nervous System, 1982
Loss of cells and failure of axons from surviving neurons to elongate through damaged CNS tissues... more Loss of cells and failure of axons from surviving neurons to elongate through damaged CNS tissues are common consequences of injury to the brain and spinal cord. Recent animal experiments using neural or sheath cell transplants have been aimed at replacing the lost or impaired cells and also at promoting and directing the growth of neuronal processes. In this review we survey some of these studies with particular emphasis on the influence of the glial environment on axonal growth.
Axons of adult mammalian retinal ganglion cells (RGCs) do not regenerate spontaneously after inju... more Axons of adult mammalian retinal ganglion cells (RGCs) do not regenerate spontaneously after injury in the optic nerve and show a persistent decrease in the rate of transport of tubulin and neurofilament proteins. To investigate further the expression of cytoskeletal proteins in these axotomized CNS neurons, mRNA levels of beta-tubulin and the 150 kDa neurofilament subunit (NF-M) were measured after interrupting the optic nerve 9 mm from the eye. Northern blots of RNA extracted from whole retinas after optic nerve transection showed that the total level of both of these mRNAs fell after injury. To determine if this decrease was a result of the death of axotomized RGCs or reflected changes in individual neurons, RNA probes were hybridized to radial cryostat sections of normal and axotomized retinas from 1 d to 6 months after injury. Grain counts revealed two trends of tubulin expression in RGCs. An early increase in tubulin mRNAs in the axotomized RGCs was followed by a later decreas...
During neural development, the orderly extension and branching of axons and dendrites makes possi... more During neural development, the orderly extension and branching of axons and dendrites makes possible the establishment of the complex networks of interconnected neurons that comprise the mature central nervous system (CNS). Offshoots from the trunks and ends of lengthy axonal projections contact cells situated in broad fields and at different levels of the neuraxis. The majority of the CNS neurons, however, have efferents that reach only nearby cells. In mammals, for instance, most retinal neurons are interneurons that have either short or no axons. Information processed by large populations of interneurons is usually conveyed to other nerve cell groups via fiber tracts. The ganglion cells, which comprise less than 2% of all retinal neurons, extend lengthy fibers in the optic nerve and tract that arborize and synapse in several areas, including the dorso-lateral geniculate nucleus, the pretectum and the superior colliculus.
The administration of neurotrophins affects neuronal survival and growth, but less is known about... more The administration of neurotrophins affects neuronal survival and growth, but less is known about their ability to modify the expression of growth associated genes following injury to CNS neurons. Here we characterize the effect of brain-derived neurotrophic factor (BDNF) on mRNA levels for T alpha1 alpha-tubulin, and for GAP-43, two genes whose expression levels in retinal ganglion cells (RGC) tend to correlate with growth. We first determined that most adult rat RGCs can retrogradely transport BDNF by injecting 125I-BDNF into RGC target sites in vivo. We then used quantitative in situ hybridization to characterize the effect of axotomy, or axotomy and BDNF administration on mRNA levels for GAP-43 and T alpha1. Axotomy alone resulted in a general decrease in T alpha1 alpha-tubulin mRNA levels by 2 weeks, and elicited an increase in GAP-43 mRNA levels in an average of 30% of surviving RGCs. The intravitreal administration of a single dose of BDNF (5 microg) to axotomized RGCs on the day of injury did not affect T alpha1 alpha-tubulin mRNA levels, but was followed by a moderate (approximately 80%), and short-lasting enhancement of GAP-43 mRNA levels in most RGCs during the first week after axotomy. No significant increase in GAP-43 mRNA levels was observed when BDNF was injected into the uninjured eye. We conclude that BDNF specifically enhances GAP-43 but not T alpha1 mRNA levels in injured RGCs. Because BDNF is known to stimulate branch length of injured RGCs, we suggest that changes in the expression of GAP-43, but not T alpha1 tubulin, correlate with branching of injured neurons as opposed to long distance regrowth.
Abstract This report describes a family with 8 members in 3 generations affected by a chronic pro... more Abstract This report describes a family with 8 members in 3 generations affected by a chronic progressive distal sensorimotor polyneuropathy. One member had thickened nerves. Six were studied electrophysiologically and found to have marked slowing of maximum motor nerve conduction and a loss of sensory nerve action potentials. Two other members were normal clinically and electrophysiologically. Sural nerve biopsies were obtained from 3 affected members and studied by quantitative histology and electron microscopy. Onion bulb formation was rare on light microscopy but there were changes of segmental demyelination and remyelination affecting mainly the larger myelinated nerve fibres, imbricate Schwann cell systems and an increase in the amount of collagen on electron microscopy. The relationship between this condition, peroneal muscular atrophy and the hereditary ataxias is discussed. Current studies have not yet offered a clue to the aetiology of this group of diseases.
This chapter considers how growth cone motility and changes in the neuronal cytoskeleton are modu... more This chapter considers how growth cone motility and changes in the neuronal cytoskeleton are modulated by cues from the local environment. It begins by examining the mechanisms by which positive and negative environmental cues guide growing axons. It then discusses the various intrinsic and extrinsic factors that can modulate changes in axonal caliber. Finally, the chapter examines the critical role of axonal environments in neuronal survival and axonal regeneration after injury.
Repair and Regeneration of the Nervous System, 1982
This group discussion deals with responses to injury at the neuronal level, with particular empha... more This group discussion deals with responses to injury at the neuronal level, with particular emphasis on injury induced by axotomy. It considers responses both in the axotomized neurons themselves and in surrounding or connected uninjured neurons in animals as diverse as leeches and man. The responses observed are considered in the light of what is now known about cellular mechanisms involved in the normal development and maintenance of neurons, in an attempt to distinguish which events are a consequence of disruption of a normal cellular process and which events are specifically concerned with attempts at regeneration. The aim is to understand more about those cellular mechanisms underlying regeneration and how they may be enhanced or promoted.
