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Journal ArticleDOI

Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor.

01 Sep 1987-Nature (Nature Publishing Group)-Vol. 329, Iss: 6134, pp 65-68
TL;DR: Continuous intracerebral infusion of NGF over a period of four weeks can partly reverse the cholinergic cell body atrophy and improve retention of a spatial memory task in behaviourally impaired aged rats.
Abstract: In aged rodents, impairments in learning and memory have been associated with an age-dependent decline in forebrain of cholinergic function, and recent evidence indicates that the cholinergic neurons in the nucleus basalis magnocellularis, the septal-diagonal band area and the striatum undergo age-dependent atrophy. Thus, as in Alzheimer-type dementia in man, degenerative changes in the forebrain cholinergic system may contribute to age-related cognitive impairments in rodents. The cause of these degenerative changes is not known. Recent studies have shown that the central cholinergic neurons in the septal-diagonal band area, nucleus basalis and striatum are sensitive to the neurotrophic protein nerve growth factor (NGF). In particular, intraventricular injections or infusions of NGF in young adult rats have been shown to prevent retrograde neuronal cell death and promote behavioural recovery after damage to the septo-hippocampal connections. It is so far not known, however, whether the atrophic cholinergic neurons in aged animals are responsive to NGF treatment. We report here that continuous intracerebral infusion of NGF over a period of four weeks can partly reverse the cholinergic cell body atrophy and improve retention of a spatial memory task in behaviourally impaired aged rats.
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Journal ArticleDOI
TL;DR: Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems, and control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.
Abstract: Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.

3,968 citations


Cites background from "Amelioration of cholinergic neuron ..."

  • ...NGF infusion has been shown to attenuate the behavioral deficits associated with cholinergic atrophy (e.g. Fischer et al 1987)....

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Journal ArticleDOI
TL;DR: The results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity, and learning.
Abstract: Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain structure that is important for memory function. Consequently, spatial learning and long-term potentiation (LTP) were tested in groups of mice housed either with a running wheel (runners) or under standard conditions (controls). Mice were injected with bromodeoxyuridine to label dividing cells and trained in the Morris water maze. LTP was studied in the dentate gyrus and area CA1 in hippocampal slices from these mice. Running improved water maze performance, increased bromodeoxyuridine-positive cell numbers, and selectively enhanced dentate gyrus LTP. Our results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity, and learning.

2,816 citations

Journal ArticleDOI
TL;DR: This article focuses on the neuronal changes that occur in response to complex stimulation by an enriched environment and emphasizes the behavioural and neurobiological consequences of specific elements of enrichment, especially exercise and learning.
Abstract: Neuronal plasticity is a central theme of modern neurobiology, from cellular and molecular mechanisms of synapse formation in Drosophila to behavioural recovery from strokes in elderly humans. Although the methods used to measure plastic responses differ, the stimuli required to elicit plasticity are thought to be activity-dependent. In this article, we focus on the neuronal changes that occur in response to complex stimulation by an enriched environment. We emphasize the behavioural and neurobiological consequences of specific elements of enrichment, especially exercise and learning.

2,281 citations


Cites background from "Amelioration of cholinergic neuron ..."

  • ...Several of these factors have also been suggested to function in learning and synaptic plasticity, in particular NGF and BDNF (ref...

    [...]

Journal ArticleDOI
TL;DR: Rapid actions of neurotrophin-3 on synaptic efficacy, as well as the regulation of their mRNAs by electrical activity, suggest that neurotrophins might play important roles in regulating neuronal connectivity in the developing and in the adult central nervous system.
Abstract: The neurotrophins are a small group of dimeric proteins that profoundly affect the development of the nervous system of vertebrates. Recent studies have established clear correlations between the survival requirements for different neurotrophins of functionally distinct subsets of sensory neurons. The biological role of the neurotrophins is not limited to the prevention of programmed cell death of specific groups of neurons during development. Neurotrophin-3 in particular seems to act on neurons well before the period of target innervation and of normally occuning cell death. In animals lacking functional neurotrophin or receptor genes, neuronal numbers do not seem to be massively reduced in the CNS, unlike in the PNS. Finally, rapid actions of neurotrophins on synaptic efficacy, as well as the regulation of their mRNAs by electrical activity, suggest that neurotrophins might play important roles in regulating neuronal connectivity in the developing and in the adult central nervous system.

