scholarly journals Suppression of Microgliosis With the Colony-Stimulating Factor 1 Receptor Inhibitor PLX3397 Does Not Attenuate Memory Defects During Epileptogenesis in the Rat

2021 ◽  
Vol 12 ◽  
Author(s):  
Season K. Wyatt-Johnson ◽  
Alexandra L. Sommer ◽  
Kevin Y. Shim ◽  
Amy L. Brewster
Keyword(s):  
Focal Epilepsy ◽  
Memory Function ◽  
Neuronal Loss ◽  
Memory Deficits ◽  
Spatial Learning And Memory ◽  
Barnes Maze ◽  
Colony Stimulating Factor ◽  
Reactive Microglia ◽  
Pilocarpine Model ◽  
Stimulating Factor

Events of status epilepticus (SE) trigger the development of temporal lobe epilepsy (TLE), a type of focal epilepsy that is commonly drug-resistant and is highly comorbid with cognitive deficits. While SE-induced hippocampal injury, accompanied by gliosis and neuronal loss, typically disrupts cognitive functions resulting in memory defects, it is not definitively known how. Our previous studies revealed extensive hippocampal microgliosis that peaked between 2 and 3 weeks after SE and paralleled the development of cognitive impairments, suggesting a role for reactive microglia in this pathophysiology. Microglial survival and proliferation are regulated by the colony-stimulating factor 1 receptor (CSF1R). The CSF1R inhibitor PLX3397 has been shown to reduce/deplete microglial populations and improve cognitive performance in models of neurodegenerative disorders. Therefore, we hypothesized that suppression of microgliosis with PLX3397 during epileptogenesis may attenuate the hippocampal-dependent spatial learning and memory deficits in the rat pilocarpine model of SE and acquired TLE. Different groups of control and SE rats were fed standard chow (SC) or chow with PLX3397 starting immediately after SE and for 3 weeks. Novel object recognition (NOR) and Barnes maze (BM) were performed to determine memory function between 2 and 3 weeks after SE. Then microglial populations were assessed using immunohistochemistry. Control rats fed with either SC or PLX3397 performed similarly in both NOR and BM tests, differentiating novel vs. familiar objects in NOR, and rapidly learning the location of the hidden platform in BM. In contrast, both SE groups (SC and PLX3397) showed significant deficits in both NOR and BM tests compared to controls. Both PLX3397-treated control and SE groups had significantly decreased numbers of microglia in the hippocampus (60%) compared to those in SC. In parallel, we found that PLX3397 treatment also reduced SE-induced hippocampal astrogliosis. Thus, despite drastic reductions in microglial cells, memory was unaffected in the PLX3397-treated groups compared to those in SC, suggesting that remaining microglia may be sufficient to help maintain hippocampal functions. In sum, PLX3397 did not improve or worsen the memory deficits in rats that sustained pilocarpine-induced SE. Further research is required to determine whether microglia play a role in cognitive decline during epileptogenesis.

scholarly journals The Contribution of Stem Cell Factor and Granulocyte-Colony Stimulating Factor in Reducing Neurodegeneration and Promoting Neural Network Reorganization after Traumatic Brain Injury

2019 ◽  
Author(s):  
Junchi He ◽  
Thomas Russell ◽  
Xuecheng Qiu ◽  
Fei Hao ◽  
Michele Kyle ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Spatial Learning And Memory ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hippocampal Ca1 ◽  
Severe Tbi ◽  
Stimulating Factor

Abstract Background Traumatic brain injury (TBI) is a major cause of death and disability in young adults worldwide. TBI-induced long-term cognitive deficits represent a growing clinical problem.Stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF)play a role in neuroprotection and neuronal plasticity.However, the knowledge concerning reparative efficacy of SCF+G-CSF treatment in post-acute TBI recovery remains incomplete. This study aims to determine the effectsof stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) on post-TBI recovery in young adult mice. The controlled cortical impact model of TBI was used for inducing a severe damage in the motor cortex of the right hemisphere in 8-week-old male C57BL mice. The combination treatment of SCF and G-CSF (SCF+G-CSF) was initiated 3 weeks after induction of TBI. Results Severe TBI led to persistent motor functional deficits (Rota-Rod test) and impaired spatial learning and memory (Morris water maze test). SCF+G-CSF treatment significantly improved the severe TBI-impaired spatial learning and memory at 6 weeks post-treatment.TBI also caused significant increases of Fluoro-Jade C positive degenerating neurons in bilateral frontal cortex, striatum and hippocampus, and significant reductions in MAP2+apical dendrites and overgrowth of SMI312+axons in peri-TBI cavity frontal cortex and in the ipsilateral hippocampal CA1 at 24 weeks post-TBI. SCF+G-CSF treatment significantly reduced TBI-induced neurodegeneration in the contralateral frontal cortex and hippocampal CA1, increased MAP2+apical dendrites in the peri-TBI cavity frontal cortex, and prevented TBI-induced axonal overgrowth in both the peri-TBI cavity frontal cortex and ipsilateral hippocampal CA1. Conclusions These findings reveal a novel pathology of axonal overgrowth after TBI and demonstrate a therapeutic potential of SCF+G-CSF in ameliorating TBI-induced long-term neuronal pathology, neural network malformation, and impairments in spatial learning and memory.

