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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.

No MeSH data available.


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Pattern of post-lesion CF ladder growth in vivo.(a) Traces from a CF ladder at two consecutive time points (t and t+1) are shown to illustrate how change in stalk and total ladder length was measured throughout the paper. The white trace is the main collateral the CF ladder emerges from. The red trace is the main stalk of the CF ladder and the blue traces are the rungs that emerge from the main stalk. Stalk length is the measurement of the red trace while total ladder length is the sum of measurements of the red trace and all the blue traces. Scale bar, 10 μm. (b) Average change in stalk length (±s.e.m., red) and total ladder length (±s.e.m., blue) per week at each time point where each time point indicates number of weeks from birth of the ladder (n=57 ladders). Average change in stalk length was significantly different over time (one-way analysis of variance with Tukey post hoc analysis: F(5, 175)=26; P<0.0001; *P<0.001 compared with time points 1, 2, 3, 4 and 5). Average change in total ladder length was significantly different over time (One-way ANOVA with Tukey Post-hoc analysis: F(5,201)=20.74, P<0.0001, *P<0.001 compared to time point 1,2,3,4,5).
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f3: Pattern of post-lesion CF ladder growth in vivo.(a) Traces from a CF ladder at two consecutive time points (t and t+1) are shown to illustrate how change in stalk and total ladder length was measured throughout the paper. The white trace is the main collateral the CF ladder emerges from. The red trace is the main stalk of the CF ladder and the blue traces are the rungs that emerge from the main stalk. Stalk length is the measurement of the red trace while total ladder length is the sum of measurements of the red trace and all the blue traces. Scale bar, 10 μm. (b) Average change in stalk length (±s.e.m., red) and total ladder length (±s.e.m., blue) per week at each time point where each time point indicates number of weeks from birth of the ladder (n=57 ladders). Average change in stalk length was significantly different over time (one-way analysis of variance with Tukey post hoc analysis: F(5, 175)=26; P<0.0001; *P<0.001 compared with time points 1, 2, 3, 4 and 5). Average change in total ladder length was significantly different over time (One-way ANOVA with Tukey Post-hoc analysis: F(5,201)=20.74, P<0.0001, *P<0.001 compared to time point 1,2,3,4,5).

Mentions: In addition to the mediolateral expansion of parent CF territory, the newly added CF ladders grow sagittally over time, making more synaptic contacts on their postsynaptic PC dendrites. While ladder addition would lead to the parent CF innervating more targets, sagittal ladder growth would allow the parent CF to strengthen its influence on those targets. Therefore, we quantified the rate of ladder growth. For each newly sprouted CF ladder, we measured the length of its main stalk and its total length (main stalk+each rung) (Fig. 3a). The length of the main stalk relates to the ability of new CFs to extend distally along PC dendrites from the initial innervation point, while the total length relates to the overall CF synaptic area on PC dendrites. The change in the length of the main stalk and total ladder over time showed an almost identical time course as a population. Although each CF ladder appeared at various time points after the lesion, ladder growth was independent of the time after the lesion and was mostly completed within 3 weeks after birth of the ladder (that is, the time point we first observed the ladder in the imaging time series, Fig. 3b). These data suggest that a discrete time window exists in which post-lesion CF collateral sprouting occurs most extensively. This window must occur from 4 to 7 weeks after the lesion, because new ladder addition peaked at 4 weeks after the lesion (Fig. 2b, inset), and these new ladders grew mostly in the next 3 weeks.


Spatiotemporal dynamics of lesion-induced axonal sprouting and its relation to functional architecture of the cerebellum
Pattern of post-lesion CF ladder growth in vivo.(a) Traces from a CF ladder at two consecutive time points (t and t+1) are shown to illustrate how change in stalk and total ladder length was measured throughout the paper. The white trace is the main collateral the CF ladder emerges from. The red trace is the main stalk of the CF ladder and the blue traces are the rungs that emerge from the main stalk. Stalk length is the measurement of the red trace while total ladder length is the sum of measurements of the red trace and all the blue traces. Scale bar, 10 μm. (b) Average change in stalk length (±s.e.m., red) and total ladder length (±s.e.m., blue) per week at each time point where each time point indicates number of weeks from birth of the ladder (n=57 ladders). Average change in stalk length was significantly different over time (one-way analysis of variance with Tukey post hoc analysis: F(5, 175)=26; P<0.0001; *P<0.001 compared with time points 1, 2, 3, 4 and 5). Average change in total ladder length was significantly different over time (One-way ANOVA with Tukey Post-hoc analysis: F(5,201)=20.74, P<0.0001, *P<0.001 compared to time point 1,2,3,4,5).
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f3: Pattern of post-lesion CF ladder growth in vivo.(a) Traces from a CF ladder at two consecutive time points (t and t+1) are shown to illustrate how change in stalk and total ladder length was measured throughout the paper. The white trace is the main collateral the CF ladder emerges from. The red trace is the main stalk of the CF ladder and the blue traces are the rungs that emerge from the main stalk. Stalk length is the measurement of the red trace while total ladder length is the sum of measurements of the red trace and all the blue traces. Scale bar, 10 μm. (b) Average change in stalk length (±s.e.m., red) and total ladder length (±s.e.m., blue) per week at each time point where each time point indicates number of weeks from birth of the ladder (n=57 ladders). Average change in stalk length was significantly different over time (one-way analysis of variance with Tukey post hoc analysis: F(5, 175)=26; P<0.0001; *P<0.001 compared with time points 1, 2, 3, 4 and 5). Average change in total ladder length was significantly different over time (One-way ANOVA with Tukey Post-hoc analysis: F(5,201)=20.74, P<0.0001, *P<0.001 compared to time point 1,2,3,4,5).
Mentions: In addition to the mediolateral expansion of parent CF territory, the newly added CF ladders grow sagittally over time, making more synaptic contacts on their postsynaptic PC dendrites. While ladder addition would lead to the parent CF innervating more targets, sagittal ladder growth would allow the parent CF to strengthen its influence on those targets. Therefore, we quantified the rate of ladder growth. For each newly sprouted CF ladder, we measured the length of its main stalk and its total length (main stalk+each rung) (Fig. 3a). The length of the main stalk relates to the ability of new CFs to extend distally along PC dendrites from the initial innervation point, while the total length relates to the overall CF synaptic area on PC dendrites. The change in the length of the main stalk and total ladder over time showed an almost identical time course as a population. Although each CF ladder appeared at various time points after the lesion, ladder growth was independent of the time after the lesion and was mostly completed within 3 weeks after birth of the ladder (that is, the time point we first observed the ladder in the imaging time series, Fig. 3b). These data suggest that a discrete time window exists in which post-lesion CF collateral sprouting occurs most extensively. This window must occur from 4 to 7 weeks after the lesion, because new ladder addition peaked at 4 weeks after the lesion (Fig. 2b, inset), and these new ladders grew mostly in the next 3 weeks.

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&ndash;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