Biology subjects

Nikulina, E.

Publications and source records attributed to Nikulina, E..

6 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↗

bioRxiv2024

Increased protein kinase Mζ expression by Minocycline and N-acetylcysteine restoreslate-phase long-term potentiation and spatial learning after closed head injury in mice

Cognitive deficits frequently arise after traumatic brain injury. The murine closed head injury (CHI) models these deficits since injured mice cannot acquire Barnes maze. Dosing of minocycline plus N-acetylcysteine beginning 12 hours post-CHI (MN12) restores Barnes maze acquisition by an unknown mechanism. Increased hippocampal synaptic efficacy is needed to acquire Barnes maze, synaptic long-term potentiation (LTP) models this increased synaptic efficacy in vitro. LTP has an early phase (E-LTP) lasting up to one hour that is mediated by second messengers that is followed by a late phase (L-LTP) that needs new synthesis of protein kinase M zeta (PKM{zeta}). PKM{zeta} has constitutive kinase activity because it lacks the autoinhibitory regulatory domain found in other PKCs. Due to its constitutive activity, the amount of PKM{zeta} kinase activity is determined by PKM{zeta} protein levels. We report that CHI bilaterally decreases PKM{zeta} levels in the CA3 and CA1 hippocampus. MN12 increases CA1 PKM{zeta} expression. CHI inhibits E-LTP in slices from the ipsilesional hippocampus and inhibits L-LTP in slices from both hippocamppi. MN12 treatment reestablishes both E-LTP and L-LTP in slices from the injured MN12-treated hippocampus. The restoration of L-LTP from injured MN12-treated hippocampus is mediated by PKM{zeta} because L-LTP is blocked by the specific PKM{zeta} inhibitor, {zeta}-stat. Hippocampal {zeta}-stat infusions also prevents Barnes maze acquisition in injured, MN12-treated mice. These data suggest that post-injury minocycline plus N-acetylcysteine targets PKM{zeta} to improve synaptic plasticity and cognition in mice with closed-head injury.

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↗

bioRxiv2021

Delayed dosing of minocycline plus N-acetylcysteine reduces neurodegeneration in distal brain regions and restores spatial memory after experimental traumatic brain injury

Multiple drugs to treat traumatic brain injury (TBI) have failed clinical trials. Most drugs lose efficacy as the time interval increases between injury and treatment onset. Insufficient therapeutic time window is a major reason underlying failure in clinical trials. Few drugs have been developed with therapeutic time windows sufficiently long enough to treat TBI because little is known about which brain functions can be targeted if therapy is delayed hours to days after injury. We identified multiple injury parameters that are improved by first initiating treatment with the drug combination minocycline (MINO) plus N-acetylcysteine (NAC) at 72 hours after injury (MN72) in a mouse closed head injury (CHI) experimental TBI model. CHI produces spatial memory deficits resulting in impaired performance on Barnes maze, hippocampal neuronal loss, and bilateral damage to hippocampal neurons, dendrites, spines and synapses. MN72 treatment restores Barnes maze acquisition and retention, protects against hippocampal neuronal loss, limits damage to dendrites, spines and synapses, and accelerates recovery of microtubule associated protein 2 (MAP2) expression, a key protein in maintaining proper dendritic architecture and synapse density. These data show that in addition to the structural integrity of the dendritic arbor, spine and synapse density can be successfully targeted with drugs first dosed days after injury. Retention of substantial drug efficacy even when first dosed 72 hours after injury makes MINO plus NAC a promising candidate to treat clinical TBI.

neuroscience↗

bioRxiv2018

Activated Protein C blocks the inhibitory effect on neurite outgrowth by extracellular histones that mediates its inhibition through a retrograde YB-1 signal

Axonal regeneration in the mature CNS is limited by extracellular inhibitory factors. Triple knockout mice lacking the major myelin-associated inhibitors do not display spontaneous regeneration after injury, indicating the presence of other inhibitors. Searching for such inhibitors we have detected elevated levels of histone H3 in human cerebrospinal fluid (CSF) 24 hours after spinal cord injury. Following dorsal column lesions in mice and optic nerve crushes in rats, elevated levels of extracellular histone H3 were detected at the injury site. Similar to myelin-associated inhibitors, these extracellular histones induced growth cone collapse and inhibited neurite outgrowth. Histones mediate inhibition through the transcription factor YB-1 and Toll-like receptor 2, and these effects are independent of the Nogo receptor. Histone-mediated inhibition can be reversed by the addition of activated protein C (APC) in vitro, and APC treatment promotes axonal regeneration in the crushed optic nerve in vivo. These findings identify extracellular histones as a new class of nerve regeneration-inhibiting molecules within the injured CNS. One sentence summaryProteins typically associated with chromatin structure play an unexpected role in limiting axonal regeneration after injury.

neuroscience↗