Evidence for Target-Specific Nerve Fiber Outgrowth from Subpopulations of Grafted Dopaminergic Neurons: A Retrograde Tracing Study Using in Oculo and Intracranial Grafting

Törnqvist, Nina; Björklund, Lars; Strömberg, Ingrid

doi:10.1006/exnr.2001.7658

Cited by 9 publications

(5 citation statements)

References 54 publications

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“…Transplantation into the anterior chamber of the eye is well established to study the mechanisms of reinnervation of tissue grafts, including pancreas, and the behavior of intrinsic nerves (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Studies have shown that iris sympathetic axons establish functional connections in intraocular brain grafts similar to the synapses normally formed in situ (40,41).…”

Section: Discussionmentioning

confidence: 99%

Noninvasive in vivo model demonstrating the effects of autonomic innervation on pancreatic islet function

Rodriguez-Diaz

Speier

Molano³

et al. 2012

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

105

115

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The autonomic nervous system is thought to modulate blood glucose homeostasis by regulating endocrine cell activity in the pancreatic islets of Langerhans. The role of islet innervation, however, has remained elusive because the direct effects of autonomic nervous input on islet cell physiology cannot be studied in the pancreas. Here, we used an in vivo model to study the role of islet nervous input in glucose homeostasis. We transplanted islets into the anterior chamber of the eye and found that islet grafts became densely innervated by the rich parasympathetic and sympathetic nervous supply of the iris. Parasympathetic innervation was imaged intravitally by using transgenic mice expressing GFP in cholinergic axons. To manipulate selectively the islet nervous input, we increased the ambient illumination to increase the parasympathetic input to the islet grafts via the pupillary light reflex. This reduced fasting glycemia and improved glucose tolerance. These effects could be blocked by topical application of the muscarinic antagonist atropine to the eye, indicating that local cholinergic innervation had a direct effect on islet function in vivo. By using this approach, we found that parasympathetic innervation influences islet function in C57BL/6 mice but not in 129X1 mice, which reflected differences in innervation densities and may explain major strain differences in glucose homeostasis. This study directly demonstrates that autonomic axons innervating the islet modulate glucose homeostasis.diabetes | beta cell | alpha cell | insulin | glucagon

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Section: Discussionmentioning

confidence: 99%

Noninvasive in vivo model demonstrating the effects of autonomic innervation on pancreatic islet function

Rodriguez-Diaz

Speier

Molano³

et al. 2012

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

105

115

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“…After thorough evaluation, clinical trials in grafting of fetal dopamine neurons into patients suffering from Parkinson's disease and results from animal experiments have demonstrated that survival of dopamine neuroblasts is poor, that nerve fiber reinnervation of the host brain terminates before the dopamine‐denervated areas are reinnervated, and that some patients develop side effects such as dyskinesia (Brundin et al, 1988; Freed et al, 2001; Hagell et al, 2002; Kordower et al, 1996). Although dopamine‐rich transplants reinnervate the host brain in a target‐specific manner, it has been shown that a subpopulation of the surviving dopamine neurons does not target the adult striatum but instead forms neurites within the graft (Hudson et al, 1994; Strömberg et al, 1992, 1997, 2001; Törnqvist et al, 2001). In attempts to increase survival of grafted dopamine neurons, it has been shown that, along with increased nerve fiber reinnervation of host brain, hyperinnervation of the graft itself also occurred (Björklund et al, 1998; Törnqvist et al, 2000).…”

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confidence: 99%

Glial influence on nerve fiber formation from rat ventral mesencephalic organotypic tissue cultures

