Biology subjects

Singletary, K. G.

Publications and source records attributed to Singletary, K. G..

5 recordsLinked to original sources

bioRxiv2025

Loss of MeCP2 leads to sleep deficits that are time-of-day dependent and worsen with sleep deprivation

Rett syndrome (RTT) is a severe, progressive neurodevelopmental disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Sleep problems are frequently reported in Rett Syndrome, but the exact nature remains relatively unexplored. Currently there is limited understanding the role of MECP2 in sleep architecture and regulation. In this study, we employed longitudinal electroencephalographic (EEG) and electromyographic (EMG) recordings to investigate sleep architecture during baseline conditions as well as the homeostatic response to sleep deprivation (SD) in Mecp2-/y male mice. At baseline, Mecp2-/y mice have more non-rapid-eye-movement (NREM) sleep and less rapid-eye-movement (REM) sleep than their wildtype littermates during the light period. However, Mecp2-/y mice display altered sleep timing during the dark period, spending more time in both NREM and REM during the first half and less time during the second half. We also observe differences in REM sleep and wake quality based on spectral properties of the EEG. In response to SD, Mecp2-/y mice can accumulate and discharge sleep pressure normally and show a sleep rebound. However, baseline differences in sleep architecture are heightened after SD. Overall, our findings show that RTT mice exhibit distinct sleep patterns compared to wildtype mice, with time-of-day-dependent variations in NREM and REM sleep, as well as altered EEG spectral properties, that become more pronounced following SD. Future research should explore the molecular mechanisms through which MECP2 regulates circadian sleep architecture to develop targeted therapeutics for sleep disturbances in RTT patients. HighlightsO_LIMecp2-/y mice show time-of-day-dependent alterations in NREM and REM sleep. C_LIO_LIEEG analysis revealed distinct sleep and wake quality in Mecp2-/y mice. C_LIO_LISleep deprivation exacerbates baseline sleep architecture differences. C_LIO_LILongitudinal EEG/EMG recordings captured comprehensive sleep patterns. C_LI

neuroscience↗

bioRxiv2023

Ontogenesis of the molecular response to sleep loss

Sleep deprivation (SD) results in profound cellular and molecular changes in the adult mammalian brain. Some of these changes may result in, or aggravate, brain disease. However, little is known about how SD impacts gene expression in developing animals. We examined the transcriptional response in the prefrontal cortex (PFC) to SD across postnatal development in male mice. We used RNA sequencing to identify functional gene categories that were specifically impacted by SD. We find that SD has dramatically different effects on PFC genes depending on developmental age. Gene expression differences after SD fall into 3 categories: present at all ages (conserved), present when mature sleep homeostasis is first emerging, and those unique to certain ages in adults. Developmentally conserved gene expression was limited to a few functional categories, including Wnt-signaling which suggests that this pathway is a core mechanism regulated by sleep. In younger ages, genes primarily related to growth and development are affected while changes in genes related to metabolism are specific to the effect of SD in adults.

neuroscience↗

bioRxiv2021

Shank3 influences mammalian sleep development

Sleep problems are prevalent in Autism Spectrum Disorder (ASD), can be observed before diagnosis, and are associated with increased restricted and repetitive behaviors. Therefore, sleep abnormalities may be a core feature of the disorder, but the developmental trajectory remains unknown. Animal models provide a unique opportunity to understand sleep ontogenesis in ASD. Previously we showed that adult mice with a truncation in the high-confidence ASD gene Shank3 (Shank3{Delta}C) recapitulate the clinical sleep phenotype. In this study we used longitudinal electro-encephalographic (EEG) recordings to define, for the first time, changes in sleep from weaning to young adulthood in an ASD mouse model. We show that Shank3{Delta}C mice sleep less overall throughout their lifespan, have increased rapid eye movement (REM) sleep early in life despite significantly reduced non-rapid eye movement (NREM) sleep, and have abnormal responses to increased sleep pressure that emerge during a specific developmental period. We demonstrate that the ability to fall asleep quickly in response to sleep loss develops normally between 24 and 30 days in mice. However, mutants are unable to reduce sleep latency after periods of prolonged waking and maintain the same response to sleep loss regardless of age. This phenomenon seems independent of homeostatic NREM sleep slow-wave dynamics. Overall, our study recapitulates both preclinical models and clinical studies showing that reduced sleep is consistently associated with ASD and suggests that problems falling asleep may reflect abnormal development of sleep and arousal mechanisms. SIGNIFICANCE STATEMENTIn this first longitudinal sleep study in an Autism mouse model, we demonstrate that sleeping less seems a core feature of the disorder while problems falling asleep emerge during development.

neuroscience↗

bioRxiv2019

A role for astroglial calcium in mammalian sleep

Mammalian sleep is characterized by dramatic changes in neuronal activity, and waking neuronal activity is thought to increase sleep need. Changes in other brain cells (glia) across the natural sleep-wake cycle and their role in sleep regulation are comparatively unexplored. We show that sleep is also accompanied by large changes in astroglial activity as measured by intracellular calcium concentrations in unanesthetized mice. These changes in calcium vary across different vigilance states and are most pronounced in distal astroglial processes. We find that reducing intracellular calcium in astrocytes impaired the homeostatic response to sleep deprivation. Thus, astroglial calcium changes dynamically across vigilance states and is a component of the sleep homeostat.\n\nOne Sentence SummaryAstroglial calcium concentrations vary with sleep and wake, change after sleep deprivation, and mediate sleep need.

neuroscience↗

bioRxiv2018

Shank3 Modulates Sleep and Expression of Circadian Transcription Factors

Autism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States and often co-presents with sleep problems. Sleep problems in ASD predict the severity of ASD core diagnostic symptoms and have a considerable impact on the quality of life of caregivers. Little is known, however, about the underlying molecular mechanisms. We investigated the role of Shank3, a high confidence ASD gene candidate, in sleep architecture and regulation. We show that mice lacking exon 21 of Shank3 have problems falling asleep even when sleepy. Using RNA-seq we show that sleep deprivation increases the differences in gene expression between mutants and wild types, downregulating circadian transcription factors Per3, Dec2, Hlf, Tef, and Reverb. Shank3 mutants also have trouble regulating wheel-running activity in constant darkness. Overall our study shows that Shank3 is an important modulator of sleep and clock gene expression.

neuroscience↗