Biology subjects

O'Hara, B. F.

Publications and source records attributed to O'Hara, B. F..

8 recordsLinked to original sources

bioRxiv2025

Dim light at night impacts circadian rhythms and Alzheimer's disease-like neuroinflammation and neuropathology in humanized APP SAA knock-in mice

Artificial light at night (light pollution) is widespread but understudied in the context of Alzheimers disease (AD). Sleep and circadian disruption have been linked to amyloid-{beta} (A{beta}) accumulation and neuroinflammation, but whether dim light at night (dLAN) modifies these processes remains unclear. We tested whether chronic dLAN exposure (8 lux during the dark phase, 8 weeks) alters circadian rhythms, amyloid pathology, and neuroinflammation in 12-13 month-old humanized APP knock-in (KI) mice. hAPPSAA KI mice, which develop plaques, were compared with hAPPWT KI controls carrying only a humanized APP sequence. dLAN reduced circadian rhythm amplitude and stability while increasing fragmentation in both genotypes within two weeks. In hAPPSAA KI mice, dLAN modestly increased hippocampal plaque burden and soluble neocortical A{beta}. Astrocyte reactivity was elevated by genotype but not altered by nighttime light exposure. In contrast, microglial markers (CD45, MHCII) were increased with dLAN with CD45+ area elevated in hippocampus, and MHCII+ cell counts greater in the cortex and hippocampus of hAPPSAA KI mice. There were also distinct spatial responses between the microglia markers suggesting that dLAN primes microglia toward an antigen-presenting phenotype (MHCII) in the presence of A{beta}. Yet, the microglia/macrophage priming was not associated with amplified cytokine or chemokine levels at the 8-week dLAN exposure timepoint in the brain. These findings add to growing evidence that nighttime light exposure can disrupt circadian and immune regulation, and suggest that environmental light pollution should be further explored as a modifiable factor contributing to Alzheimers disease progression. Statement of SignificanceLight at night is a common feature of modern life, yet its influence on Alzheimers disease remains poorly understood. We show that dim light at night disrupts circadian rhythms, modestly increases amyloid pathology, and shifts microglia toward an antigen-presenting state in an amyloid-prone model. These findings identify light at night as a modifiable factor that may worsen risk or progression of neurodegenerative disease. A critical gap is whether circadian and immune changes resolve after darkness at night is restored. If they persist, early exposure could leave lasting imprints on brain aging. Addressing this question is essential for guiding strategies to mitigate the impact of light pollution.

neuroscience↗

bioRxiv2025

Unbiased genetics identifies a glutamatergic signaling network as a mediator of daily sleep patterns.

Sleep is a fundamental, conserved behavior important for survival. In many species, sleep behavior is controlled by poorly understood interactions between a system of circadian rhythms (CR), which promote sleep at ecologically appropriate times, and a homeostatic sleep drive that accumulates with time awake. The CR is a cellular phenomenon, driven by molecular oscillations of "clock genes" in nearly all cells. Emerging evidence indicates neuronal synapses are a key locus for the accumulation and resolution of sleep need, supporting a cellular basis of sleep need. Indeed, efforts to understand the genetic basis of sleep need identified Homer1a, a regulator of synapse homeostasis. To develop further insight into the genetic basis of sleep regulation, we measured daily sleep patterns in genetically diverse strains of mice from the Collaborative Cross. Strains with 1) highly consolidated light-phase sleep, or 2) fragmented, arrhythmic sleep, were identified for genetic analysis using quantitative trait loci (QTL) mapping. Excitingly, in F2 hybrids, 19 of 32 metrics of sleep and circadian behavior mapped to a narrow QTL containing GRM5, a postsynaptic glutamate receptor and binding partner of Homer1a, and GCPII, an astrocytic enzyme that regulates NAAG, a peptide agonist for the presynaptic/astrocytic glutamate receptor GRM3. Collectively, these genes form a coordinated glutamatergic signaling network across the tri-partite synapse. Pharmacology targeting GRM5, GCPII, and GRM3 strongly modulated sleep, functionally validating them as sleep-regulating genes. Our findings support a model in which synapses act as a cellular site for integration of circadian and sleep-need signals to regulate daily sleep patterns. Significance StatementSleep is a fundamental pillar of human health. Restorative sleep is supported by circadian rhythms (CR). Sleep and CR disruptions are prevalent in neuropsychiatric conditions and are increasingly understood as causal drivers of altered brain function and behavior. Therefore, sleep and CR are attractive therapeutic targets to improve health. However, the basic biological mechanisms that couple our need to sleep with the CR are not understood. Genetic discovery using diverse strains of mice identifies a glutamatergic signaling network coordinated across the synapse as an underlying genetic basis for daily sleep patterns. This work builds upon a growing body showing that excitatory synapses are a cellular site for the resolution of sleep need and interaction with the CR.

