Changes in 24 h Rhythmicity of Spontaneous Locomotor Activity in the Triple Transgenic Mouse for Alzheimer’s Disease (3xTg-AD) in a Jet Lag Protocol: Correlations with Retinal Sensitivity

González-Luna, Irma Angélica; Juárez-Tapia, Cinthia; Aguilar-Vázquez, Azucena; Arnold, Edith; Dı́az-Cintra, Sofı́a; Miranda‐Anaya, Manuel; Dı́az-Muñoz, Mauricio

doi:10.5334/jcr.214

Cited by 2 publications

(6 citation statements)

References 56 publications

(75 reference statements)

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“…This is the first report, to our knowledge, of altered jet lag behavior in AD model mice. Previous studies in APP/PS1 mice ( Otalora et al, 2012 ; Kent et al, 2019 ) and male 3xTg mice ( González-Luna et al, 2021 ) did not show altered re-entrainment in the jet lag paradigm. However, the APP/PS1 model has been criticized as not replicating some circadian phenotypes observed in AD patients ( Sheehan and Musiek, 2020 ) and most studies find less severe pathophysiology and behavioral phenotypes in male than female 3xTg mice ( Dennison et al, 2021 ).…”

Section: Discussionmentioning

confidence: 61%

“…Our finding of increased sensitivity to low-intensity photic circadian cues in an AD model suggests mechanisms outside the SCN may play a role in the jet lag phenotype. A previous study found increased negative masking in male 3xTg mice ( González-Luna et al, 2021 ) but did not examine behavior at low light levels. The retinal degeneration in AD models, including 3xTg mice ( Grimaldi et al, 2018 ), and ipRGC loss in AD ( La Morgia et al, 2016 ) suggest decreased sensitivity, not increased.…”

Section: Discussionmentioning

confidence: 86%

“…In a photic phase shift experiment, which measures the shifting of circadian behavior caused by one pulse of light during the dark phase, female 3xTg mice showed a trend toward greater phase shifting while males did not ( Sterniczuk et al, 2010 ). We examined re-entrainment in these mice using a shifted light-dark (LD) cycle, simulating travel across 6 time zones and subsequent “jet lag.” This behavior is not altered in male 3xTg mice ( González-Luna et al, 2021 ), but female mice, which have more severe AD pathology than males, have not been studied in this paradigm. We allowed female 8-month-old (mo) 3xTg and B6129SF2/J wild type (WT) control mice to entrain to a 12:12 L:D light cycle and monitored their behavior on a running wheel.…”

Section: Resultsmentioning

confidence: 99%

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Altered circadian behavior and light sensing in mouse models of Alzheimer’s disease

Weigel¹,

Guo²,

Güler³

et al. 2023

Front. Aging Neurosci.

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Circadian symptoms have long been observed in Alzheimer’s disease (AD) and often appear before cognitive symptoms, but the mechanisms underlying circadian alterations in AD are poorly understood. We studied circadian re-entrainment in AD model mice using a “jet lag” paradigm, observing their behavior on a running wheel after a 6 h advance in the light:dark cycle. Female 3xTg mice, which carry mutations producing progressive amyloid beta and tau pathology, re-entrained following jet lag more rapidly than age-matched wild type controls at both 8 and 13 months of age. This re-entrainment phenotype has not been previously reported in a murine AD model. Because microglia are activated in AD and in AD models, and inflammation can affect circadian rhythms, we hypothesized that microglia contribute to this re-entrainment phenotype. To test this, we used the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, which rapidly depletes microglia from the brain. Microglia depletion did not alter re-entrainment in either wild type or 3xTg mice, demonstrating that microglia activation is not acutely responsible for the re-entrainment phenotype. To test whether mutant tau pathology is necessary for this behavioral phenotype, we repeated the jet lag behavioral test with the 5xFAD mouse model, which develops amyloid plaques, but not neurofibrillary tangles. As with 3xTg mice, 7-month-old female 5xFAD mice re-entrained more rapidly than controls, demonstrating that mutant tau is not necessary for the re-entrainment phenotype. Because AD pathology affects the retina, we tested whether differences in light sensing may contribute to altered entrainment behavior. 3xTg mice demonstrated heightened negative masking, a circadian behavior measuring responses to different levels of light, and re-entrained dramatically faster than WT mice in a jet lag experiment performed in dim light. 3xTg mice show a heightened sensitivity to light as a circadian cue that may contribute to accelerated photic re-entrainment. Together, these experiments demonstrate novel circadian behavioral phenotypes with heightened responses to photic cues in AD model mice which are not dependent on tauopathy or microglia.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Altered circadian behavior and light sensing in mouse models of Alzheimer’s disease

