Biology subjects

Bergold, P.

Publications and source records attributed to Bergold, P..

4 recordsLinked to original sources

bioRxiv2026

Tau Isoform Expression Drives Disease Outcomes Following a Single Closed Head Injury

Tau protein has been implicated as an important mediator of traumatic brain injury (TBI). Adult human brain expresses 6 tau isoforms expressing 3 (3R) or 4 (4R) microtubule binding sites; adult mouse brain expresses only 4R tau. A role for tau isoform expression on TBI disease course is tested using wild-type C57/BL6 mice (WT) and C57/BL6 with a knocked-in human tau coding region (MAPTKI). Uninjured WT and MAPTKI mice have similar brain histology and behavior as they age. At subacute times (14 days post-injury (DPI)), injured MAPTKI mice have less white matter damage with similar neuronal loss as WT. At chronic times (90DPI), MAPTKI mice demyelinate while WT mice remyelinate. At 14DPI, tau phosphorylation differs between WT and MAPTKI mice. At 90DPI, thioflavin-S+ protein aggregates in MAPTKI corpus callosum are higher than WT. At 14 or 90DPI, WT and MAPTKI mice acquire Barnes maze, WT retention is impaired at 14DPI and MAPTKI retention impaired at 90DPI. At 14DPI, only MAPTKI mice acquire and retain active place avoidance; at 90DPI, only WT mice acquire active place avoidance. At 14DPI, only injured MAPTKI mice acquire alternating T-maze. These data suggest that WT and MAPTKI differ in both subacute and chronic disease course. At 14DPI, WT mice have greater white matter damage and behavioral impairments than MAPTKI mice. At 90DPI, impairments in WT mice partially recover, yet worsen in MAPTKI mice. This data suggests that 3R tau isoform expression alters the disease course of head injury. HighlightsPost-injury disease course of MAPTKI mice expressing 3R and 4R tau differs from wild-type mice expressing only 4R tau. At subacute times post-injury, MAPTKI mice have less white matter, yet similar gray matter, injury than wild-type mice. At chronic times post-injury, white matter damage in MAPTKI worsens. At subacute times post-injury, MAPTKI mice have fewer behavioral deficits than wild type mice. At chronic times post-injury, MAPTKI mice develop behavioral deficits not present at subacute times.

neuroscience↗

bioRxiv2022

A single closed head injury in mice induces chronic, progressive white matter atrophy and increased phospho-tau expressing oligodendrocytes

Traumatic brain injury (TBI) acutely damages the brain; this injury can evolve into chronic neurodegeneration. While much is known about the chronic effects arising from multiple mild TBIs, far less is known about the long-term effects of a single moderate to severe TBI. We found that a single moderate closed head injury to mice induces diffuse axonal injury within 1-day post-injury (DPI). At 14 DPI, injured animals have atrophy of ipsilesional cortex, thalamus, and corpus callosum, with bilateral atrophy of the dorsal fornix. Atrophy of the ipsilesional corpus callosum is accompanied by decreased fractional anisotropy and increased mean and radial diffusivity that remains unchanged between 14 and 180 DPI. Injured animals increased density of phospho-tau immunoreactive (pTau+) cells in the ipsilesional cortex and thalamus, and bilaterally in corpus callosum. Between 14 and 180 DPI, atrophy occurs in the ipsilesional ventral fornix, contralesional corpus callosum, and bilateral internal capsule. Diffusion tensor MRI parameters remain unchanged in white matter regions with delayed atrophy. Between 14 and 180 DPI, pTau+ cell density increases bilaterally in corpus callosum, but decreases in cortex and thalamus. The location of pTau+ cells within the ipsilesional corpus callosum changes between 14 and 180 DPI; density of all cells increases including pTau+ or pTau- cells. Greater than 90% of the pTau+ cells are in the oligodendrocyte lineage in both gray and white matter. Density of thioflavin-S+ cells in thalamus increases by 180 DPI. These data suggest a single closed head impact produces multiple forms of chronic neurodegeneration. Gray and white matter regions proximal to the impact site undergo rapid atrophy. More distal white matter regions undergo chronic, progressive white matter atrophy with an increasing density of oligodendrocytes containing pTau. These data suggest that the chronic neurodegeneration arising from a single moderate CHI differs greatly from the chronic traumatic encephalopathy produced by multiple mild head injuries. HighlightsGray and white matter atrophy begins within 14 days after a single closed head injury White matter atrophy progresses between 14 and 180 days post injury with minimal changes in diffusion tensor MRI parameters. CHI increases the density of oligodendrocytes with perinuclear accumulation of phosphorylated tau Thioflavin-S+ cells increase in thalamus at 180 days post injury

