Publications by authors named "Karen L Gamble"

68 Publications

Dysregulated clock gene expression and abnormal diurnal regulation of hippocampal inhibitory transmission and spatial memory in a mouse model of Alzheimer's disease.

Neurobiol Dis 2021 Jul 29:105454. Epub 2021 Jul 29.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Patients with Alzheimer's disease (AD) often have fragmentation of sleep/wake cycles and disrupted 24-h (circadian) activity. Despite this, little work has investigated the potential underlying day/night disruptions in cognition and neuronal physiology in the hippocampus. The molecular clock, an intrinsic transcription-translation feedback loop that regulates circadian behavior, may also regulate hippocampal neurophysiological activity. We hypothesized that disrupted diurnal variation in clock gene expression in the hippocampus corresponds with loss of normal day/night differences in membrane excitability, synaptic physiology, and cognition. We previously reported that the Tg-SwDI mouse model of AD has disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock). Here, we report that Tg-SwDI mice failed to show day-night differences in a spatial working memory task, unlike wild-type controls that exhibited enhanced spatial working memory at night. Moreover, Tg-SwDI mice had lower levels of Per2, one of the core components of the molecular clock, at both mRNA and protein levels when compared to age-matched controls. Interestingly, we discovered neurophysiological impairments in area CA1 of the Tg-SwDI hippocampus. In controls, spontaneous inhibitory post-synaptic currents (sIPSCs) in pyramidal cells showed greater amplitude and lower inter-event interval during the day than the night. However, the normal day/night differences in sIPSCs were absent (amplitude) or reversed (inter-event interval) in pyramidal cells from Tg-SwDI mice. In control mice, current injection into CA1 pyramidal cells produced more firing during the night than during the day, but no day/night difference in excitability was observed in Tg-SwDI mice. The normal day/night difference in excitability in controls was blocked by GABA receptor inhibition. Together, these results demonstrate that the normal diurnal regulation of inhibitory transmission in the hippocampus is diminished in a mouse model of AD, leading to decreased daytime inhibition onto hippocampal CA1 pyramidal cells. Uncovering disrupted day/night differences in circadian gene regulation, hippocampal physiology, and memory in AD mouse models may provide insight into possible chronotherapeutic strategies to ameliorate Alzheimer's disease symptoms or delay pathological onset.
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http://dx.doi.org/10.1016/j.nbd.2021.105454DOI Listing
July 2021

Time-restricted feeding rescues high-fat-diet-induced hippocampal impairment.

iScience 2021 Jun 11;24(6):102532. Epub 2021 May 11.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 1720 7th Avenue S., Birmingham, AL 35294, USA.

Feeding rodents a high-fat diet (HFD) disrupts normal behavioral rhythms, particularly meal timing. Within the brain, mistimed feeding shifts molecular rhythms in the hippocampus and impairs memory. We hypothesize that altered meal timing induced by an HFD leads to cognitive impairment and that restricting HFD access to the "active period" (i.e., night) rescues the normal hippocampal function. In male mice, access to an HFD for 20 weeks increased body weight and fat mass, increased daytime meal consumption, reduced hippocampal long-term potentiation (LTP), and eliminated day/night differences in spatial working memory. Importantly, two weeks of time-restricted feeding (TRF) at the end of the chronic HFD protocol rescued spatial working memory and restored LTP magnitude, even though there was no change in body composition and total daily caloric intake. These findings suggest that short-term TRF is an effective mechanism for rescuing HFD-induced impaired cognition and hippocampal function.
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http://dx.doi.org/10.1016/j.isci.2021.102532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188491PMC
June 2021

Chronobiology of Natriuretic Peptides and Blood Pressure in Lean and Obese Individuals.

J Am Coll Cardiol 2021 May;77(18):2291-2303

Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA; Section of Cardiology, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, USA. Electronic address:

Background: Diurnal variation of natriuretic peptide (NP) levels and its relationship with 24-h blood pressure (BP) rhythm has not been established. Obese individuals have a relative NP deficiency and disturbed BP rhythmicity.

Objectives: This clinical trial evaluated the diurnal rhythmicity of NPs (B-type natriuretic peptide [BNP], mid-regional pro-atrial natriuretic peptide [MR-proANP], N-terminal pro-B-type natriuretic peptide [NT-proBNP]) and the relationship of NP rhythm with 24-h BP rhythm in healthy lean and obese individuals.

Methods: On the background of a standardized diet, healthy, normotensive, lean (body mass index 18.5 to 25 kg/m) and obese (body mass index 30 to 45 kg/m) individuals, age 18 to 40 years, underwent 24-h inpatient protocol involving ambulatory BP monitoring starting 24 h prior to the visit, controlled light intensity, and repeated blood draws for assessment of analytes. Cosinor analysis of normalized NP levels (normalized to 24-h mean value) was conducted to assess the diurnal NP rhythm and its relationship with systolic BP.

