Scheduled feeding improves behavioral outcomes and reduces inflammation in a mouse model of Fragile X syndrome

Published: Feb. 21, 2025

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the abnormal expansion of CGG repeats in fragile mental retardation 1 (FMR1) gene. Many FXS patients experience sleep disruptions, and we sought to explore these symptoms along with possible benefits scheduled feeding intervention using Fmr1 knockout (KO) mouse model. These mutants displayed clear evidence for circadian disturbances including delay onset fragmented activity rhythms increases cycle-to-cycle variability. Importantly, KO mice exhibited deficits their behavioral response light reduced masking, longer time resetting shifts Light-Dark cycle, altered synchronization skeleton photoperiod lower magnitude light-induced phase rhythms. Investigation retinal input surprachiasmatic nucleus (SCN) neurotracer cholera toxin (β subunit) quantification light-evoked cFos expression SCN revealed an innervation KO, providing mechanistic explanation observed deficits. Interestingly, disruptions social repetitive behaviors correlated duration fragmentation. Understanding nature deficits, decided apply regimen (6-hr/18-hr feed/fast cycle) as circadian-based strategy boast independently light. This significantly improved mutants. Strikingly, ameliorated interactions well levels Interferon-gamma Interleukin-12 mutants, suggesting that timed eating may be effective way lessen inflammation. Collectively, this work adds support efforts develop based interventions help disorders.

Language: Английский

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Adult Inception of Ketogenic Diet Therapy Increases Sleep during the Dark Cycle in C57BL/6J Wild Type and Fragile X Mice

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6679 - 6679

Published: June 18, 2024

Sleep problems are a significant phenotype in children with fragile X syndrome. Our prior work assessed sleep–wake cycles Fmr1KO male mice and wild type (WT) littermate controls response to ketogenic diet therapy where were treated from weaning (postnatal day 18) through study completion (5–6 months of age). A potentially confounding issue commencing treatment during an active period growth is the reduction weight gain diet. The aim here was employ sleep electroencephalography (EEG) assess Fmr1 genotype diet, starting at postnatal 95. EEG results compared outcomes determine if later intervention efficacious, as well published rest-activity patterns actigraphy viable surrogate for EEG. data replicated findings that exhibit similar littermates dark cycle when maintained on control purified-ingredient but revealed genotype-specific difference hours 4–6 light increased wake (decreased NREM) state mice. Treatment high-fat, low-carbohydrate percentage NREM both cycle. Differences microstructure (length bouts) supported altered states Commencing adulthood resulted 15% 8.6% (Fmr1KO) decrease body after 28 days treatment, not severe associated weaning. We conclude lack evidence improved (mouse time) two studies suggests may be beneficial treating reliable

Language: Английский

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Enhanced CB1 receptor function in GABAergic neurons mediates hyperexcitability and impaired sensory-driven synchrony of cortical circuits in Fragile X Syndrome model mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Electroencephalographic (EEG) recordings in individuals with Fragile X Syndrome (FXS) and the mouse model of FXS ( Fmr1 KO) display cortical hyperexcitability at rest, as well deficits sensory-driven network synchrony. A form circuit is observed ex vivo slices KO mice prolonged persistent activity, or Up, states. It unknown if mechanisms that cause Up states contribute to FXS-relevant EEG phenotypes. Here we examined role endocannabinoids (eCB) resting phenotypes awake mice. Bidirectional changes eCB function are reported depend on synapse type (excitatory inhibitory). We demonstrate pharmacological genetic reduction Cannabinoid Receptor 1 (CB1R) GABAergic neurons rescues synchrony In support these findings, from Layer (L) 2/3 pyramidal revealed enhanced CB1R-mediated suppression inhibitory synaptic currents. contrast, Cnr1 glutamatergic did not affect state duration, but deletion same was sufficient long These findings a where loss leads transmission, activation reduced synchronization. Results suggest antagonism CB1Rs therapeutic strategy correct sensory processing FXS.

