Altered EEG, disrupted hippocampal long-term potentiation and neurobehavioral deficits implicate a delirium-like state in a mouse model of sepsis

Consoli, David C.; Spitznagel, Brittany D.; Owen, Benjamin; Kang, Hakmook; Roberson, Shawniqua Williams; Pandharipande, Pratik; Ely, E. Wesley; Nobis, William P.; Bastarache, Julie A.; Harrison, Fiona E.

doi:10.1016/j.bbi.2022.10.003

Cited by 6 publications

(2 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mice were single-housed and given 5 g of cotton nestlet (Ancare, Bellmore, NY) in the afternoon the day prior. The next morning, amount shredded and quality of nests was scored by a blinded observer using a 0-5 scale adapted from previous work, in 0.5 increments (42,56,57). Following nest building assessment, mice were re-housed in groups of 4-5 before all other behavioral tasks.…”

Section: Nest Buildingmentioning

confidence: 99%

Knockdown of microglial iron import gene, DMT1, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer’s disease

Robertson,

Rodriguez,

Cartailler

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Background Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer’s disease (AD). In vitro, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of microglial-specific knockdown of Slc11a2 on AD-related cognitive decline and microglial transcriptional phenotype. Methods In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1Cre − ERT2;Slc11a2flfl;APP/PS1+ or – mice were generated and administered corn oil or tamoxifen to induce knockdown at 5–6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12–15 months of age). Hippocampal CD11b + microglia were magnetically isolated from female mice (15–17 months) and bulk RNA-sequencing analysis was conducted. Results DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2KD APP/PS1 females displayed significant increases in Enpp2, Ttr, and the iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2KD cells from APP/PS1 females also exhibited decreased expression of markers associated with disease-associated microglia (DAMs), such as Apoe, Ctsb, Csf1, and Hif1α. Conclusions This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in Slc11a2KD APP/PS1 female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.

show abstract

Section: Nest Buildingmentioning

confidence: 99%

Knockdown of microglial iron import gene, DMT1, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer’s disease

Robertson,

Rodriguez,

Cartailler

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several groups have reported that EEG can help objectively assess responses to LPS and other inflammatory triggers (19)(20)(21). However, their studies focused on only young mice and did not evaluate the influence of age, which is a well-known major risk factor for delirium.…”

Section: Introductionmentioning

confidence: 99%

The bispectral EEG (BSEEG) method quantifies post-operative delirium-like states in young and aged mice after head mount implantation surgery

Nishiguchi,

Shibata,

Yamanishi

et al. 2024

Preprint

View full text Add to dashboard Cite

Delirium, a syndrome characterized by an acute change in attention, awareness, and cognition, is commonly observed in older adults and has multiple potential triggers, including illness, drug, trauma, and surgery. There are few quantitative monitoring methods in clinical settings. We developed the bispectral electroencephalography (BSEEG) method in clinical research that can detect the presence of and quantify the severity of delirium using a novel algorithm. In the pre-clinical model, we reported that the BSEEG method can capture a delirium-like state in mice following LPS administration. However, its application to post-operative delirium (POD) has not yet been validated in animal experiments. Therefore, this study aimed to create a POD model mouse with the BSEEG method by monitoring BSEEG scores after EEG head-mount implantation surgery throughout the recovery phase. We compared the BSEEG scores of C57BL/6J young (2-3 months old) with aged (18-19 months old) mice for quantitative evaluation of the delirium-like state after the surgery. Postoperatively, both groups showed increased BSEEG scores and a loss of regular diurnal changes in BSEEG scores every daytime and night. In young mice, BSEEG scores and regular diurnal changes recovered relatively quickly to baseline by around postoperative day 3. On the other hand, aged mice had prolonged increases in postoperative BSEEG scores and it reached steady state only after around postoperative day 8. This study suggests the BSEEG method can be utilized to quantitatively evaluate POD and also assess the effect of aging on recovery from POD in pre-clinical model.

show abstract

Microglial-specific knockdown of iron import gene, Slc11a2, blunts LPS-induced neuroinflammatory responses in a sex-specific manner

Volk Robertson,

Schleh,

Harrison

et al. 2024

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

Altered EEG, disrupted hippocampal long-term potentiation and neurobehavioral deficits implicate a delirium-like state in a mouse model of sepsis

Cited by 6 publications

References 91 publications

Knockdown of microglial iron import gene, DMT1, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer’s disease

Knockdown of microglial iron import gene, DMT1, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer’s disease

The bispectral EEG (BSEEG) method quantifies post-operative delirium-like states in young and aged mice after head mount implantation surgery

Microglial-specific knockdown of iron import gene, Slc11a2, blunts LPS-induced neuroinflammatory responses in a sex-specific manner

Contact Info

Product

Resources

About