Repair and Regeneration of the Nervous System, 1982
Loss of cells and failure of axons from surviving neurons to elongate through damaged CNS tissues... more Loss of cells and failure of axons from surviving neurons to elongate through damaged CNS tissues are common consequences of injury to the brain and spinal cord. Recent animal experiments using neural or sheath cell transplants have been aimed at replacing the lost or impaired cells and also at promoting and directing the growth of neuronal processes. In this review we survey some of these studies with particular emphasis on the influence of the glial environment on axonal growth.
Axons of adult mammalian retinal ganglion cells (RGCs) do not regenerate spontaneously after inju... more Axons of adult mammalian retinal ganglion cells (RGCs) do not regenerate spontaneously after injury in the optic nerve and show a persistent decrease in the rate of transport of tubulin and neurofilament proteins. To investigate further the expression of cytoskeletal proteins in these axotomized CNS neurons, mRNA levels of beta-tubulin and the 150 kDa neurofilament subunit (NF-M) were measured after interrupting the optic nerve 9 mm from the eye. Northern blots of RNA extracted from whole retinas after optic nerve transection showed that the total level of both of these mRNAs fell after injury. To determine if this decrease was a result of the death of axotomized RGCs or reflected changes in individual neurons, RNA probes were hybridized to radial cryostat sections of normal and axotomized retinas from 1 d to 6 months after injury. Grain counts revealed two trends of tubulin expression in RGCs. An early increase in tubulin mRNAs in the axotomized RGCs was followed by a later decreas...
During neural development, the orderly extension and branching of axons and dendrites makes possi... more During neural development, the orderly extension and branching of axons and dendrites makes possible the establishment of the complex networks of interconnected neurons that comprise the mature central nervous system (CNS). Offshoots from the trunks and ends of lengthy axonal projections contact cells situated in broad fields and at different levels of the neuraxis. The majority of the CNS neurons, however, have efferents that reach only nearby cells. In mammals, for instance, most retinal neurons are interneurons that have either short or no axons. Information processed by large populations of interneurons is usually conveyed to other nerve cell groups via fiber tracts. The ganglion cells, which comprise less than 2% of all retinal neurons, extend lengthy fibers in the optic nerve and tract that arborize and synapse in several areas, including the dorso-lateral geniculate nucleus, the pretectum and the superior colliculus.
The administration of neurotrophins affects neuronal survival and growth, but less is known about... more The administration of neurotrophins affects neuronal survival and growth, but less is known about their ability to modify the expression of growth associated genes following injury to CNS neurons. Here we characterize the effect of brain-derived neurotrophic factor (BDNF) on mRNA levels for T alpha1 alpha-tubulin, and for GAP-43, two genes whose expression levels in retinal ganglion cells (RGC) tend to correlate with growth. We first determined that most adult rat RGCs can retrogradely transport BDNF by injecting 125I-BDNF into RGC target sites in vivo. We then used quantitative in situ hybridization to characterize the effect of axotomy, or axotomy and BDNF administration on mRNA levels for GAP-43 and T alpha1. Axotomy alone resulted in a general decrease in T alpha1 alpha-tubulin mRNA levels by 2 weeks, and elicited an increase in GAP-43 mRNA levels in an average of 30% of surviving RGCs. The intravitreal administration of a single dose of BDNF (5 microg) to axotomized RGCs on the day of injury did not affect T alpha1 alpha-tubulin mRNA levels, but was followed by a moderate (approximately 80%), and short-lasting enhancement of GAP-43 mRNA levels in most RGCs during the first week after axotomy. No significant increase in GAP-43 mRNA levels was observed when BDNF was injected into the uninjured eye. We conclude that BDNF specifically enhances GAP-43 but not T alpha1 mRNA levels in injured RGCs. Because BDNF is known to stimulate branch length of injured RGCs, we suggest that changes in the expression of GAP-43, but not T alpha1 tubulin, correlate with branching of injured neurons as opposed to long distance regrowth.
Abstract This report describes a family with 8 members in 3 generations affected by a chronic pro... more Abstract This report describes a family with 8 members in 3 generations affected by a chronic progressive distal sensorimotor polyneuropathy. One member had thickened nerves. Six were studied electrophysiologically and found to have marked slowing of maximum motor nerve conduction and a loss of sensory nerve action potentials. Two other members were normal clinically and electrophysiologically. Sural nerve biopsies were obtained from 3 affected members and studied by quantitative histology and electron microscopy. Onion bulb formation was rare on light microscopy but there were changes of segmental demyelination and remyelination affecting mainly the larger myelinated nerve fibres, imbricate Schwann cell systems and an increase in the amount of collagen on electron microscopy. The relationship between this condition, peroneal muscular atrophy and the hereditary ataxias is discussed. Current studies have not yet offered a clue to the aetiology of this group of diseases.
This chapter considers how growth cone motility and changes in the neuronal cytoskeleton are modu... more This chapter considers how growth cone motility and changes in the neuronal cytoskeleton are modulated by cues from the local environment. It begins by examining the mechanisms by which positive and negative environmental cues guide growing axons. It then discusses the various intrinsic and extrinsic factors that can modulate changes in axonal caliber. Finally, the chapter examines the critical role of axonal environments in neuronal survival and axonal regeneration after injury.
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Papers by Albert Aguayo