Language: Английский

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Auditory steady-state response deficits in Fragile X Syndrome implicate deficits in stimulus representation maintenance and GABAergic modulation

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Fragile X Syndrome (FXS) is a rare, neurodevelopmental disorder caused by mutation to the messenger ribonucleoprotein 1 ( Fmr1 ) gene and characterized sensory processing abnormalities sensitivities, including neural auditory oscillatory disruptions reduced entrainment chirp stimuli. The present study aims evaluate 40 Hz steady state response (ASSR) in FXS stimulus representation maintenance FXS. Adolescents adults (N = 67; 34 33 age, sex-matched typically developed controls (TDC)) completed task during electroencephalography (EEG). Time-frequency analyses using Morlet wavelets were intertrial phase coherence (ITC) event-related spectral perturbation (ERSP), characterization of transient sustained components ASSR. Both ITC p .003) ERSP .004) at for compared TDC. Interestingly, TDC exhibited significantly elevated early, component (100 - 400 ms) which both transition (650 3000 whereas consistently across ASSR suggesting ability mount response. Individuals with exhibit robust reductions magnitude temporal precision stimulus. may represent GABAergic modulation where overall reduction reflect excitatory/inhibitory balance between NMDA input.

Language: Английский

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Scheduled feeding improves behavioral outcomes and reduces inflammation in a mouse model of Fragile X syndrome

Published: Feb. 21, 2025

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the abnormal expansion of CGG repeats in fragile mental retardation 1 (FMR1) gene. Many FXS patients experience sleep disruptions, and we sought to explore these symptoms along with possible benefits scheduled feeding intervention using Fmr1 knockout (KO) mouse model. These mutants displayed clear evidence for circadian disturbances including delay onset fragmented activity rhythms increases cycle-to-cycle variability. Importantly, KO mice exhibited deficits their behavioral response light reduced masking, longer time resetting shifts Light-Dark cycle, altered synchronization skeleton photoperiod lower magnitude light-induced phase rhythms. Investigation retinal input surprachiasmatic nucleus (SCN) neurotracer cholera toxin (β subunit) quantification light-evoked cFos expression SCN revealed an innervation KO, providing mechanistic explanation observed deficits. Interestingly, disruptions social repetitive behaviors correlated duration fragmentation. Understanding nature deficits, decided apply regimen (6-hr/18-hr feed/fast cycle) as circadian-based strategy boast independently light. This significantly improved mutants. Strikingly, ameliorated interactions well levels Interferon-gamma Interleukin-12 mutants, suggesting that timed eating may be effective way lessen inflammation. Collectively, this work adds support efforts develop based interventions help disorders.

Language: Английский

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Scheduled feeding improves behavioral outcomes and reduces inflammation in a mouse model of Fragile X syndrome

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 16, 2024

Abstract Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the abnormal expansion of CGG repeats in fragile mental retardation 1 (FMR1) gene. Many FXS patients experience sleep disruptions, and we sought to explore these symptoms along with possible benefits scheduled feeding intervention using Fmr1 knockout (KO) mouse model. These mutants displayed clear evidence for circadian disturbances including delay onset fragmented activity rhythms increases cycle-to-cycle variability. The KO mice exhibited deficits their behavioral response light reduced masking, longer time resetting shifts LD cycle, altered synchronization skeleton photoperiod lower magnitude light-induced phase rhythms. Investigation retinal input surprachiasmatic nucleus (SCN) neurotracer cholera toxin (β subunit) quantification light-evoked cFos expression SCN revealed an innervation KO, providing mechanistic explanation observed deficits. Interestingly, disruptions social repetitive behavior correlated duration fragmentation. Understanding nature deficits, decided apply regimen (6-hr/18-hr feed/fast cycle) as circadian-based strategy boast independently light. This significantly improved mutants. Strikingly, ameliorated interactions behaviors well levels Interferon-gamma Interleukin-12 mutants, suggesting that timed eating may be effective way reduce inflammation. Collectively, this work adds support efforts develop based interventions help disorders.

Language: Английский

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