Bruce O'Hara - Academia.edu (original) (raw)

Papers by Bruce O'Hara

SLEEP

Introduction Passive rhythmic movement–rocking – is found to enhance sleep, particularly in infan... more Introduction Passive rhythmic movement–rocking – is found to enhance sleep, particularly in infants and young wild type (WT) mice. Rocking can potentially enhance sleep at all ages, with the added benefit of being non-invasive, easy to translate for human use, and with negligible side effects. Furthermore, sleep enhancement tools should be especially valuable to patients with sleep disturbances, a pervasive feature of age-related dementia including Alzheimer’s disease (AD). However, rocking has not been explored widely as a means of sleep enhancement. Therefore, our study explores the impact of rocking on sleep architecture in both WT and APP/PS1 KI mice (a model of human AD). Methods Male C57BL/6J (WT; n=3) and APPxPS1 KI (AD; n=4) mice (10-12 months old) were kept under a 12h:12h light/dark cycle with access to food and water ad libitum. A reciprocating platform was used to laterally rock individually housed mice at 1 Hz, a rate previously shown to enhance sleep in younger mice, f...

SLEEP

Introduction There is growing evidence that disordered sleep in Alzheimer’s disease (AD) may acce... more Introduction There is growing evidence that disordered sleep in Alzheimer’s disease (AD) may accelerate neuropathology, thus promoting a vicious cycle. In a previous study, we found that improving sleep through thermoneutral ambient temperature exposure may slow disease progression in 3xTg-AD mice. However, the confounding effects of temperature on metabolism in addition to sleep remained an open question. Methods To test whether the effect of thermoneutral warming on amyloid pathology is mediated by sleep changes rather than other non-specific physiologic effects of temperature, we conducted a new study on APP/PS1 knock-in (KI) mice. First, 6-m.o. male APP/PS1-KI mice were instrumented for EEG/EMG sleep analysis. After a week-long baseline recording, we split the mice into 4 separate groups: 1. SE (n=8), which were exposed to 30°C thermoneutral ambient temperature during the 12-hour light period; 2. SE-SD (n=9), which received sleep disruption through mild intermittent cage vibrati...

Supplemental data associated with GENETICS/2019/303013<br>

Proceedings of the National Academy of Sciences, 2021

Significance Abnormal microglia–neuron interaction is increasingly implicated in neurodevelopment... more Significance Abnormal 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 Alzheimer’s disease. This study demonstrates that the 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 the microglial function could provide a therapeutic strategy for the treatment of neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2020

Sleep loss contributes to the development of cardiovascular, metabolic, and neurological disorder... more Sleep loss contributes to the development of cardiovascular, metabolic, and neurological disorders by promoting a systemic proinflammatory phenotype. The neuroendocrine-immune mechanisms contributing to such pathologies are poorly understood. The sympathetic nervous system (SNS) regulates immunity and is often activated following sleep disturbances. The aims of this study were to determine 1) the effect of SNS inhibition on inflammatory responses to sleep fragmentation (SF) and 2) whether homeostasis can be restored after 1 wk of recovery sleep. We measured stress responses (norepinephrine and corticosterone), gene expression levels of pro- and anti-inflammatory cytokines in peripheral (heart, liver, and spleen) tissues, and protein levels of cytokines and chemokines in serum of female mice that were subjected to acute SF for 24 h, chronic SF for 8 wk, or 7 days of recovery after chronic SF. In each experiment, SF and control mice were chemically sympathectomized with 6-hydroxydopam...

In the U.S., opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014, leadi... more 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. ...

Journal of Virology, 1988

A total of 318 progeny from four backcrosses involving different laboratory strains and subspecie... more A total of 318 progeny from four backcrosses involving different laboratory strains and subspecies of Mus musculus were analyzed to map the Mx gene to the region of mouse chromosome 16 (MMU 16) which is homologous to human chromosome 21 (HSA 21). This result suggests that Mx will be found in the region of HSA 21 which has been implicated in Down syndrome when inherited in three copies.