scholarly journals G-CSF Administration is Neuroprotective following Transient Cerebral Ischemia Even in the Absence of a Functional NOS-2 Gene

2010 ◽  
Vol 30 (4) ◽  
pp. 739-743 ◽  
Author(s):  
Claire L Gibson ◽  
Philip MW Bath ◽  
Sean P Murphy
Keyword(s):  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Neuronal Loss ◽  
Motor Deficit ◽  
Motor Deficits ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Oxide Synthase ◽  
Stimulating Factor ◽  
Deficient Mice

Granulocyte colony-stimulating factor (G-CSF) is a candidate neuroprotective factor following cerebral ischemia. To determine whether G-CSF acts partly through the inhibition of nitric oxide synthase (NOS)-2 expression, we administered G-CSF to male NOS-2−/− mice after cerebral ischemia. Although male NOS-2−/− mice exhibit resistance to the gross effects of cerebral ischemia, they display neuronal loss and skilled motor deficits following cerebral ischemia. Administration of G-CSF during reperfusion reduced motor deficit and neuronal loss. Thus, G-CSF is still effective in NOS-2 gene-deficient mice, suggesting that part of the mechanism of action is independent of NOS-2.

scholarly journals Deleterious Effects of Ethanol, Δ(9)-Tetrahydrocannabinol (THC), and Their Combination on the Spatial Memory and Cognitive Flexibility in Adolescent and Adult Male Rats in the Barnes Maze Task

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 654
Author(s):  
Ewa Gibula-Tarlowska ◽  
Karolina Wydra ◽  
Jolanta H. Kotlinska
Keyword(s):  
Spatial Memory ◽  
Cognitive Flexibility ◽  
Drugs Of Abuse ◽  
Memory Function ◽  
Male Rats ◽  
Spatial Learning And Memory ◽  
Barnes Maze ◽  
Maze Task ◽  
Adult Rats ◽  
Ethanol Abuse

Research demonstrates that adolescents differ from adults in their response to drugs of abuse. The aim of the present study was to examine the influence of ethanol, Δ9-tetrahydrocannabinol hydrochloride (THC), and a combination of these drugs given during adolescence on spatial memory in adolescent and adult rats. Thus, adolescent rats (postnatal day (PND) 30) were subjected to the following groups: 0.9% NaCl; 1.5 g/kg ethanol; 1.0 mg/kg THC; 1.5 g/kg ethanol + 1.0 mg/kg THC. Rats received drug injection four times at three-day intervals. One day after the last injection, half of the treated animals were tested in the Barnes maze task, whereas the remaining animals were tested on PND 70. Results show that there was a significant age effect on spatial memory in the Barnes maze task after these drug administrations. Adolescent animals demonstrated more potent deficits in the spatial learning and memory (probe trial) and in cognitive flexibility (reversal learning) than did adults. However, in adult rats that received these drugs in adolescence, memory decline was observed only after ethanol and ethanol + THC administration. Thus, our results are important in understanding the deleterious impact of THC and/or ethanol abuse during adolescence on memory function across the lifespan (adolescent versus adult).

scholarly journals Abrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairments

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kisha Greer ◽  
Erwin Kristobal Gudenschwager Basso ◽  
Colin Kelly ◽  
Alison Cash ◽  
Elizabeth Kowalski ◽  
...  
Keyword(s):  
Brain Injury ◽  
Learning And Memory ◽  
Cell Fate ◽  
Neural Progenitor Cells ◽  
Memory Deficits ◽  
Spatial Learning And Memory ◽  
Barnes Maze ◽  
Wild Type ◽  
Memory Impairments ◽  
Cell Changes

Abstract Brain injury resulting from repeated mild traumatic insult is associated with cognitive dysfunction and other chronic co-morbidities. The current study tested the effects of aberrant neurogenesis in a mouse model of repeated mild traumatic brain injury (rmTBI). Using Barnes Maze analysis, we found a significant reduction in spatial learning and memory at 24 days post-rmTBI compared to repeated sham (rSham) injury. Cell fate analysis showed a greater number of BrdU-labeled cells which co-expressed Prox-1 in the DG of rmTBI-injured mice which coincided with enhanced cFos expression for neuronal activity. We then selectively ablated dividing neural progenitor cells using a 7-day continuous infusion of Ara-C prior to rSham or rmTBI. This resulted in attenuation of cFos and BrdU-labeled cell changes and prevented associated learning and memory deficits. We further showed this phenotype was ameliorated in EphA4f./f/Tie2-Cre knockout compared to EphA4f./f wild type mice, which coincided with altered mRNA transcript levels of MCP-1, Cx43 and TGFβ. These findings demonstrate that cognitive decline is associated with an increased presence of immature neurons and gene expression changes in the DG following rmTBI. Our data also suggests that vascular EphA4-mediated neurogenic remodeling adversely affects learning and memory behavior in response to repeated insult.

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