Results: Among 52 participants screened, 40 participants (18 lean, 22 obese; 50% women; 65% Black) completed the study. The median range spread (percentage difference between the minimum and maximum values) over 24 h for MR-proANP, BNP, and NT-proBNP levels was 72.0% (interquartile range [IQR]: 50.9% to 119.6%), 75.5% (IQR: 50.7% to 106.8%), and 135.0% (IQR: 66.3% to 270.4%), respectively. A cosine wave-shaped 24-h oscillation of normalized NP levels (BNP, MR-proANP, and NT-proBNP) was noted both in lean and obese individuals (p <0.05 for all). A larger phase difference between MR-proANP BP rhythm (-4.9 h vs. -0.7 h) and BNP BP rhythm (-3.3 h vs. -0.9 h) was seen in obese compared with lean individuals.

Conclusions: This human physiological trial elucidates evidence of diurnal NP rhythmicity and the presence of an NP-BP rhythm axis. There exists a misalignment of the NP-BP diurnal rhythm in the obese, which may contribute to the disturbed diurnal BP pattern observed among obese individuals. (The Diurnal Rhythm in Natriuretic Peptide Levels; NCT03834168).
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http://dx.doi.org/10.1016/j.jacc.2021.03.291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138944PMC
May 2021

Workshop report. Circadian rhythm sleep-wake disorders: gaps and opportunities.

Sleep 2021 05;44(5)

Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

This White Paper presents the results from a workshop cosponsored by the Sleep Research Society (SRS) and the Society for Research on Biological Rhythms (SRBR) whose goals were to bring together sleep clinicians and sleep and circadian rhythm researchers to identify existing gaps in diagnosis and treatment and areas of high-priority research in circadian rhythm sleep-wake disorders (CRSWD). CRSWD are a distinct class of sleep disorders caused by alterations of the circadian time-keeping system, its entrainment mechanisms, or a misalignment of the endogenous circadian rhythm and the external environment. In these disorders, the timing of the primary sleep episode is either earlier or later than desired, irregular from day-to-day, and/or sleep occurs at the wrong circadian time. While there are incomplete and insufficient prevalence data, CRSWD likely affect at least 800,000 and perhaps as many as 3 million individuals in the United States, and if Shift Work Disorder and Jet Lag are included, then many millions more are impacted. The SRS Advocacy Taskforce has identified CRSWD as a class of sleep disorders for which additional high-quality research could have a significant impact to improve patient care. Participants were selected for their expertise and were assigned to one of three working groups: Phase Disorders, Entrainment Disorders, and Other. Each working group presented a summary of the current state of the science for their specific CRSWD area, followed by discussion from all participants. The outcome of those presentations and discussions are presented here.
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http://dx.doi.org/10.1093/sleep/zsaa281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120340PMC
May 2021

Timing of Food Intake Drives the Circadian Rhythm of Blood Pressure.

Function (Oxf) 2021 24;2(1):zqaa034. Epub 2020 Nov 24.

Division of Nephrology, Department of Medicine.

Timing of food intake has become a critical factor in determining overall cardiometabolic health. We hypothesized that timing of food intake entrains circadian rhythms of blood pressure (BP) and renal excretion in mice. Male C57BL/6J mice were fed ad libitum or reverse feeding (RF) where food was available at all times of day or only available during the 12-h lights-on period, respectively. Mice eating ad libitum had a significantly higher mean arterial pressure (MAP) during lights-off compared to lights-on (113 ± 2 mmHg vs 100 ± 2 mmHg, respectively;  < 0.0001); however, RF for 6 days inverted the diurnal rhythm of MAP (99 ± 3 vs 110 ± 3 mmHg, respectively;  < 0.0001). In contrast to MAP, diurnal rhythms of urine volume and sodium excretion remained intact after RF. Male knockout mice (Bmal1KO) underwent the same feeding protocol. As previously reported, Bmal1KO mice did not exhibit a diurnal MAP rhythm during ad libitum feeding (95 ± 1 mmHg vs 92 ± 3 mmHg, lights-off vs lights-on;  > 0.05); however, RF induced a diurnal rhythm of MAP (79 ± 3 mmHg vs 95 ± 2 mmHg, lights-off vs lights-on phase;  < 0.01). Transgenic PERIOD2::LUCIFERASE knock-in mice were used to assess the rhythm of the clock protein PERIOD2 in ex vivo tissue cultures. The timing of the PER2::LUC rhythm in the renal cortex and suprachiasmatic nucleus was not affected by RF; however, RF induced significant phase shifts in the liver, renal inner medulla, and adrenal gland. In conclusion, the timing of food intake controls BP rhythms in mice independent of Bmal1, urine volume, or sodium excretion.
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http://dx.doi.org/10.1093/function/zqaa034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772288PMC
November 2020

Glucagon receptor signaling regulates weight loss via central KLB receptor complexes.

JCI Insight 2021 Feb 22;6(4). Epub 2021 Feb 22.

Comprehensive Diabetes Center and Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.

