Biology subjects

Shaver, J.

Publications and source records attributed to Shaver, J..

5 recordsLinked to original sources

bioRxiv2025

In C57Bl6 Mice, Obesity and Subsequent Weight Loss Negatively Affected the Skeleton and Shifted the Cortical Bone Metabolome

Obesity and calorie restriction each negatively affect skeletal health. Despite the negative effects of weight loss on the skeleton, obese patients are advised to lose weight via calorie restriction. Additionally, obesity and weight loss individually alter both whole-body and local metabolism. Little is known about bone quality and changes to the cortical metabolome following calorie restriction in obese preclinical models. We hypothesized that caloric restriction would worsen bone quality in obese mice by shifting the cortical bone metabolome. To induce obesity, 8-week-old male and female C57BL6/J mice received 60% high-fat diet for 12 weeks. From 20 to 30 weeks of age, mice either remained obese or lost weight through 30% caloric restriction. Control animals received a 10% low-fat diet. Bodyweight and fat mass were increased by obesity and decreased with calorie restriction. Similarly, glucose and insulin tolerance were worsened with obesity but improved by weight loss. Compared to obesity, calorie restriction elicited more bone loss in both cortical and trabecular compartments. Weight loss also reduced bone formation. Both obesity and subsequent calorie restriction altered the cortical bone metabolome in a sex-dependent manner. Metabolic pathways altered with diet generally mapped to amino acid or fatty acid metabolism. In males, weight loss was associated with a downregulation of pathways related to tryptophan, tyrosine, ubiquinone, and fatty acids. In females, calorie restriction downregulated taurine and hypotaurine metabolism but upregulated pyrimidine metabolism, nicotinate and nicotinamide metabolism, and pantothenate and CoA biosynthesis. Our findings highlight the negative effects of obesity and subsequent caloric restriction on the skeleton. Despite improvements in components of systemic metabolism, caloric restriction in obese preclinical models did not restore bone morphology or the cortical metabolome to control conditions.

cell biology↗

bioRxiv2023

Hypnotic treatment reverses NREM sleep disruption and EEG desynchronization in a mouse model of Fragile X syndrome to rescue memory consolidation deficits.

Fragile X syndrome (FXS) is a highly-prevalent genetic cause of intellectual disability, associated with disrupted cognition and sleep abnormalities. Sleep loss itself negatively impacts cognitive function, yet the contribution of sleep loss to impaired cognition in FXS is vastly understudied. One untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We hypothesized that restoration of sleep-dependent mechanisms could improve functions such as memory consolidation in FXS. We examined whether administration of ML297, a hypnotic drug acting on G-protein-activated inward-rectifying potassium channels, could restore sleep phenotypes and improve disrupted memory consolidation in Fmr1-/y mice. Using 24-h polysomnographic recordings, we found that Fmr1-/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM sleep architecture, alterations in NREM EEG spectral power (including reductions in sleep spindles), and reduced EEG coherence between cortical areas. These alterations were reversed in the hours following ML297 administration. Hypnotic treatment following contextual fear or spatial learning also ameliorated disrupted memory consolidation in Fmr1-/y mice. Hippocampal activation patterns during memory recall was altered in Fmr1-/y mice, reflecting an altered balance of activity among principal neurons vs. parvalbumin-expressing (PV+) interneurons. This phenotype was partially reversed by post-learning ML297 administration. These studies suggest that sleep disruption could have a major impact on neurophysiological and behavioral phenotypes in FXS, and that hypnotic therapy may significantly improve disrupted cognition in this disorder.

neuroscience↗

bioRxiv2020

Non-REM sleep facilitates consolidation of contextual fear memory through temporal coding among hippocampal neurons

Sleep plays a critical role in memory consolidation, although the exact mechanisms mediating this process are unknown. Combining computational and in vivo experimental approaches, we test the hypothesis that reduced cholinergic input to the hippocampus during non-rapid eye movement (NREM) sleep generates stable spike timing relationships between neurons. We find that the order of firing among neurons during a period of NREM sleep reflects their relative firing rates during prior wake, and changes as a function of prior learning. We show that learning-dependent pattern formation (e.g. "replay") in the hippocampus during NREM, together with spike timing dependent plasticity (STDP), restructures network activity in a manner similar to that observed in brain circuits across periods of sleep. This suggests that sleep actively promotes memory consolidation by switching the network from rate-based to firing phase-based information encoding.

neuroscience↗

bioRxiv2020

Causal role for sleep-dependent reactivation of learning-activated sensory ensembles for fear memory consolidation

Learning-activated engram neurons play a critical role in memory recall. An untested hypothesis is that these same neurons play an instructive role in offline memory consolidation. Here we show that a visually-cued fear memory is consolidated during post-conditioning sleep in mice. We then use TRAP (targeted recombination in active populations) to genetically label or optogenetically manipulate primary visual cortex (V1) neurons responsive to the visual cue. Following fear conditioning, mice respond to activation of this visual engram population in a manner similar to visual presentation of fear cues. Cue-responsive neurons are selectively reactivated in V1 during post-conditioning sleep. Mimicking visual engram reactivation optogenetically leads to increased representation of the visual cue in V1. Optogenetic inhibition of the engram population during post-conditioning sleep disrupts consolidation of fear memory. We conclude that selective sleep-associated reactivation of learning-activated sensory populations serves as a necessary instructive mechanism for memory consolidation.

neuroscience↗

bioRxiv2019

Network resonance during slow-wave sleep facilitates memory consolidation through phase-coding

Sleep plays a critical role in memory consolidation, however, the exact role that sleep and its effects on neural network dynamics play in this process is still unclear. Here, we combine computational and experimental approaches to study the dynamical, network-wide underpinnings of hippocampal memory consolidation during sleep. We provide data to support a novel hypothesis on the role of cellular resonance with sleep-associated theta band (4-12 Hz) hippocampal oscillations in this process. We show that increases in the stability of hippocampal memory representations after learning (which predicts successful memory consolidation) are mediated through emergent network-wide resonance and locking of neuronal activity to network oscillations. These changes arise in the network as a function of changes to network structure during learning, and mirror experimental findings in the hippocampus. Finally, we show that input-dependent pattern formation (e.g. "replay") in the hippocampus during sleep states, together with spike timing dependent plasticity (STDP)-based memory consolidation, leads to universal network activity reorganization. This reorganization generates heterogeneous changes in neuronal spiking frequency, similar to what has been observed in a variety of brain circuits across periods of sleep. Our results support the hypothesis that sleep plays an active role in memory consolidation by switching the hippocampal network from rate-based to phase-based information representation. The mechanisms through which this occurs supports the integration of heterogeneous cell populations into memory traces. Significance StatementIn this study, we provide a mechanistic explanation of how sleep selectively facilitates memory consolidation, through recruitment of heterogeneous neuronal populations and structural reorganization of the network into an engram. Specifically, we show that emergent theta band oscillations during sleep facilitate stabilization of memory representations via spike timing dependent reinforcement. This stabilization, together with STDP, allows for systematic reorganization of synaptic connections within these populations, universally redistributing firing rates of participating neurons. Simultaneously, network oscillations facilitate a switch from rate-to phase-coding of information among neuronal populations with highly heterogenous firing frequencies, incorporating more neurons into the engram. Our results reconcile discrepant findings on network reorganization during sleep, and demonstrate a clear mechanism for both strengthening and weakening of synaptic efficacy during sleep.

neuroscience↗