Frontiers in Neuroscience, 2019

People with diabetes are more likely to experience sleep disturbance than those without. Sleep di... more People with diabetes are more likely to experience sleep disturbance than those without. Sleep disturbance can cause daytime sleepiness in diabetic patients, which may impair their daytime performance or even lead to workplace injuries. Therefore, restoring the normal sleep-wake cycle is critical for diabetic patients who experience daytime sleepiness. Previous data on a diabetic mouse model, the db/db mice, have demonstrated that the total sleep time and sleep fragmentation are increased and the daily rhythm of the sleep-wake cycle is attenuated. Accumulating evidence has shown that active time-restricted feeding (ATRF), in which the timing of food availability is restricted to the active-phase, is beneficial to metabolic health. However, it is unknown whether ATRF restores the normal sleep-wake cycle in diabetes. To test that, we used a non-invasive piezoelectric system to monitor the sleep-wake profile in the db/db mice with ad libitum feeding (ALF) as a baseline and then followed with ATRF. The results showed that at baseline, db/db mice exhibited abnormal sleep-wake patterns: the sleep time percent during the light-phase was decreased, while during the dark-phase it was increased with unusual cycling compared to control mice. In addition, the sleep bout length during both the light-phase and the full 24-h period was shortened in db/db mice. Analysis of the sleep-wake circadian rhythm showed that ATRF effectively restored the circadian but suppressed the ultradian oscillations of the sleep-wake cycle in the db/db mice. In conclusion, ATRF may serve as a novel strategy for treating diabetes-induced irregularity of the sleep-wake cycle.

Nature and Science of Sleep, 2019

The role of the microbiome in health and disease involves complex networks of host genetics, geno... more The role of the microbiome in health and disease involves complex networks of host genetics, genomics, microbes and environment. Identifying the mechanisms of these interactions has remained challenging. Systems genetics in the laboratory mouse enables data-driven discovery of network components and mechanisms of host-microbial interactions underlying multiple disease phenotypes. To examine the interplay among the whole host genome, transcriptome and microbiome, we mapped quantitative trait loci and correlated the abundance of cecal mRNA, luminal microflora, physiology and behavior in incipient strains of the highly diverse Collaborative Cross mouse population. The relationships that are extracted can be tested experimentally to ascribe causality among host and microbe in behavior and physiology, providing insight into disease. Application of this strategy in the Collaborative Cross population revealed experimentally validated mechanisms of microbial involvement in models of autism,...

OBM Integrative and Complementary Medicine, 2019

Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2019

IntroductionSleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerb... more IntroductionSleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD‐relevant mouse model, 5XFAD.MethodsWild‐type (C57Bl6/SJL) and 5XFAD mice received chronic treatment with vehicle or DORA‐22. Piezoelectric recordings monitored sleep and spatial memory was assessed via spontaneous Y‐maze alternations. Aβ plaques, Aβ levels, and neuroinflammatory markers were measured by immunohistochemistry, enzyme‐linked immunosorbent assay, and real‐time polymerase chain reaction, respectively.ResultsIn 5XFAD mice, DORA‐22 significantly increased light‐phase sleep without reducing Aβ levels, plaque density, or neuroinflammation. Effects of DORA‐22 on cognitive deficits could not be determined because the 5XFAD mice did not exhibit deficits.DiscussionThese findings suggest that DO...

The objective was to determine the effects of sleep or lying deprivation on the behavior of dairy... more 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 c...

Sleep is a critical process that is well-conserved across mammalian species, and perhaps most ani... more 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 ...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2001

Maternal smoking is a major risk factor for sudden infant death syndrome (SIDS). The mechanisms b... more Maternal smoking is a major risk factor for sudden infant death syndrome (SIDS). The mechanisms by which cigarette smoke predisposes infants to SIDS are not known. We examined the effects of prenatal nicotine exposure on sleep/wake ontogenesis and central cholinergic receptor gene expression in the neonatal rat. Prenatal nicotine exposure transiently increased sleep continuity and accelerated sleep/wake ontogeny in the neonatal rat. Prenatal nicotine also upregulated nicotinic and muscarinic cholinergic receptor mRNAs in brain regions involved in regulating vigilance states. These findings suggest that the nicotine contained in cigarette smoke may predispose human infants to SIDS by interfering with the normal maturation of sleep and wake.

