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Spatiotemporal dynamics of lesion-induced axonal sprouting and its relation to functional architecture of the cerebellum

View Article: PubMed Central - PubMed

ABSTRACT

Neurodegenerative lesions induce sprouting of new collaterals from surviving axons, but the extent to which this form of axonal remodelling alters brain functional structure remains unclear. To understand how collateral sprouting proceeds in the adult brain, we imaged post-lesion sprouting of cerebellar climbing fibres (CFs) in mice using in vivo time-lapse microscopy. Here we show that newly sprouted CF collaterals innervate multiple Purkinje cells (PCs) over several months, with most innervations emerging at 3–4 weeks post lesion. Simultaneous imaging of cerebellar functional structure reveals that surviving CFs similarly innervate functionally relevant and non-relevant PCs, but have more synaptic area on PCs near the collateral origin than on distant PCs. These results suggest that newly sprouted axon collaterals do not preferentially innervate functionally relevant postsynaptic targets. Nonetheless, the spatial gradient of collateral innervation might help to loosely maintain functional synaptic circuits if functionally relevant neurons are clustered in the lesioned area.

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Correlation between CF ladder growth and distance from zonal boundary.(a) Representative in vivo image showing axonal degeneration in lobule VIII occurs at the boundary of positive and negative zebrin II zone. A maximum projection (top-down view) of the CFs and the zonal boundary in the molecular layer is shown. Four out of the six double-transgenic animals showed similar type of CF degeneration (zonal degeneration) after 3-AP injection. Scale bar, 50 μm. (b) Traces of CF ladders growing very close (upper traces) or far (lower traces) from zonal boundary at two time points about 3 or 4 weeks apart. Distance mentioned above the images is measured from native zone boundary. Scale bar, 10 μm. (c) Correlation between stalk length at birth of the ladder (t=0, black circles, n=30 ladders) or at 3 or 4 weeks from the birth of the ladder (t=3/4, grey circles, n=20 ladders) and distance from native zone boundary. (d) Correlation between total ladder length at birth of the ladder (t=0, black circles, n=30 ladders) or at 3 or 4 weeks from the birth of the ladder (t=3/4, grey circles, n=20 ladders) and distance from native zone boundary.
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f6: Correlation between CF ladder growth and distance from zonal boundary.(a) Representative in vivo image showing axonal degeneration in lobule VIII occurs at the boundary of positive and negative zebrin II zone. A maximum projection (top-down view) of the CFs and the zonal boundary in the molecular layer is shown. Four out of the six double-transgenic animals showed similar type of CF degeneration (zonal degeneration) after 3-AP injection. Scale bar, 50 μm. (b) Traces of CF ladders growing very close (upper traces) or far (lower traces) from zonal boundary at two time points about 3 or 4 weeks apart. Distance mentioned above the images is measured from native zone boundary. Scale bar, 10 μm. (c) Correlation between stalk length at birth of the ladder (t=0, black circles, n=30 ladders) or at 3 or 4 weeks from the birth of the ladder (t=3/4, grey circles, n=20 ladders) and distance from native zone boundary. (d) Correlation between total ladder length at birth of the ladder (t=0, black circles, n=30 ladders) or at 3 or 4 weeks from the birth of the ladder (t=3/4, grey circles, n=20 ladders) and distance from native zone boundary.

Mentions: Since functional boundary did not limit territorial expansion (ladder addition) or strengthening of innervation (sagittal ladder growth) of CF collaterals, we sought to determine if collateral sprouting is affected simply by the distance from the collateral origin. To quantify how the distance from the origin affects collateral sprouting, we measured CF ladder growth in relation to the distance between the ladders and the zonal boundary. Ideally, the distance between the ladders and the collateral origin should be measured, but the origin was difficult to identify in some cases (for example, Figs 1d and 6a). However, as shown in Fig. 6a, the boundary between surviving and degenerated CFs was often very close to the zebrin II zonal boundary in the double-transgenic mice, hence collateral sprouting mostly starts near the boundary in our experimental condition. We therefore used the zonal boundary as the starting point of the measurement. We found that when CF ladders first appeared average stalk length and the total ladder length were negatively correlated with the distance from the boundary, suggesting that ladder growth is slower for distant CFs (Fig. 6b–d). This negative correlation was maintained even after the ladders were fully grown (>3–4 weeks after birth of the ladder, Fig. 6b–d). These results suggest that although sprouted CF collaterals can innervate distant PCs beyond the functional boundary, the surviving, parent CFs have more synaptic influence on nearby PCs than distant PCs.