neuroscience↗

bioRxiv2024

Characterization of sleep in a mouse model of CLN3 disease revealed sex-specific sleep disturbances

The neuronal ceroid lipofuscinoses (NCLs) are a group of recessively inherited neurodegenerative diseases characterized by lysosomal storage of fluorescent materials. CLN3 disease, or juvenile Batten disease, is the most common NCL that is caused by mutations in the Ceroid Lipofuscinosis, Neuronal 3 (CLN3) gene. Sleep disturbances are among the most common symptoms associated with CLN3 disease, yet this is understudied and has not been delineated in an animal model of the disease. The current study utilized a non-invasive, automated piezoelectric motion sensing system (PiezoSleep) to classify sleep and wakefulness in a Cln3{phi}..ex1-6/{phi}..ex1-6 (Cln3KO) mouse model and age- and sex-matched wild-type (WT) controls. The sleep-wake classification by PiezoSleep was found to be about 90% accurate when validated against simultaneous gold standard polysomnographic recordings including electroencephalography (EEG) and electromyography (EMG) in a small cohort of WT and Cln3KO mice. Our large cohort PiezoSleep study reveals sleep abnormalities during the light period (LP) in male Cln3KO mice compared to WT male, and more subtle differences in Cln3KO female mice throughout the dark period (DP) compared to WT female, recapitulating sleep abnormalities seen in CLN3 disease patients. Our characterization of sleep in a mouse model of CLN3 disease contributes to a better understanding of the sleep disturbances commonly reported for CLN3 disease and other NCLs, which will facilitate the development of new disease treatment and management strategies.

neuroscience↗

bioRxiv2021

Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1

Growing evidence indicates that microglia impact brain function by regulating synaptic pruning and formation, as well as synaptic transmission and plasticity. Iba1 (Ionized Ca+2-binding adapter protein 1), encoded by the Allograft inflammatory factor 1 (Aif1) gene, is an actin-interacting protein in microglia. Although Iba1 has long been used as a cellular marker for microglia, its functional role remains unknown. Here, we used global Iba1-deficient (Aif1-/-) mice to characterize microglial activity, synaptic function and behavior. Microglial imaging in acute hippocampal slices and fixed tissues from juvenile mice revealed that Aif1-/- microglia display reductions in ATP-induced motility and ramification, respectively. Biochemical assays further demonstrated that Aif1-/- brain tissues exhibit an altered expression of microglial-enriched proteins associated with synaptic pruning. Consistent with these changes, juvenile Aif1-/- mice displayed deficits in excitatory synapse number and synaptic transmission assessed by neuronal labeling and whole-cell patch-clamp recording in acute hippocampal slices. Unexpectedly, microglial synaptic engulfment capacity was diminished in juvenile Aif1-/- mice. During early postnatal development when synapse formation is a predominant event in the hippocampus, excitatory synapse number was still reduced in Aif1-/- mice. Together these findings support an overall role of Iba1 in excitatory synaptic growth in juvenile mice. Lastly, postnatal synaptic deficits persisted in the adulthood and correlated with significant behavioral changes in adult Aif1-/- mice, which exhibited impairments in object recognition memory and social interaction. These results suggest that Iba1 critically contributes to microglial activity underlying essential neuro-glia developmental processes that may deeply influence behavior. SignificanceAbnormal microglia-neuron interaction is increasingly implicated in neurodevelopmental and neuropsychiatric conditions such as autism spectrum disorders and schizophrenia, as well as in neurodegenerative disorders such as Alzheimers disease. This study demonstrates that deletion of the microglia-specific protein Iba1, which has long been utilized as a selective microglial marker but whose role has remained unidentified, results in microglial structural and functional impairments that significantly impact synaptic development and behavior. These findings not only highlight the importance of microglia in brain function but may also suggest that modifying microglial function could provide a therapeutic strategy for treatment of neurodevelopmental, neuropsychiatric and neurodegenerative disorders.