1,969 citations

Journal ArticleDOI
23 Mar 1990-Science
TL;DR: The distribution of NT-3 messenger RNA and its biological activity on a variety of neuronal populations clearly distinguishNT-3 from NGF and BDNF, and provide compelling evidence that NT- 3 is an authentic neurotrophic factor that has its own characteristic role in vivo.
Abstract: The development and maintenance of the nervous system depends on proteins known as neurotrophic factors. Although the prototypical neurotrophic factor, nerve growth factor (NGF), has been intensively studied for decades, the discovery and characterization of additional such factors has been impeded by their low abundance. Sequence homologies between NGF and the recently cloned brain-derived neurotrophic factor (BDNF) were used to design a strategy that has now resulted in the cloning of a gene encoding a novel neurotrophic factor, termed neurotrophin-3 (NT-3). The distribution of NT-3 messenger RNA and its biological activity on a variety of neuronal populations clearly distinguish NT-3 from NGF and BDNF, and provide compelling evidence that NT-3 is an authentic neurotrophic factor that has its own characteristic role in vivo.

1,355 citations

References
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Journal ArticleDOI
TL;DR: Developments of an open-field water-maze procedure in which rats learn to escape from opaque water onto a hidden platform are described, suggesting that they may lend themselves to a variety of behavioural investigations, including pharmacological work and studies of cerebral function.

6,609 citations

Journal ArticleDOI
30 Jul 1982-Science
TL;DR: Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed and an attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature.
Abstract: Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

5,318 citations

Journal ArticleDOI
TL;DR: It is suggested that fimbrial transections resulted in retrograde degeneration of cholinergic septo-hippocampal neurons and that NGF treatment strongly attenuated this lesion-induced degeneration.
Abstract: Several findings obtained in recent years suggest that NGF, aside from its well-established function as a neurotrophic factor for peripheral sympathetic and sensory neurons, also has trophic influence on the cholinergic neurons of the basal forebrain. The present study assessed whether NGF was able to affect survival of central cholinergic neurons after axonal transections in adult rats. The septo-hippocampal pathway was transected unilaterally by cutting the fimbria, and animals were implanted with a cannula through which NGF or control solutions were injected intraventricularly over 4 weeks. The lesions reduced the number of large cell bodies, as visualized by Nissl staining in the medial septal nucleus and in the vertical limb of the diagonal band of Broca. Furthermore, in the same nuclei, they reduced the number of cell bodies positively stained for AChE after pretreatment with diisopropylfluorophosphate (a method known to result in reliable identification of cholinergic neurons in the septal area). On lesioned sides, the number of cholinergic cells in medial septal nucleus and the vertical limb of the diagonal band was reduced by 50 +/- 4%, as compared to the number on contralateral sides. On lesioned sides of animals chronically treated with NGF, the number of AChE-positive cells in these areas was reduced only by 12 +/- 6%, as compared to control levels. These findings suggest that fimbrial transections resulted in retrograde degeneration of cholinergic septo-hippocampal neurons and that NGF treatment strongly attenuated this lesion-induced degeneration.(ABSTRACT TRUNCATED AT 250 WORDS)

1,428 citations

Journal ArticleDOI
09 Jan 1987-Science
TL;DR: Cholinergic neuronal degeneration after axotomy has been proposed to be due to the loss of a retrogradely transported neurotrophic factor, possibly nerve growth factor (NGF), and NGF was continuously infused into the lateral ventricles of adult rats that had received bilateral lesions of all cholinergic axons projecting from the medial septum to the dorsal hippocampus.
Abstract: Cholinergic neuronal degeneration after axotomy has been proposed to be due to the loss of a retrogradely transported neurotrophic factor, possibly nerve growth factor (NGF). To test this hypothesis, NGF was continuously infused into the lateral ventricles of adult rats that had received bilateral lesions of all cholinergic axons projecting from the medial septum to the dorsal hippocampus. After 2 weeks of NGF treatment, identification of cholinergic neurons by the presence of the biosynthetic enzyme choline acetyltransferase revealed a dramatic increase (350%) in the survival of the axotomized septal cholinergic neurons. Thus, NGF or an NGF-like molecule can act as a neurotrophic factor for these neurons.

932 citations