Glucagon regulates glucose and lipid metabolism and promotes weight loss. Thus, therapeutics stimulating glucagon receptor (GCGR) signaling are promising for obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating fibroblast growth factor 21 (FGF21), a potent regulator of energy balance. We reported that mice deficient for liver Fgf21 are partially resistant to GCGR-mediated weight loss, implicating FGF21 as a regulator of glucagon's weight loss effects. FGF21 signaling requires an obligate coreceptor (β-Klotho, KLB), with expression limited to adipose tissue, liver, pancreas, and brain. We hypothesized that the GCGR-FGF21 system mediates weight loss through a central mechanism. Mice deficient for neuronal Klb exhibited a partial reduction in body weight with chronic GCGR agonism (via IUB288) compared with controls, supporting a role for central FGF21 signaling in GCGR-mediated weight loss. Substantiating these results, mice with central KLB inhibition via a pharmacological KLB antagonist, 1153, also displayed partial weight loss. Central KLB, however, is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides. Together, these data suggest GCGR agonism mediates part of its weight loss properties through central KLB and has implications for future treatments of obesity and metabolic syndrome.
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http://dx.doi.org/10.1172/jci.insight.141323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934938PMC
February 2021

High-Fat and High-Sucrose Diets Impair Time-of-Day Differences in Spatial Working Memory of Male Mice.

Obesity (Silver Spring) 2020 12 11;28(12):2347-2356. Epub 2020 Oct 11.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Objective: This study aimed to investigate both the long-term and short-term impacts of high-fat diets (HFD) or high-sucrose diets (HSD) on the normal diurnal pattern of cognitive function, protein expression, and the molecular clock in mice.

Methods: This study used both 6-month and 4-week feeding strategies by providing male C57BL/6J mice access to either a standard chow, HFD, or HSD. Spatial working memory and synaptic plasticity were assessed both day and night, and hippocampal tissue was measured for changes in NMDA and AMPA receptor subunits (GluN2B, GluA1), as well as molecular clock gene expression.

Results: HFD and HSD both disrupted normal day/night fluctuations in spatial working memory and synaptic plasticity. Mice fed HFD altered their food intake to consume more calories during the day. Both diets disrupted normal hippocampal clock gene expression, and HFD reduced GluN2B levels in hippocampal tissue.

Conclusions: Taken together, these results suggest that both HFD and HSD induce a loss of day/night performance in spatial working memory and synaptic plasticity as well as trigger a cascade of changes that include disruption to the hippocampal molecular clock.
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http://dx.doi.org/10.1002/oby.22983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686286PMC
December 2020

Alcohol and Liver Clock Disruption Increase Small Droplet Macrosteatosis, Alter Lipid Metabolism and Clock Gene mRNA Rhythms, and Remodel the Triglyceride Lipidome in Mouse Liver.

Front Physiol 2020 7;11:1048. Epub 2020 Sep 7.

Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States.

Heavy alcohol drinking dysregulates lipid metabolism, promoting hepatic steatosis - the first stage of alcohol-related liver disease (ALD). The molecular circadian clock plays a major role in synchronizing daily rhythms in behavior and metabolism and clock disruption can cause pathology, including liver disease. Previous studies indicate that alcohol consumption alters liver clock function, but the impact alcohol or clock disruption, or both have on the temporal control of hepatic lipid metabolism and injury remains unclear. Here, we undertook studies to determine whether genetic disruption of the liver clock exacerbates alterations in lipid metabolism and worsens steatosis in alcohol-fed mice. To address this question, male liver-specific knockout (LKO) and flox/flox (Fl/Fl) control mice were fed a control or alcohol-containing diet for 5 weeks. Alcohol significantly dampened diurnal rhythms of mRNA levels in clock genes and , phase advanced /REV-ERBα, and induced arrhythmicity in , , and /E4BP4, with further disruption in livers of LKO mice. Alcohol-fed LKO mice exhibited higher plasma triglyceride (TG) and different time-of-day patterns of hepatic TG and macrosteatosis, with elevated levels of small droplet macrosteatosis compared to alcohol-fed Fl/Fl mice. Diurnal rhythms in mRNA levels of lipid metabolism transcription factors (, , and ) were significantly altered by alcohol and clock disruption. Alcohol and/or clock disruption significantly altered diurnal rhythms in mRNA levels of fatty acid (FA) synthesis and oxidation (, , , , , and ), TG turnover (, , , , and ), and lipid droplet (, , , and ) genes, along with protein abundances of p-ACC, MCD, and FASN. Lipidomics analyses showed that alcohol, clock disruption, or both significantly altered FA saturation and remodeled the FA composition of the hepatic TG pool, with higher percentages of several long and very long chain FA in livers of alcohol-fed LKO mice. In conclusion, these results show that the liver clock is important for maintaining temporal control of hepatic lipid metabolism and that disrupting the liver clock exacerbates alcohol-related hepatic steatosis.
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http://dx.doi.org/10.3389/fphys.2020.01048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504911PMC
September 2020

Rhythms in Neurometabolism Decline with Age.