neuroscience↗

bioRxiv2020

Genetic Variation Regulates Opioid-Induced Respiratory Depression in Mice

In the U.S., opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014, leading to an epidemic in addiction and overdose deaths. The most common cause of opioid overdose and death is opioid-induced respiratory depression (OIRD), a life-threatening depression in respiratory rate thought to be caused by stimulation of opioid receptors in the inspiratory-generating regions of the brain. Studies in mice have revealed that variation in opiate lethality is associated with strain differences, suggesting that sensitivity to OIRD is genetically determined. We first tested the hypothesis that genetic variation in inbred strains of mice influences the innate variability in opioid-induced responses in respiratory depression, recovery time and survival time. Using the founders of the advanced, high-diversity mouse populations, the Collaborative Cross (CC) and Diversity Outbred (DO), we found substantial sex and genetic effects on respiratory sensitivity and opiate lethality. To define genetic modifiers of OIRD, we then used the high precision DO population treated with morphine to map and identify quantitative trait loci (QTL) for respiratory depression, recovery time and survival time. Trait mapping and integrative functional genomic analysis in GeneWeaver has allowed us to implicate Galnt11, an N-acetylgalactosaminyltransferase, as a candidate gene that regulates OIRD.

genetics↗

bioRxiv2019

Effects of acute lying and sleep deprivation on the behavior of lactating dairy cows

The objective was to determine the effects of sleep or lying deprivation on the behavior of dairy cows. Data were collected from 8 multi- and 4 primiparous cows (DIM = 199 {+/-} 44 (mean {+/-} SD); days pregnant = 77 {+/-} 30). Using a crossover design, each cow experienced: 1) sleep deprivation implemented by noise or physical contact when their posture suggested sleep, and 2) lying deprivation imposed by a grid placed on the pen floor. One day before treatment (baseline), and treatment day (treatment) were followed by a 12-d washout period. Study days were organized from 2100 to 2059. During habituation (d -3 and -2 before treatment), baseline (d -1), and trt (d 0), housing was individual boxstalls (mattress with no bedding). After treatment, cows returned to sand-bedded freestalls for a 7-d recovery period (d 1 to 7) where data on lying behaviors were collected. Daily lying time, number lying bouts, bout duration, and number of steps were recorded by dataloggers attached to the hind leg of cows throughout the study period. Data were analyzed using a mixed model in SAS including fixed effects of treatment (sleep deprivation vs. sleep and lying deprivation), day, and their interaction with significant main effects separated using a PDIFF statement (P [≤] 0.05). Interactions between treatment and day were detected for daily lying time and the number of bouts. Lying time was lower for both treatments during the treatment period compared to baseline. Lying time increased during the recovery period for both lying and sleep deprived cows. However, it took 4 d for the lying deprived cows to fully recover their lying time after treatment, whereas it took the sleep deprived cows 2 d for their lying time to return to baseline levels. Results suggest that both sleep and lying deprivation can have impact cow behavior. Management factors that limit freestall access likely reduce lying time and sleep, causing negative welfare implications for dairy cows.

animal behavior and cognition↗

bioRxiv2019

Noninvasive sleep monitoring in large-scale screening of knock-out mice reveals novel sleep-related genes