Spatiotemporal dynamics of lesion-induced axonal sprouting and its relation to functional architecture of the cerebellum
Correlation between CF ladder growth and distance from zonal boundary.(a) Representative in vivo image showing axonal degeneration in lobule VIII occurs at the boundary of positive and negative zebrin II zone. A maximum projection (top-down view) of the CFs and the zonal boundary in the molecular layer is shown. Four out of the six double-transgenic animals showed similar type of CF degeneration (zonal degeneration) after 3-AP injection. Scale bar, 50 μm. (b) Traces of CF ladders growing very close (upper traces) or far (lower traces) from zonal boundary at two time points about 3 or 4 weeks apart. Distance mentioned above the images is measured from native zone boundary. Scale bar, 10 μm. (c) Correlation between stalk length at birth of the ladder (t=0, black circles, n=30 ladders) or at 3 or 4 weeks from the birth of the ladder (t=3/4, grey circles, n=20 ladders) and distance from native zone boundary. (d) Correlation between total ladder length at birth of the ladder (t=0, black circles, n=30 ladders) or at 3 or 4 weeks from the birth of the ladder (t=3/4, grey circles, n=20 ladders) and distance from native zone boundary.
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Related In: Results  -  Collection

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f6: Correlation between CF ladder growth and distance from zonal boundary.(a) Representative in vivo image showing axonal degeneration in lobule VIII occurs at the boundary of positive and negative zebrin II zone. A maximum projection (top-down view) of the CFs and the zonal boundary in the molecular layer is shown. Four out of the six double-transgenic animals showed similar type of CF degeneration (zonal degeneration) after 3-AP injection. Scale bar, 50 μm. (b) Traces of CF ladders growing very close (upper traces) or far (lower traces) from zonal boundary at two time points about 3 or 4 weeks apart. Distance mentioned above the images is measured from native zone boundary. Scale bar, 10 μm. (c) Correlation between stalk length at birth of the ladder (t=0, black circles, n=30 ladders) or at 3 or 4 weeks from the birth of the ladder (t=3/4, grey circles, n=20 ladders) and distance from native zone boundary. (d) Correlation between total ladder length at birth of the ladder (t=0, black circles, n=30 ladders) or at 3 or 4 weeks from the birth of the ladder (t=3/4, grey circles, n=20 ladders) and distance from native zone boundary.
Mentions: Since functional boundary did not limit territorial expansion (ladder addition) or strengthening of innervation (sagittal ladder growth) of CF collaterals, we sought to determine if collateral sprouting is affected simply by the distance from the collateral origin. To quantify how the distance from the origin affects collateral sprouting, we measured CF ladder growth in relation to the distance between the ladders and the zonal boundary. Ideally, the distance between the ladders and the collateral origin should be measured, but the origin was difficult to identify in some cases (for example, Figs 1d and 6a). However, as shown in Fig. 6a, the boundary between surviving and degenerated CFs was often very close to the zebrin II zonal boundary in the double-transgenic mice, hence collateral sprouting mostly starts near the boundary in our experimental condition. We therefore used the zonal boundary as the starting point of the measurement. We found that when CF ladders first appeared average stalk length and the total ladder length were negatively correlated with the distance from the boundary, suggesting that ladder growth is slower for distant CFs (Fig. 6b–d). This negative correlation was maintained even after the ladders were fully grown (>3–4 weeks after birth of the ladder, Fig. 6b–d). These results suggest that although sprouted CF collaterals can innervate distant PCs beyond the functional boundary, the surviving, parent CFs have more synaptic influence on nearby PCs than distant PCs.

View Article: PubMed Central - PubMed

ABSTRACT

Neurodegenerative lesions induce sprouting of new collaterals from surviving axons, but the extent to which this form of axonal remodelling alters brain functional structure remains unclear. To understand how collateral sprouting proceeds in the adult brain, we imaged post-lesion sprouting of cerebellar climbing fibres (CFs) in mice using in vivo time-lapse microscopy. Here we show that newly sprouted CF collaterals innervate multiple Purkinje cells (PCs) over several months, with most innervations emerging at 3–4 weeks post lesion. Simultaneous imaging of cerebellar functional structure reveals that surviving CFs similarly innervate functionally relevant and non-relevant PCs, but have more synaptic area on PCs near the collateral origin than on distant PCs. These results suggest that newly sprouted axon collaterals do not preferentially innervate functionally relevant postsynaptic targets. Nonetheless, the spatial gradient of collateral innervation might help to loosely maintain functional synaptic circuits if functionally relevant neurons are clustered in the lesioned area.

No MeSH data available.


Related in: MedlinePlus