Authors:
Karen L Gamble

Neuroscience 2020 11 14;448:299. Epub 2020 Sep 14.

University of Alabama at Birmingham, Department of Psychiatry and Behavioral Neurobiology, 1720 7th Avenue South, Birmingham, AL 35294, USA. Electronic address:

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http://dx.doi.org/10.1016/j.neuroscience.2020.09.014DOI Listing
November 2020

Diurnal, metabolic and thermogenic alterations in a murine model of accelerated aging.

Chronobiol Int 2020 08 20;37(8):1119-1139. Epub 2020 Aug 20.

Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama, USA.

Senescence-Accelerated Mouse-Prone 8 (SAMP8) mice exhibit characteristics of premature aging, including hair loss, cognitive dysfunction, reduced physical activity, impaired metabolic homeostasis, cardiac dysfunction and reduced lifespan. Interestingly, circadian disruption can induce or augment many of these same pathologies. Moreover, previous studies have reported that SAMP8 mice exhibit abnormalities in circadian wheel-running behavior, indicating possible alterations in circadian clock function. These observations led to the hypothesis that 24 h rhythms in behavior and/or circadian clock function are altered in SAMP8 mice and that these alterations may contribute to perturbations in whole-body metabolism. Here, we report that 6-month-old SAMP8 mice exhibit a more prominent biphasic pattern in daily behaviors (food intake and physical activity) and whole-body metabolism (energy expenditure, respiratory exchange ratio), relative to SAMR1 control mice. Consistent with a delayed onset of food intake at the end of the light phase, SAMP8 mice exhibit a phase delay (1.3-1.9 h) in 24 h gene expression rhythms of major circadian clock components () in peripheral tissues (liver, skeletal muscle, white adipose tissue [WAT], brown adipose tissue [BAT]). Forcing mice to consume food only during the dark period improved alignment of both whole-body metabolism and oscillations in expression of clock genes in peripheral tissues between SAMP8 and SAMR1 mice. Next, interrogation of metabolic genes revealed altered expression of thermogenesis mediators () in WAT and/or BAT in SAMP8 mice. Interestingly, SAMP8 mice exhibit a decreased tolerance to an acute (5 h) cold challenge. Moreover, SAMP8 and SAMR1 mice exhibited differential responses to a chronic (1 week) decrease in ambient temperature; the greatest response in whole-body substrate selection was observed in SAMR1 mice. Collectively, these observations reveal differential behaviors (e.g. 24 h food intake patterns) in SAMP8 mice that are associated with perturbations in peripheral circadian clocks, metabolism and thermogenesis.
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http://dx.doi.org/10.1080/07420528.2020.1796699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530102PMC
August 2020

Circadian rhythmicity and the community of clockworkers.

Eur J Neurosci 2020 06 27;51(12):2314-2328. Epub 2019 Dec 27.

Department of Neuroscience, Barnard College, New York, NY, USA.

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http://dx.doi.org/10.1111/ejn.14626DOI Listing
June 2020

Effect of positive airway pressure therapy in children with obstructive sleep apnea syndrome: does positive airway pressure use reduce pedestrian injury risk?

Sleep Health 2019 04 14;5(2):161-165. Epub 2019 Jan 14.

University of Alabama at Birmingham, Department of Psychology, Birmingham, AL. Electronic address:

Introduction: Treatment with positive airway pressure (PAP) therapy reduces injury risk among adults with obstructive sleep apnea syndrome (OSAS), but the effect of PAP therapy on children's injury risk is unknown. This study investigated whether treatment of OSAS with PAP reduces children's pedestrian injury risk in a virtual reality pedestrian environment.

Methods: Forty-two children ages 8-16 years with OSAS were enrolled upon diagnosis by polysomnography. Children crossed a simulated street several times upon enrollment, prior to PAP treatment, and again after 3 months of PAP therapy. Children underwent sleep studies at all time points.

Results: Children adherent with PAP had a significant reduction in hits by a virtual vehicle (P < .01) and less time to contact with oncoming vehicles (P < .01) following treatment. Those who were nonadherent did not show improved safety. There was no change in attention to oncoming traffic.

Conclusions: OSAS may have significant consequences on children's daytime functioning in a critical domain of personal safety: pedestrian skills. In pedestrian simulation, children with OSAS adherent to PAP therapy showed improvement in pedestrian safety and had fewer collisions with a virtual vehicle following treatment. Results highlight need for heightened awareness of the real-world benefits of treatment for pediatric sleep disorders.

Level Of Evidence: Level II Therapeutic Study.
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http://dx.doi.org/10.1016/j.sleh.2018.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443098PMC
April 2019

Shift Work Disrupts Circadian Regulation of the Transcriptome in Hospital Nurses.

J Biol Rhythms 2019 04 4;34(2):167-177. Epub 2019 Feb 4.