neuroscience↗

bioRxiv2021

Chronic and progressive deficits after a single closed head injury in mice

BackgroundAcute injury following brain trauma may evolve into a chronic and progressive disorder. Chronic consequences of TBI have been understudied, in part, due to the lack of robust behavioral changes that are delayed in onset as well as chronic and progressive. Assessment of the chronic consequences of TBI also must distinguish behavioral changes that arises due to age vs those that develop and evolve over time due to injury. MethodsC57BL/6 mice receive single closed head injury (CHI) and are analyzed at 7DPI, 14DPI or 180DPI on neurological severity score, open field, rotarod, beam walk, and simple-complex wheel. ResultsIn the center of open field, injured mice have a turn bias at 180 days post-injury (DPI) not present at 7DPI. On rotarod, injured mice have shorter latencies at 7DPI, but not at 180DPI due to a large age effect in sham-injured mice. On beam walk at 180DPI, both sham and injured groups more slowly traverse a 2cm and 1cm beam than at 7DPI. Foot-faults show no significant effects of age or injury. On simple wheel injury affects speed at 14DPI with no effect on distance travelled. The lack of injury-dependent effects on beam walk or simple-complex wheel despite visible impairment was the impetus to assess limb position using Deeplabcut markerless tracking. Custom Python scripts were then developed to compute beam walk absition or foot fault severity (integral of limb displacement over time), and step frequency and quadrupedal limb coordination in simple-complex wheel. On the 2cm beam, age increased absition in all limbs of uninjured mice and both forelimbs of injured mice. On the 1cm beam both forelimbs and the left hindlimb of injured mice at 180DPI have larger absition than uninjured mice at 180DPI or injured mice at 7DPI. On a simple wheel injury affected speed only at 14 DPI with no effect on distance travelled. In contrast, injured mice at 180DPI developed a compensatory running strategy by increasing step frequency variability. This allowed injured mice at 180 DPI to reach sham-level quadrupedal limb coordination and improve running speed as compared to 14 DPI assessment. On complex wheel, injured mice at 180DPI do not express this compensatory running strategy resulting in impaired quadrupedal limb coordination. These data suggest chronic and progressive motor deficits of injured mice at 180DPI. ConclusionsA single impact produces chronic and progressive motor deficits. Quantitative motor analysis using DeepLabCut tracking reveals deficits not seen using standard outcomes.

neuroscience↗

bioRxiv2020

PKMζ traces hippocampal LTP maintenance and spatial long-term memory

PKM{zeta} is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other protein kinases that are transiently stimulated by second messengers, PKM{zeta} is persistently activated through sustained increases in kinase protein expression. Therefore, visualizing increases in PKM{zeta} expression during long-term memory storage might reveal the sites of its persistent action and thus the location of memory-associated LTP maintenance in the brain. Using quantitative immunohistochemistry validated by the lack of staining in PKM{zeta}-null mice, we examined the amount and distribution of PKM{zeta} in subregions of the hippocampal formation of wild-type mice during LTP maintenance and spatial long-term memory storage. During LTP maintenance in hippocampal slices, PKM{zeta} increases in the pyramidal cell body and stimulated dendritic layers of CA1 for at least 2 h. During spatial memory storage, PKM{zeta} increases in CA1 pyramidal cells for at least 1 month, paralleling the persistence of the memory. The subset of CA1 pyramidal cells that are tagged by immediate early gene Arc-driven transcription of fluorescent proteins, whose expression increases during initial memory formation, also expresses the persistent increase of PKM{zeta} during memory storage. In the memory-tagged cells, the increased PKM{zeta} expression persists in dendritic compartments within stratum radiatum for 1 month, indicating the long-term storage of information in the CA3-to-CA1 pathway during remote spatial memory. We conclude that persistent increases in PKM{zeta} trace the molecular mechanism of LTP maintenance and thus the sites of information storage within brain circuitry during long-term memory.

neuroscience↗