Berglöf

Bjerkén

Strömberg

2007

J of Comparative Neurology

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Rat fetal ventral mesencephalic organotypic cultures have demonstrated two morphologically different dopamine nerve fiber growth patterns, in which the initial nerve fibers are formed in the absence of astrocytes and the second wave is guided by astrocytes. In this study, the presence of subpopulations of dopamine neurons, other neuronal populations, and glial cells was determined. We used "roller-drum" organotypic cultures, and the results revealed that beta-tubulin-positive/tyrosine hydroxylase (TH)-negative nerve fibers were present as early as 1 day in vitro (DIV). A similar growth pattern produced by TH-positive neurons was present from 2 DIV. These neurites grew to reach distances over 4 mm and over time appeared to be degenerating. Thin, vimentin-positive processes were found among these nerve fibers. As the first growth was retracted, a second outgrowth was initiated and formed on migrating astrocytes. TH- and aldehyde dehydrogenase-1 (ALDH1)-positive nerve fibers formed both the nonglia-associated and the glia-associated outgrowth. In cultures with membrane inserts, only the glia-associated outgrowth was found. Vimentin-positive cells preceded migration of NG2-positive oligodendrocytes and Iba-1-positive microglia. Oligodendrocytes appeared not to be involved in guiding neuritic growth, but microglia was absent over areas dense with TH-positive neurons. In conclusion, in "roller-drum" cultures, nerve fibers are generally formed in two sequences. The early-formed nerve fibers grow in the presence of thin, vimentin-positive processes. The second nerve fiber outgrowth is formed on astroglia, with no correlation to the presence of oligodendrocytes or microglia. ALDH1-positive nerve fibers, presumably derived from A9 dopamine neurons, participate in formation of both sequences of outgrowth.

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“…Interestingly, when survival of intrastriatally transplanted neurons is improved by neurotrophic factors, nerve fiber density is also increased within the graft (Törnqvist et al,2000). This increase is thought to be produced by a subpopulation of grafted dopamine neurons that never target adult striatal tissue (Törnqvist et al,2001). Therefore the increased nerve fiber density found in the present study might reflect the fact that the enhanced survival of TH‐positive neurons was not an overall effect on nerve fiber density within the VM transplants, but instead an effect produced by a specific subpopulation of the VM dopamine neurons included in the grafted tissue.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of antioxidant‐enriched diet for tyrosine hydroxylase‐positive neurons in ventral mesencephalic tissue in oculo grafts

Berglöf

Small

Bickford

et al. 2009

J of Comparative Neurology

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Supplementation of antioxidants to the diet has been proved to be beneficial in aging and after brain injury. Furthermore, it has been postulated that the locus coeruleus promotes survival of dopamine neurons. Thus, this study was performed to elucidate the effects of a blueberry-enriched diet on fetal ventral mesencephalic tissue in the presence or absence of locus coeruleus utilizing the in oculo grafting method. Sprague-Dawley rats were given control diet or diet supplemented with 2% blueberries, and solid tissue pieces of fetal locus coeruleus and ventral mesencephalon were implanted as single and co-grafts. The results revealed that the presence of locus coeruleus tissue or the addition of blueberries enhanced the survival of ventral mesencephalic tyrosine hydroxylase (TH)-positive neurons, whereas no additive effects were observed for the two treatments. The density of TH-positive nerve fibers in ventral mesencephalic tissue was significantly elevated when it was attached to the locus coeruleus or by blueberry treatment, whereas the innervation of dopamine-beta-hydroxylase-positive nerve fibers was not altered. The presence of locus coeruleus tissue or bluberry supplementation reduced the number of Iba-1-positive microglia in the ventral mesencephalic portion of single and co-grafts, respectively, whereas almost no OX6 immunoreactivity was found. Furthermore, neither the attachment of ventral mesencephalic tissue nor the addition of blueberries improved the survival of TH-positive neurons in the locus coerulean grafts. To conclude, locus coeruleus and blueberries are beneficial for the survival of fetal ventral mesencephalic tissue, findings that could be useful when grafting tissue in Parkinson's disease.

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Evidence for Target-Specific Nerve Fiber Outgrowth from Subpopulations of Grafted Dopaminergic Neurons: A Retrograde Tracing Study Using in Oculo and Intracranial Grafting

Cited by 9 publications

References 54 publications

Noninvasive in vivo model demonstrating the effects of autonomic innervation on pancreatic islet function

Noninvasive in vivo model demonstrating the effects of autonomic innervation on pancreatic islet function

Glial influence on nerve fiber formation from rat ventral mesencephalic organotypic tissue cultures

Beneficial effects of antioxidant‐enriched diet for tyrosine hydroxylase‐positive neurons in ventral mesencephalic tissue in oculo grafts

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