Department of Psychiatry and Behavioral Neurobiology.

Circadian misalignment between sleep and behavioral/feeding rhythms is thought to lead to various health impairments in shift workers. Therefore, we investigated how shift work leads to genome-wide circadian dysregulation in hospital nurses. Female nurses from the University of Alabama at Birmingham (UAB) Hospital working night shift ( n = 9; 29.6 ± 11.4 y) and day shift ( n = 8; 34.9 ± 9.4 y) participated in a 9-day study measuring locomotor activity and core body temperature (CBT) continuously. Additionally, cortisol and melatonin were assayed and peripheral blood mononuclear cells (PBMCs) were harvested for RNA extraction every 3 h on a day off from work. We saw phase desynchrony of core body temperature, peak cortisol, and dim light melatonin onset in individual night-shift subjects compared with day-shift subjects. This variability was evident even though day- and night-shift nurses had similar sleep timing and scheduled meal times on days off. Surprisingly, the phase and rhythmicity of the expression of the clock gene, PER1, in PBMCs were similar for day-shift and night-shift subjects. Genome-wide microarray analysis of PBMCs from a subset of nurses revealed distinct gene expression patterns between night-shift and day-shift subjects. Enrichment analysis showed that day-shift subjects expressed pathways involved in generic transcription and regulation of signal transduction, whereas night-shift subjects expressed pathways such as RNA polymerase I promoter opening, the matrisome, and endocytosis. In addition, there was large variability in the number of rhythmic transcripts among subjects, regardless of shift type. Interestingly, the amplitude of the CBT rhythm appeared to be more consistent with the number of cycling transcripts for each of the 6 subjects than was melatonin rhythm. In summary, we show that shift-work patterns affect circadian alignment and gene expression in PBMCs.
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http://dx.doi.org/10.1177/0748730419826694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542471PMC
April 2019

Circadian regulation of membrane physiology in neural oscillators throughout the brain.

Eur J Neurosci 2020 01 29;51(1):109-138. Epub 2019 Jan 29.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama.

Twenty-four-hour rhythmicity in physiology and behavior are driven by changes in neurophysiological activity that vary across the light-dark and rest-activity cycle. Although this neural code is most prominent in neurons of the primary circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus, there are many other regions in the brain where region-specific function and behavioral rhythmicity may be encoded by changes in electrical properties of those neurons. In this review, we explore the existing evidence for molecular clocks and/or neurophysiological rhythms (i.e., 24 hr) in brain regions outside the SCN. In addition, we highlight the brain regions that are ripe for future investigation into the critical role of circadian rhythmicity for local oscillators. For example, the cerebellum expresses rhythmicity in over 2,000 gene transcripts, and yet we know very little about how circadian regulation drives 24-hr changes in the neural coding responsible for motor coordination. Finally, we conclude with a discussion of how our understanding of circadian regulation of electrical properties may yield insight into disease mechanisms which may lead to novel chronotherapeutic strategies in the future.
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http://dx.doi.org/10.1111/ejn.14343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625955PMC
January 2020

Misaligned core body temperature rhythms impact cognitive performance of hospital shift work nurses.

Neurobiol Learn Mem 2019 04 3;160:151-159. Epub 2019 Jan 3.

UAB School of Nursing, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Circadian rhythms greatly influence 24-h variation in cognition in nearly all organisms, including humans. Circadian clock impairment and sleep disruption are detrimental to hippocampus-dependent memory and negatively influence the acquisition and recall of learned behaviors. The circadian clock can become out of sync with the environment during circadian misalignment. Shift work represents a real-world model of circadian misalignment that can be studied for its physiological implications. The present study aimed to test the hypothesis that circadian misalignment disrupts vigilance and cognitive performance on occupationally relevant tasks using shift work as a model. As such, we sought to (1) explore the general effects of night- and day-shift worker schedules on sleep-wake parameters and core body temperature (CBT) phase, and (2) determine whether shift-type and CBT phase impact cognitive performance and vigilance at the end of a 12-h shift. We observed a sample of day-shift and night-shift hospital nurses over a 10-day period. At the end of three, consecutive, 12-h shifts (7 pm-7am or 7am-7 pm), participants completed a cognitive battery assessing vigilance, cognitive throughput, and medication calculation fluency (via an investigator developed and tested metric). Night-shift nurses exhibited significantly greater sleep fragmentation as well as a greater disparity between their wake-time and time of CBT minimum compared to day-shift nurses. Night-shift nurses exhibited significantly slower cognitive proficiency at the end of their shifts, even after adjustment for CBT phase. These results suggest that circadian disruption and reduced sleep quality both contribute to cognitive functioning and performance.
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http://dx.doi.org/10.1016/j.nlm.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486423PMC
April 2019

Behavioral and SCN neurophysiological disruption in the Tg-SwDI mouse model of Alzheimer's disease.