SLEEP

Introduction Passive rhythmic movement–rocking – is found to enhance sleep, particularly in infan... more Introduction Passive rhythmic movement–rocking – is found to enhance sleep, particularly in infants and young wild type (WT) mice. Rocking can potentially enhance sleep at all ages, with the added benefit of being non-invasive, easy to translate for human use, and with negligible side effects. Furthermore, sleep enhancement tools should be especially valuable to patients with sleep disturbances, a pervasive feature of age-related dementia including Alzheimer’s disease (AD). However, rocking has not been explored widely as a means of sleep enhancement. Therefore, our study explores the impact of rocking on sleep architecture in both WT and APP/PS1 KI mice (a model of human AD). Methods Male C57BL/6J (WT; n=3) and APPxPS1 KI (AD; n=4) mice (10-12 months old) were kept under a 12h:12h light/dark cycle with access to food and water ad libitum. A reciprocating platform was used to laterally rock individually housed mice at 1 Hz, a rate previously shown to enhance sleep in younger mice, f...

SLEEP

Introduction There is growing evidence that disordered sleep in Alzheimer’s disease (AD) may acce... more Introduction There is growing evidence that disordered sleep in Alzheimer’s disease (AD) may accelerate neuropathology, thus promoting a vicious cycle. In a previous study, we found that improving sleep through thermoneutral ambient temperature exposure may slow disease progression in 3xTg-AD mice. However, the confounding effects of temperature on metabolism in addition to sleep remained an open question. Methods To test whether the effect of thermoneutral warming on amyloid pathology is mediated by sleep changes rather than other non-specific physiologic effects of temperature, we conducted a new study on APP/PS1 knock-in (KI) mice. First, 6-m.o. male APP/PS1-KI mice were instrumented for EEG/EMG sleep analysis. After a week-long baseline recording, we split the mice into 4 separate groups: 1. SE (n=8), which were exposed to 30°C thermoneutral ambient temperature during the 12-hour light period; 2. SE-SD (n=9), which received sleep disruption through mild intermittent cage vibrati...

Supplemental data associated with GENETICS/2019/303013<br>

Proceedings of the National Academy of Sciences, 2021

Significance Abnormal microglia–neuron interaction is increasingly implicated in neurodevelopment... more Significance Abnormal 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 Alzheimer’s disease. This study demonstrates that the 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 the microglial function could provide a therapeutic strategy for the treatment of neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2020

Sleep loss contributes to the development of cardiovascular, metabolic, and neurological disorder... more Sleep loss contributes to the development of cardiovascular, metabolic, and neurological disorders by promoting a systemic proinflammatory phenotype. The neuroendocrine-immune mechanisms contributing to such pathologies are poorly understood. The sympathetic nervous system (SNS) regulates immunity and is often activated following sleep disturbances. The aims of this study were to determine 1) the effect of SNS inhibition on inflammatory responses to sleep fragmentation (SF) and 2) whether homeostasis can be restored after 1 wk of recovery sleep. We measured stress responses (norepinephrine and corticosterone), gene expression levels of pro- and anti-inflammatory cytokines in peripheral (heart, liver, and spleen) tissues, and protein levels of cytokines and chemokines in serum of female mice that were subjected to acute SF for 24 h, chronic SF for 8 wk, or 7 days of recovery after chronic SF. In each experiment, SF and control mice were chemically sympathectomized with 6-hydroxydopam...

In the U.S., opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014, leadi... more 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. ...

Journal of Virology, 1988

A total of 318 progeny from four backcrosses involving different laboratory strains and subspecie... more A total of 318 progeny from four backcrosses involving different laboratory strains and subspecies of Mus musculus were analyzed to map the Mx gene to the region of mouse chromosome 16 (MMU 16) which is homologous to human chromosome 21 (HSA 21). This result suggests that Mx will be found in the region of HSA 21 which has been implicated in Down syndrome when inherited in three copies.

