Aged Rats: Recovery of Motor Impairments by Intrastriatal Nigral Grafts

Gage, NH; Dunnett, S. B.; Stenevi, Ulf; Björklund, Anders

doi:10.1126/science.6879196

Cited by 157 publications

(30 citation statements)

References 32 publications

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“…It will also be important to determine (i) the mechanism(s) by which NGF prevents the death of the central nervous system cholinergic neurons; (it) the effect of NGF on their transmitter-related function; (iii) which types of noncholinergic neurons in the MS/VDB region benefit from the NGF treatment and how they do so; (iv) whether NGF, in addition to its effects on neuronal survival, can stimulate collateral or regenerative axonal sprouting from the transected neurons; and (v) whether NGF can influence behavioral recovery from fimbria fornix lesions. In addition, experimental models of central nervous system dysfunction in aged animals, which may be related to degenerative changes in central cholinergic projection systems (60) (12).…”

Section: Discussionmentioning

confidence: 99%

Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection.

Williams¹,

Varon²,

Peterson³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

820

330

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Neurons in the rat medial septum (MS) and vertical limb of the diagonal band of Broca (VDB) undergo a rapid and severe cell death after transection of their dorsal projection to the hippocampus by aspiration of the ipsilateral fimbria fornix and supracallosal striae. By 2 weeks posttransection, the extent of neuronal loss was 50% of the total neurons and 70% of the cholinergic neurons in the MS and 30% of the total neurons and 40% of the cholinergic neurons in the VDB.We hypothesized that (t) the death was due to the loss of a hippocampus-derived neuronotrophic factor, and (ii) exogenous nerve growth factor (NGF) might provide trophic support to the MS/VDB cholinergic neurons, in light of recent reports that the septal diagonal band cholinergic neurons are responsive to NGF and that NGF is present and produced in the hippocampus. In the present study, we attempted to prevent the transection-induced neuronal death by continuous infusion of exogenous 7S NGF (1 jag/wk) through an intraventricular cannula device. We report here that NGF treatment significantly reduces both the total neuronal and cholinergic neuronal death found 2 weeks after runbria fornix transection; there was a sparing of 50% of the neurons in the MS and essentially 100% of those in the VDB that otherwise would have died. We conclude that NGF also has a protective effect on noncholinergic neurons since calculations indicate that 80% of the NGFaffected neurons are noncholinergic.

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Section: Discussionmentioning

confidence: 99%

Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection.

Williams¹,

Varon²,

Peterson³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

820

330

View full text Add to dashboard Cite

show abstract

“…The nigrostriatal dopaminergic projection, which degenerates in Parkinson's disease, plays a critical role in the modulation of basal ganglia f unction in humans. Similarly, dopaminergic activity in the striatum modulates motor f unctions in rodents (Gage et al, 1983;Walsh and Wagner, 1992;Emerich et al, 1993;Z hou and Palmiter, 1995).…”

mentioning

confidence: 99%

Defective Motor Behavior and Neural Gene Expression in RIIβ-Protein Kinase A Mutant Mice

et al. 1998

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Motor behavior is modulated by dopamine-responsive neurons in the striatum, where dopaminergic signaling uses G-proteincoupled pathways, including those that result in the activation of cAMP-dependent protein kinase (PKA). The RII␤ isoform of PKA is highly enriched in the striatum, and targeted disruption of the RII␤ gene in mice leads to a dramatic reduction in total PKA activity in this region. Although the mutant mice show typical locomotor responses after acute administration of dopaminergic drugs, they display abnormalities in two experience-dependent locomotor behaviors: training on the rotarod task and locomotor sensitization to amphetamine. In addition, amphetamine induction of fos is absent, and the basal expression of dynorphin mRNA is reduced in the striatum. These results demonstrate that motor learning and the regulation of neuronal gene expression require RII␤ PKA, whereas the acute locomotor effects of dopaminergic drugs are relatively unaffected by this PKA deficiency.

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“…Also, striatal transplants would likely provide comparatively more dopamine in the target region. This concept was formulated by Anders Björklund and his collaborators [98,99] as the idea of dopaminergic tissue transplants for Parkinson's disease was initially proposed. Previously described limitations to extensive axon growth through the adult CNS would clearly support this notion.…”

Section: Adaptation Of Endogenous Host Tissue To Neural Transplantationmentioning

confidence: 99%

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell Replacement Therapy for either Huntington’s or Parkinson’s Disease

Sandstrom¹,

Anderson²,

Jayaprakash³

et al. 2018

Neuroplasticity - Insights of Neural Reorganization

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Although stem cell transplant therapy offers considerable promise for deteriorative diseases, the efficacy of its application may be mitigated by endogenous compensatory mechanisms in the host brain. Plastic compensation follows neurodegeneration, beginning at its very onset and minimizing early symptom expression. As researchers attempt to correlate symptom remission with the ability of transplanted cells to adopt specific cell phenotypes, they need to be vigilant of the possibility that competing, local compensatory effects may be altering the outcome. Clearly plastic compensatory mechanisms could confound desired transplant-derived improvements by supplanting the beneficial contributions of the transplants. As circuit-level adaptations occur, more explicit explorations of their relevance to neuronal transplantation success are needed. Conceptual models of undirected transplanted cells adopting preconceived appropriate roles require revision. The notion that newly transplanted neuronal precursors will incorporate themselves into host circuitry with mutual cooperation across both parties (i.e., transplant and host) without some symbiosis-promoting mechanism is naïve. Undirected local circuits could react to newly transplanted additions as intruders. We advocate that appropriate signaling from transplanted cells to the host environment is required to optimize the therapeutic relevance of transplantation. This review surveys critical signaling mechanisms that might promote symbiotic interdependence between the host and new transplants.

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Aged Rats: Recovery of Motor Impairments by Intrastriatal Nigral Grafts

Cited by 157 publications

References 32 publications

Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection.

Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection.

Defective Motor Behavior and Neural Gene Expression in RIIβ-Protein Kinase A Mutant Mice

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell Replacement Therapy for either Huntington’s or Parkinson’s Disease

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