Neurobiol Dis 2018 06 11;114:194-200. Epub 2018 Mar 11.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Disruption of circadian rhythms is commonly reported in individuals with Alzheimer's disease (AD). Neurons in the primary circadian pacemaker, the suprachiasmatic nucleus (SCN), exhibit daily rhythms in spontaneous neuronal activity which are important for maintaining circadian behavioral rhythms. Disruption of SCN neuronal activity has been reported in animal models of other neurodegenerative disorders; however, the effect of AD on SCN neurophysiology remains unknown. In this study we examined circadian behavioral and electrophysiological changes in a mouse model of AD, using male mice from the Tg-SwDI line which expresses human amyloid precursor protein with the familial Swedish (K670N/M671L), Dutch (E693Q), Iowa (D694N) mutations. The free-running period of wheel-running behavior was significantly shorter in Tg-SwDI mice compared to wild-type (WT) controls at all ages examined (3, 6, and 10 months). At the SCN level, the day/night difference in spike rate was significantly dampened in 6-8 month-old Tg-SwDI mice, with decreased AP firing during the day and an increase in neuronal activity at night. The dampening of SCN excitability rhythms in Tg-SwDI mice was not associated with changes in input resistance, resting membrane potential, or action potential afterhyperpolarization amplitude; however, SCN neurons from Tg-SwDI mice had significantly reduced A-type potassium current (I) during the day compared to WT cells. Taken together, these results provide the first evidence of SCN neurophysiological disruption in a mouse model of AD, and highlight I as a potential target for AD treatment strategies in the future.
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http://dx.doi.org/10.1016/j.nbd.2018.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891366PMC
June 2018

Genetic deletion of the circadian clock transcription factor BMAL1 and chronic alcohol consumption differentially alter hepatic glycogen in mice.

Am J Physiol Gastrointest Liver Physiol 2018 03 30;314(3):G431-G447. Epub 2017 Nov 30.

Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham , Birmingham, Alabama.

Multiple metabolic pathways exhibit time-of-day-dependent rhythms that are controlled by the molecular circadian clock. We have shown that chronic alcohol is capable of altering the molecular clock and diurnal oscillations in several elements of hepatic glycogen metabolism ( 19 , 44 ). Herein, we sought to determine whether genetic disruption of the hepatocyte clock differentially impacts hepatic glycogen content in chronic alcohol-fed mice. Male hepatocyte-specific BMAL1 knockout (HBK) and littermate controls were fed control or alcohol-containing diets for 5 wk to alter hepatic glycogen content. Glycogen displayed a significant diurnal rhythm in livers of control genotype mice fed the control diet. While rhythmic, alcohol significantly altered the diurnal oscillation of glycogen in livers of control genotype mice. The glycogen rhythm was mildly altered in livers of control-fed HBK mice. Importantly, glycogen content was arrhythmic in livers of alcohol-fed HBK mice. Consistent with these changes in hepatic glycogen content, we observed that some glycogen and glucose metabolism genes were differentially altered by chronic alcohol consumption in livers of HBK and littermate control mice. Diurnal rhythms in glycogen synthase (mRNA and protein) were significantly altered by alcohol feeding and clock disruption. Alcohol consumption significantly altered Gck, Glut2, and Ppp1r3g rhythms in livers of control genotype mice, with diurnal rhythms of Pklr, Glut2, Ppp1r3c, and Ppp1r3g further disrupted (dampened or arrhythmic) in livers of HBK mice. Taken together, these findings show that chronic alcohol consumption and hepatocyte clock disruption differentially influence the diurnal rhythm of glycogen and various key glycogen metabolism-related genes in the liver. NEW & NOTEWORTHY We report that circadian clock disruption exacerbates alcohol-mediated alterations in hepatic glycogen. We observed differential responsiveness in diurnal rhythms of glycogen and glycogen metabolism genes and proteins in livers of hepatocyte-specific BMAL1 knockout and littermate control mice fed alcohol. Our findings provide new insights into potential mechanisms by which alcohol alters glycogen, an important energy source for liver and other organs.
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http://dx.doi.org/10.1152/ajpgi.00281.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899240PMC
March 2018

High dietary sodium causes dyssynchrony of the renal molecular clock in rats.

Am J Physiol Renal Physiol 2018 01 27;314(1):F89-F98. Epub 2017 Sep 27.

Cardio-Renal Physiology and Medicine, Department of Medicine, Division of Nephrology, University of Alabama at Birmingham , Birmingham, Alabama.