Weigel¹,

Guo²,

Güler³

et al. 2023

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…This is the first report, to our knowledge, of altered jet lag behavior in AD model mice. Previous studies in APP/PS1 mice (Kent et al, 2019;Otalora et al, 2012) and male 3xTg mice (González-Luna et al, 2021) did not show altered re-entrainment in the jet lag paradigm. However, the APP/PS1 model has been criticized as not replicating some circadian phenotypes observed in AD patients and most studies find less severe pathophysiology and behavioral phenotypes in male than female 3xTg mice (Dennison et al, 2021).…”

Section: Discussionmentioning

confidence: 63%

“…We examined re-entrainment in these mice using a shifted light-dark (LD) cycle, simulating travel across 6 time zones and subsequent "jet lag". This behavior is not altered in male 3xTg mice (González-Luna et al, 2021), but female mice, which have more severe AD pathology than males, have not been studied in this paradigm. We allowed female 8-month-old 3xTg and B6129SF2/J wild type (WT) control mice to entrain to a 12:12 L:D light cycle and monitored their behavior on a running wheel.…”

Section: Xtg Mice Have Accelerated Circadian Re-entrainmentmentioning

confidence: 96%

Altered circadian behavior and light sensing in mouse models of Alzheimer’s disease

Weigel

Guo

Güler

et al. 2023

Preprint

View full text Add to dashboard Cite

Circadian symptoms have long been observed in Alzheimer's disease (AD) and often appear before cognitive symptoms, but the mechanisms underlying circadian alterations in AD are poorly understood. We studied circadian re-entrainment in AD model mice using a "jet lag" paradigm, observing their behavior on a running wheel after a six hour advance in the light:dark cycle. Female 3xTg mice, which carry mutations producing progressive amyloid beta and tau pathology, re-entrained following jet lag more rapidly than age-matched wild type controls at both 8 and 13 months of age. This re-entrainment phenotype has not been previously reported in a murine AD model. Because microglia are activated in AD and in AD models, and inflammation can affect circadian rhythms, we hypothesized that microglia contribute to this re-entrainment phenotype. To test this, we used the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, which rapidly depletes microglia from the brain. Microglia depletion did not alter re-entrainment in either wild type or 3xTg mice, demonstrating that microglia activation is not acutely responsible for the re-entrainment phenotype. To test whether mutant tau pathology is necessary for this behavioral phenotype, we repeated the jet lag behavioral test with the 5xFAD mouse model, which develops amyloid plaques, but not neurofibrillary tangles. As with 3xTg mice, 7-month-old female 5xFAD mice re-entrained more rapidly than controls, demonstrating that mutant tau is not necessary for the re-entrainment phenotype. Because AD pathology affects the retina, we tested whether differences in light sensing may contribute to altered entrainment behavior. 3xTg mice demonstrated heightened negative masking, an SCN-independent circadian behavior measuring responses to different levels of light, and re-entrained dramatically faster than WT mice in a jet lag experiment performed in dim light. 3xTg mice show a heightened sensitivity to light as a circadian cue that may contribute to accelerated photic re-entrainment. Together, these experiments demonstrate novel circadian behavioral phenotypes with heightened responses to photic cues in AD model mice which are not dependent on tauopathy or microglia.

show abstract

Changes in 24 h Rhythmicity of Spontaneous Locomotor Activity in the Triple Transgenic Mouse for Alzheimer’s Disease (3xTg-AD) in a Jet Lag Protocol: Correlations with Retinal Sensitivity

Cited by 2 publications

References 56 publications

Altered circadian behavior and light sensing in mouse models of Alzheimer’s disease

Altered circadian behavior and light sensing in mouse models of Alzheimer’s disease

Altered circadian behavior and light sensing in mouse models of Alzheimer’s disease

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