Tailored behavioural tests reveal early and progressive cognitive deficits in M1000 prion disease
Prion diseases are pathogenically linked to the normal cellular prion protein (PrPC) misfolding into abnormal conformers (PrPSc), with PrPSc accumulation underpinning both transmission and neurotoxicity. Despite achieving this canonical understanding, however fundamental questions remain incompletel...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999612300089X |
| _version_ | 1797847326729961472 |
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| author | Matteo Senesi Victoria Lewis Paul A. Adlard David I. Finkelstein Jee Hyun Kim Steven J. Collins |
| author_facet | Matteo Senesi Victoria Lewis Paul A. Adlard David I. Finkelstein Jee Hyun Kim Steven J. Collins |
| author_sort | Matteo Senesi |
| collection | DOAJ |
| description | Prion diseases are pathogenically linked to the normal cellular prion protein (PrPC) misfolding into abnormal conformers (PrPSc), with PrPSc accumulation underpinning both transmission and neurotoxicity. Despite achieving this canonical understanding, however fundamental questions remain incompletely resolved, including the level of pathophysiological overlap between neurotoxic and transmitting species of PrPSc and the temporal profiles of their propagation. To further investigate the likely time of occurrence of significant levels of neurotoxic species during prion disease development, the well characterised in vivo M1000 murine model was employed. Following intracerebral inoculation, detailed serial cognitive and ethological testing at specified time points suggested subtle transition to early symptomatic disease from ∼50% of the overall disease course. In addition to observing a chronological order for impaired behaviours, different behavioural tests also showed distinctive profiles of evolving cognitive impairments with the Barnes maze demonstrating a relatively simple linear worsening of spatial learning and memory over an extended period while in contrast a conditioned fear memory paradigm previously untested in murine prion disease demonstrated more complex alterations during disease progression. These observations support the likely production of neurotoxic PrPSc from at least just prior to the mid-point of murine M1000 prion disease and illustrate the likely need to tailor the types of behavioural testing across the time course of disease progression for optimal detection of cognitive deficits. |
| first_indexed | 2024-04-09T18:09:29Z |
| format | Article |
| id | doaj.art-e051d3d5902747f88ade199fd99b7b7c |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-04-09T18:09:29Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-e051d3d5902747f88ade199fd99b7b7c2023-04-14T04:18:44ZengElsevierNeurobiology of Disease1095-953X2023-05-01180106075Tailored behavioural tests reveal early and progressive cognitive deficits in M1000 prion diseaseMatteo Senesi0Victoria Lewis1Paul A. Adlard2David I. Finkelstein3Jee Hyun Kim4Steven J. Collins5Department of Medicine, The University of Melbourne, 30 Royal Parade, Parkville, VIC, AustraliaDepartment of Medicine, The University of Melbourne, 30 Royal Parade, Parkville, VIC, AustraliaFlorey Department of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, AustraliaFlorey Department of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, AustraliaFlorey Department of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, Australia; The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, AustraliaDepartment of Medicine, The University of Melbourne, 30 Royal Parade, Parkville, VIC, Australia; Florey Department of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, Australia; Corresponding author at: Department of Medicine, The University of Melbourne, 30 Royal Parade, Parkville, VIC, Australia.Prion diseases are pathogenically linked to the normal cellular prion protein (PrPC) misfolding into abnormal conformers (PrPSc), with PrPSc accumulation underpinning both transmission and neurotoxicity. Despite achieving this canonical understanding, however fundamental questions remain incompletely resolved, including the level of pathophysiological overlap between neurotoxic and transmitting species of PrPSc and the temporal profiles of their propagation. To further investigate the likely time of occurrence of significant levels of neurotoxic species during prion disease development, the well characterised in vivo M1000 murine model was employed. Following intracerebral inoculation, detailed serial cognitive and ethological testing at specified time points suggested subtle transition to early symptomatic disease from ∼50% of the overall disease course. In addition to observing a chronological order for impaired behaviours, different behavioural tests also showed distinctive profiles of evolving cognitive impairments with the Barnes maze demonstrating a relatively simple linear worsening of spatial learning and memory over an extended period while in contrast a conditioned fear memory paradigm previously untested in murine prion disease demonstrated more complex alterations during disease progression. These observations support the likely production of neurotoxic PrPSc from at least just prior to the mid-point of murine M1000 prion disease and illustrate the likely need to tailor the types of behavioural testing across the time course of disease progression for optimal detection of cognitive deficits.http://www.sciencedirect.com/science/article/pii/S096999612300089XPrionM1000Barnes mazeFear conditionNestingInfectious disease |
| spellingShingle | Matteo Senesi Victoria Lewis Paul A. Adlard David I. Finkelstein Jee Hyun Kim Steven J. Collins Tailored behavioural tests reveal early and progressive cognitive deficits in M1000 prion disease Neurobiology of Disease Prion M1000 Barnes maze Fear condition Nesting Infectious disease |
| title | Tailored behavioural tests reveal early and progressive cognitive deficits in M1000 prion disease |
| title_full | Tailored behavioural tests reveal early and progressive cognitive deficits in M1000 prion disease |
| title_fullStr | Tailored behavioural tests reveal early and progressive cognitive deficits in M1000 prion disease |
| title_full_unstemmed | Tailored behavioural tests reveal early and progressive cognitive deficits in M1000 prion disease |
| title_short | Tailored behavioural tests reveal early and progressive cognitive deficits in M1000 prion disease |
| title_sort | tailored behavioural tests reveal early and progressive cognitive deficits in m1000 prion disease |
| topic | Prion M1000 Barnes maze Fear condition Nesting Infectious disease |
| url | http://www.sciencedirect.com/science/article/pii/S096999612300089X |
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