Sleep is a critical process that is well-conserved across mammalian species, and perhaps most animals, yet its functions and underlying mechanisms remain poorly understood. Identification of genes and pathways that can influence sleep may shed new light on these functions. Genomic screens enable the detection of previously unsuspected molecular processes that influence sleep. In this study, we report results from a large-scale phenotyping study of sleep-wake parameters for a population of single-gene knockout mice. Sleep-wake parameters were measured using a high throughput, non-invasive piezoelectric system called PiezoSleep. Knockout mice generated on a C57BL6/N (B6N) background were monitored for sleep and wake parameters for five days. By analyzing data from over 6000 mice representing 343 single gene knockout lines, we identified 122 genes influencing traits like sleep duration and bout length that have not been previously implicated in sleep, including those that affect sleep only during a specific circadian phase. PiezoSleep also allows assessment of breath rates during sleep and this was integrated as a supplemental tool in identifying aberrant physiology in these knockout lines. Sex differences were evident in both normal and altered sleep behavior. Through a combination of genetic and phenotypic associations, and known QTLs for sleep, we propose a set of candidate genes playing specific roles in sleep. The high \"hit rate\" demonstrates that many genes can alter normal sleep behaviors through a variety of mechanisms. Further investigation of these genes may provide insight into the pathways regulating sleep, functional aspects of sleep, or indirect potentially pathological processes that alter normal sleep.

neuroscience↗

bioRxiv2017

Rapid, noninvasive, and unsupervised detection of sleep/wake using piezoelectric monitoring for pharmacological studies in narcoleptic mice

BackgroundAssessment of sleep/wake by electroencephalography (EEG) and electromyography (EMG) is invasive, resource intensive, and not amenable to rapid screening at scale for drug discovery. In the preclinical development of therapeutics for narcolepsy, efficacy tests are hindered by the lack of a non-EEG/EMG based translational test of symptom severity. The current methods study offers proof-of-principle that PiezoSleep (noninvasive, unsupervised piezoelectric monitoring of gross body movement, together with respiration patterns during behavioral quiescence), can be used to determine sleep/wake as applicable to the development of wake-promoting therapeutics. First, the translational wake-maintenance score (WMS, the ratio of time during the first half of the dark period spent in long wake bouts to short sleep bouts) of the PiezoSleep narcolepsy screen was introduced as a means by which to rank narcoleptic orexin/ataxin-3 mice and wild type mice by sleep/wake fragmentation severity. Accuracy of the WMS to detect narcoleptic phenotypes were determined in genotype-confirmed orexin/ataxin-3 mice and wild type colony mates. The WMS was used to identify the most highly symptomatic mice for resource-intensive EEG/EMG studies for further analysis of specific arousal states. Second, PiezoSleep was demonstrated for use in high-throughput screening of wake-promoting compounds using modafinil in orexin/ataxin-3 and wild type mice.\n\nResultsThe WMS detected a narcoleptic phenotype with 89% sensitivity, 92% specificity and 98% positive predictive value. A 15-fold difference in WMS differentiated wild type littermates from the most severely affected orexin/ataxin-3 mice. Follow-up EEG/EMG study indicated 82% of the orexin/ataxin-3 mice with the lowest wake-maintenance scores met or exceeded the cataplexy-occurrence threshold ([≥] 3 bouts) for inclusion in therapeutic efficacy studies. In the PiezoSleep dose-response study, the ED50 for wake-promotion by modafinil was approximately 50 mg/kg in both genotypes. Using unsupervised piezoelectric monitoring, the efficacy of wake-promoting compounds can be determined in a 5-arm study with 60 mice in less than one week--a fraction of the time compared to EEG/EMG studies.\n\nConclusionsThe WMS on the PiezoSleep narcolepsy screen quantifies the inability to sustain wakefulness and provides an accurate measure of the narcoleptic phenotype in mice. PiezoSleep offers rapid, scalable assessment of sleep/wake for high-throughput screening in drug discovery.

neuroscience↗