Speed JS, Hyndman KA, Roth K, Heimlich JB, Kasztan M, Fox BM, Johnston JG, Becker BK, Jin C, Gamble KL, Young ME, Pollock JS, Pollock DM. High dietary sodium causes dyssynchrony of the renal molecular clock in rats. Am J Physiol Renal Physiol 314: F89-F98, 2018. First published September 27, 2017; doi:10.1152/ajprenal.00028.2017.-Dyssynchrony of circadian rhythms is associated with various disorders, including cardiovascular and metabolic diseases. The cell autonomous molecular clock maintains circadian control; however, environmental factors that may cause circadian dyssynchrony either within or between organ systems are poorly understood. Our laboratory recently reported that the endothelin (ET-1) B (ET) receptor functions to facilitate Na excretion in a time of day-dependent manner. Therefore, the present study was designed to determine whether high salt (HS) intake leads to circadian dyssynchrony within the kidney and whether the renal endothelin system contributes to control of the renal molecular clock. We observed that HS feeding led to region-specific alterations in circadian clock components within the kidney. For instance, HS caused a significant 5.5-h phase delay in the peak expression of Bmal1 and suppressed Cry1 and Per2 expression in the renal inner medulla, but not the renal cortex, of control rats. The phase delay in Bmal1 expression appears to be mediated by ET-1 because this phenomenon was not observed in the ET-deficient rat. In cultured inner medullary collecting duct cells, ET-1 suppressed Bmal1 mRNA expression. Furthermore, Bmal1 knockdown in these cells reduced epithelial Na channel expression. These data reveal that HS feeding leads to intrarenal circadian dyssynchrony mediated, in part, through activation of ET receptors within the renal inner medulla.
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http://dx.doi.org/10.1152/ajprenal.00028.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866350PMC
January 2018

GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity.

Hippocampus 2017 08 27;27(8):890-898. Epub 2017 May 27.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama.

Hippocampal rhythms in clock gene expression, enzymatic activity, and long-term potentiation (LTP) are thought to underlie day-night differences in memory acquisition and recall. Glycogen synthase kinase 3-beta (GSK3β) is a known regulator of hippocampal function, and inhibitory phosphorylation of GSK3β exhibits region-specific differences over the light-dark cycle. Here, we sought to determine whether phosphorylation of both GSK3α and GSK3β isoforms has an endogenous circadian rhythm in specific areas of the hippocampus and whether chronic inhibition or activation alters the molecular clock and hippocampal plasticity (LTP). Results indicated a significant endogenous circadian rhythm in phosphorylation of GSK3β, but not GSK3α, in hippocampal CA1 extracts from mice housed in constant darkness for at least 2 weeks. To examine the importance of this rhythm, genetic and pharmacological strategies were used to disrupt the GSK3 activity rhythm by chronically activating or inhibiting GSK3. Chronic activation of both GSK3 isoforms in transgenic mice (GSK3-KI mice) diminished rhythmic BMAL1 expression. On the other hand, chronic treatment with a GSK3 inhibitor significantly shortened the molecular clock period of organotypic hippocampal PER2::LUC cultures. While WT mice exhibited higher LTP magnitude at night compared to day, the day-night difference in LTP magnitude remained with greater magnitude at both times of day in mice with chronic GSK3 activity. On the other hand, pharmacological GSK3 inhibition impaired day-night differences in LTP by blocking LTP selectively at night. Taken together, these results support the model that circadian rhythmicity of hippocampal GSK3β activation state regulates day/night differences in molecular clock periodicity and a major form of synaptic plasticity (LTP).
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http://dx.doi.org/10.1002/hipo.22739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511075PMC
August 2017

Correcting delayed circadian phase with bright light therapy predicts improvement in ADHD symptoms: A pilot study.

J Psychiatr Res 2017 08 6;91:105-110. Epub 2017 Mar 6.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Attention-deficit/hyperactivity disorder (ADHD) is a common condition with comorbid insomnia reported in >70% of children and adults. These patients demonstrate delays in sleep-wake rhythms, nocturnal rise in melatonin, and early morning rise in cortisol. Given that standard psychopharmacologic treatments for ADHD often do not completely control symptoms in participants with circadian rhythm delay, we sought to test whether bright light therapy (BLT) advances circadian rhythms and further reduces ADHD symptoms over standard treatments. In addition to standard of care, participants with ADHD diagnosis underwent 1 week of baseline assessment followed by 2-weeks of 30-min morning 10,000-lux BLT beginning 3 h after mid-sleep time. Participants minimized overhead light after 4 p.m., wore an actigraphy watch, and recorded BLT time on daily sleep logs. Dim Light Melatonin Onset (DLMO) was assessed at baseline and after 2-week treatment. ADHD symptoms were measured by the ADHD-Rating Scales (ADHD-RS). BLT significantly advanced the phase of DLMO by 31 min [mean time (SEM), 20:36 (0:21) advanced to 20:05 (0:20)] and mid-sleep time by 57 min [4:37 (0:22) advanced to 3:40 (0:16); paired t-tests, p = 0.002 and 0.004, respectively). Phase advances (in DLMO or mid-sleep time) were significantly correlated with decreased ADHD-RS total scores (p = 0.027 and 0.044) and Hyperactive-Impulsive sub-scores (p = 0.014 and 0.013, respectively). Actigraphy analysis for a subset of 8 participants with significant DLMO phase advance revealed no significant changes in total sleep time, sleep efficiency, wake after sleep onset, or percent wake during sleep interval. This is the first successful use of BLT for advancing melatonin phase and improving ADHD symptoms in adults. BLT may be a complementary treatment for both delayed sleep timing and ADHD symptoms in adults.
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http://dx.doi.org/10.1016/j.jpsychires.2017.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959333PMC
August 2017

Glycogen synthase kinase 3 regulates photic signaling in the suprachiasmatic nucleus.

