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Experimental cerebral palsy causes microstructural brain damage in areas associated to motor deficits but no spatial
E F Sanches1, A S Carvalho2, Y van de Looij3
1Division of Child Development and Growth, Department of Pediatrics, Gynecology and Obstetrics, School of Medicine, University of Geneva, Geneva, Switzerland.
Insights
This study demonstrates that experimental cerebral palsy (CP) in rats leads to long-term brain damage, including altered myelination and motor cortex cell death, resulting in significant locomotor impairments. These findings offer insights into CP
Area of Science:
- Neuroscience
- Developmental Biology
- Pathology
Background:
- Cerebral palsy (CP) is a leading cause of childhood motor and cognitive impairments, often resulting from developing brain injury.
- Understanding the long-term effects of CP-inducing factors on brain structure and function is crucial for developing effective interventions.
Purpose of the Study:
- To investigate brain damage and behavioral alterations in an early adult rodent model of cerebral palsy.
- To characterize the microstructural and macrostructural brain changes associated with experimental CP.
Main Methods:
- A rat model of CP was established using maternal inflammation (LPS), perinatal anoxia, and postnatal sensorimotor restriction.
- Locomotor and cognitive functions were assessed using Rota-Rod, Ladder Walking, and Morris water Maze tests.
- Ex-vivo MRI (DTI, NODDI), immunofluorescence, and histological analyses were employed to evaluate brain structure, myelination, cell death, and glial reactivity.
Main Results:
- CP model animals exhibited reduced body weight and significant deficits in both gross and fine motor tasks, with no observed cognitive impairments.
- Ex-vivo MRI revealed decreased brain volumes and impaired microstructure in the cingulate gyrus and sensory cortex.
- Histological analysis indicated increased apoptosis in the hindlimb primary motor cortex, altered myelination, and increased microglial activation with apoptotic markers.
Conclusions:
- Experimental CP induces persistent microstructural brain alterations, particularly in myelinated structures and the motor cortex.
- The study highlights cell death in the motor cortex and locomotor deficits as key long-term consequences of experimental CP.
- These findings contribute to understanding CP pathophysiology and may inform future neuroprotective and neurorehabilitative strategies.
Introduction:
Cerebral palsy (CP) is the major cause of motor and cognitive impairments during childhood. CP can result from direct or indirect structural injury to the developing brain. In this study, we aimed to describe brain damage and behavioural alterations during early adult life in a CP model using the combination of maternal inflammation, perinatal anoxia and postnatal sensorimotor restriction.
Methods:
Pregnant Wistar rats were injected intraperitoneally with 200 µg/kg LPS at embryonic days E18 and E19. Between 3 and 6 h after birth (postnatal day 0 - PND0), pups of both sexes were exposed to anoxia for 20 min. From postnatal day 2 to 21, hindlimbs of animals were immobilized for 16 h daily during their active phase. From PND40, locomotor and cognitive tests were performed using Rota-Rod, Ladder Walking and Morris water Maze. Ex-vivo MRI Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) were used to assess macro and microstructural damage and brain volume alterations induced by the model. Myelination and expression of neuronal, astroglial and microglial markers, as well as apoptotic cell death were evaluated by immunofluorescence.
Results:
CP animals showed decreased body weight, deficits in gross (rota-rod) and fine (ladder walking) motor tasks compared to Controls. No cognitive impairments were observed. Ex-vivo MRI showed decreased brain volumes and impaired microstructure in the cingulate gyrus and sensory cortex in CP brains. Histological analysis showed increased cell death, astrocytic reactivity and decreased thickness of the corpus callosum and altered myelination in CP animals. Hindlimb primary motor cortex analysis showed increased apoptosis in CP animals. Despite the increase in NeuN and GFAP, no differences between groups were observed as well as no co-localization with the apoptotic marker. However, an increase in Iba-1+ microglia with co-localization to cleaved caspase 3 was observed.
Conclusion:
Our results suggest that experimental CP induces long-term brain microstructural alterations in myelinated structures, cell death in the hindlimb primary motor cortex and locomotor impairments. Such new evidence of brain damage could help to better understand CP pathophysiological mechanisms and guide further research for neuroprotective and neurorehabilitative strategies for CP patients.
