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Early behavioral changes and quantitative analysis of neuropathological features in murine prion disease:
Roseane Borner1, João Bento-Torres, Diego R V Souza
1Laboratory of Neurodegeneration and Infection at the University Hospital João de Barros Barreto, Federal University of Pará, Belém, Pará, Brazil.
Abstract:
Behavioral and neuropathological changes have been widely investigated in murine prion disease but stereological based unbiased estimates of key neuropathological features have not been carried out. After injections of ME7 infected (ME7) or normal brain homogenates (NBH) into dorsal CA1 of albino Swiss mice and C57BL6, we assessed behavioral changes on hippocampal-dependent tasks. We also estimated by optical fractionator at 15 and 18 weeks post-injections (w.p.i.) the total number of neurons, reactive astrocytes, activated microglia and perineuronal nets (PN) in the polymorphic layer of dentate gyrus (PolDG), CA1 and septum in albino Swiss mice. On average, early behavioral changes in albino Swiss mice start four weeks later than in C57BL6. Cluster and discriminant analysis of behavioral data in albino Swiss mice revealed that four of nine subjects start to change their behavior at 12 w.p.i. and reach terminal stage at 22 w.p.i and the remaining subjects start at 22 w.p.i. and reach terminal stage at 26 w.p.i. Biotinylated dextran-amine BDA-tracer experiments in mossy fiber pathway confirmed axonal degeneration, and stereological data showed that early astrocytosis, microgliosis and reduction in the perineuronal nets are independent of a change in the number of neuronal cell bodies. Statistical analysis revealed that the septal region had greater levels of neuroinflammation and extracellular matrix damage than CA1. This stereological and multivariate analysis at early stages of disease in an outbred model of prion disease provided new insights connecting behavioral changes and neuroinflammation and seems to be important to understand the mechanisms of prion disease progression.
Insights
This study quantifies neuropathological changes in prion disease using stereology. Early neuroinflammation and extracellular matrix damage in the septum correlate with behavioral changes, independent of neuronal loss.
Area of Science:
- Neuroscience
- Neuropathology
- Prion Disease Research
Background:
- Murine prion disease research often examines behavioral and neuropathological changes.
- Unbiased stereological estimates of key neuropathological features have been lacking.
Purpose of the Study:
- To perform stereological estimation of neuropathological features in prion disease.
- To correlate behavioral changes with neuropathology in an outbred mouse model.
Main Methods:
- Injected ME7 infected or normal brain homogenates into mice.
- Assessed behavior using hippocampal-dependent tasks.
- Used optical fractionator for stereological estimation of neurons, astrocytes, microglia, and perineuronal nets.
- Conducted biotinylated dextran-amine tracer experiments.
Main Results:
- Behavioral changes manifested later in albino Swiss mice compared to C57BL6.
- Early astrocytosis, microgliosis, and reduced perineuronal nets occurred independently of neuronal number changes.
- The septal region exhibited higher neuroinflammation and extracellular matrix damage than CA1.
- Axonal degeneration was confirmed in the mossy fiber pathway.
Conclusions:
- Stereological analysis provides unbiased estimates of neuropathological changes in prion disease.
- Early neuroinflammation and extracellular matrix damage in the septum are linked to behavioral alterations.
- These findings offer insights into prion disease progression mechanisms.