Frontiers in Neuroscience, 2019

People with diabetes are more likely to experience sleep disturbance than those without. Sleep di... more People with diabetes are more likely to experience sleep disturbance than those without. Sleep disturbance can cause daytime sleepiness in diabetic patients, which may impair their daytime performance or even lead to workplace injuries. Therefore, restoring the normal sleep-wake cycle is critical for diabetic patients who experience daytime sleepiness. Previous data on a diabetic mouse model, the db/db mice, have demonstrated that the total sleep time and sleep fragmentation are increased and the daily rhythm of the sleep-wake cycle is attenuated. Accumulating evidence has shown that active time-restricted feeding (ATRF), in which the timing of food availability is restricted to the active-phase, is beneficial to metabolic health. However, it is unknown whether ATRF restores the normal sleep-wake cycle in diabetes. To test that, we used a non-invasive piezoelectric system to monitor the sleep-wake profile in the db/db mice with ad libitum feeding (ALF) as a baseline and then followed with ATRF. The results showed that at baseline, db/db mice exhibited abnormal sleep-wake patterns: the sleep time percent during the light-phase was decreased, while during the dark-phase it was increased with unusual cycling compared to control mice. In addition, the sleep bout length during both the light-phase and the full 24-h period was shortened in db/db mice. Analysis of the sleep-wake circadian rhythm showed that ATRF effectively restored the circadian but suppressed the ultradian oscillations of the sleep-wake cycle in the db/db mice. In conclusion, ATRF may serve as a novel strategy for treating diabetes-induced irregularity of the sleep-wake cycle.

Nature and Science of Sleep, 2019

The role of the microbiome in health and disease involves complex networks of host genetics, geno... more The role of the microbiome in health and disease involves complex networks of host genetics, genomics, microbes and environment. Identifying the mechanisms of these interactions has remained challenging. Systems genetics in the laboratory mouse enables data-driven discovery of network components and mechanisms of host-microbial interactions underlying multiple disease phenotypes. To examine the interplay among the whole host genome, transcriptome and microbiome, we mapped quantitative trait loci and correlated the abundance of cecal mRNA, luminal microflora, physiology and behavior in incipient strains of the highly diverse Collaborative Cross mouse population. The relationships that are extracted can be tested experimentally to ascribe causality among host and microbe in behavior and physiology, providing insight into disease. Application of this strategy in the Collaborative Cross population revealed experimentally validated mechanisms of microbial involvement in models of autism,...

OBM Integrative and Complementary Medicine, 2019

Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2019

IntroductionSleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerb... more IntroductionSleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD‐relevant mouse model, 5XFAD.MethodsWild‐type (C57Bl6/SJL) and 5XFAD mice received chronic treatment with vehicle or DORA‐22. Piezoelectric recordings monitored sleep and spatial memory was assessed via spontaneous Y‐maze alternations. Aβ plaques, Aβ levels, and neuroinflammatory markers were measured by immunohistochemistry, enzyme‐linked immunosorbent assay, and real‐time polymerase chain reaction, respectively.ResultsIn 5XFAD mice, DORA‐22 significantly increased light‐phase sleep without reducing Aβ levels, plaque density, or neuroinflammation. Effects of DORA‐22 on cognitive deficits could not be determined because the 5XFAD mice did not exhibit deficits.DiscussionThese findings suggest that DO...

The objective was to determine the effects of sleep or lying deprivation on the behavior of dairy... more 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 c...

Sleep is a critical process that is well-conserved across mammalian species, and perhaps most ani... more 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 ...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2001

Maternal smoking is a major risk factor for sudden infant death syndrome (SIDS). The mechanisms b... more Maternal smoking is a major risk factor for sudden infant death syndrome (SIDS). The mechanisms by which cigarette smoke predisposes infants to SIDS are not known. We examined the effects of prenatal nicotine exposure on sleep/wake ontogenesis and central cholinergic receptor gene expression in the neonatal rat. Prenatal nicotine exposure transiently increased sleep continuity and accelerated sleep/wake ontogeny in the neonatal rat. Prenatal nicotine also upregulated nicotinic and muscarinic cholinergic receptor mRNAs in brain regions involved in regulating vigilance states. These findings suggest that the nicotine contained in cigarette smoke may predispose human infants to SIDS by interfering with the normal maturation of sleep and wake.