Eur J Neurosci 2017 04 21;45(8):1102-1110. Epub 2017 Mar 21.

Departments of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.

Glycogen synthase kinase 3 (GSK3) is a serine-threonine kinase that regulates mammalian circadian rhythms at the behavioral, molecular and neurophysiological levels. In the central circadian pacemaker, the suprachiasmatic nucleus (SCN), inhibitory phosphorylation of GSK3 exhibits a rhythm across the 24 h day. We have recently shown that GSK3 is capable of influencing both the molecular clock and SCN neuronal activity rhythms. However, it is not known whether GSK3 regulates the response to environmental cues such as light. The goal of this study was to test the hypothesis that GSK3 activation mediates light-induced SCN excitability and photic entrainment. Immunofluorescence staining in the SCN of mice showed that late-night light exposure significantly increased GSK3 activity (decreased pGSK3β levels) 30-60 min after the light-pulse. In addition, pharmacological inhibition of GSK3 blocked the expected light-induced excitability in SCN neurons; however, this effect was not associated with changes in resting membrane potential or input resistance. Behaviorally, mice with constitutively active GSK3 (GSK3-KI) re-entrained to a 6-h phase advance in the light-dark cycle in significantly fewer days than WT control animals. Furthermore, the behavioral and SCN neuronal activity of GSK3-KI mice was phase-advanced compared to WT, in both normal and light-exposed conditions. Finally, GSK3-KI mice exhibited normal negative-masking behavior and electroretinographic responses to light, suggesting that the enhanced photic entrainment is not due to an overall increased sensitivity to light in these animals. Taken together, these results provide strong evidence that GSK3 activation contributes to light-induced phase-resetting at both the neurophysiological and behavioral levels.
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http://dx.doi.org/10.1111/ejn.13549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395359PMC
April 2017

The impact of meal timing on cardiometabolic syndrome indicators in shift workers.

Chronobiol Int 2017 20;34(3):337-348. Epub 2017 Jan 20.

e Department of Psychiatry and Behavioral Neurobiology , University of Alabama at Birmingham , Birmingham , AL , USA.

The aims of this study were to 1) compare the inflammatory potential of night- and day-shift nurses' diets with regard to time of day and work status and 2) explore how the timing of food intake during work and off-work is associated with cardiometabolic syndrome (CMS) risk factors between these two groups. Female nurses (N = 17; 8 day-shift and 9 night-shift) reported food intake over 9 days. On a middle day off of work, metabolic parameters were measured after an overnight fast. Energy/macronutrient intake and inflammatory potential of dietary intake (as assessed via the Dietary Inflammatory Index) were calculated for nurses' workdays, work nights, off-work days, and off-work nights. Work-night total food intake (grams) accounted for a significant amount of variance in CMS risk factors for night-shift nurses only. Increased total gram consumption during night-shift nurses' work nights was associated with increased lipid levels - independent of the macronutrient composition of the food consumed. Alternatively, for night-shift nurses, work-day intake of several food parameters accounted for a significant proportion of variance in HDL cholesterol levels, with higher intake associated with higher HDL levels. For both day- and night-shift nurses, food intake during the day was more pro-inflammatory regardless of shift type or work status. Our novel approach of combining time-of-day-specific and work-day-specific analyses of dietary inflammatory factors and macronutrient composition with measurement of CMS risk factors suggests a link between meal timing and cardiometabolic health for shift-working nurses.
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http://dx.doi.org/10.1080/07420528.2016.1259242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527274PMC
February 2018

The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus.

Front Neuroendocrinol 2017 01 25;44:35-82. Epub 2016 Nov 25.

Center for Behavioral Neuroscience, Atlanta, GA 30302, United States; Department of Psychology, Morehouse College, Atlanta, GA 30314, United States.

Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extracellular levels of GABA within the SCN are determined by a complex interaction of synthesis and transport, as well as synaptic and non-synaptic release. The response to GABA is mediated by GABA receptors that respond to both phasic and tonic GABA release and that can produce excitatory as well as inhibitory cellular responses. GABA also influences circadian control through the exclusively inhibitory effects of GABA receptors. Both GABA and neuropeptide signaling occur within the SCN, although the functional consequences of the interactions of these signals are not well understood. This review considers the role of GABA in the circadian pacemaker, in the mechanisms responsible for the generation of circadian rhythms, in the ability of non-photic stimuli to reset the phase of the pacemaker, and in the ability of the day-night cycle to entrain the pacemaker.
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http://dx.doi.org/10.1016/j.yfrne.2016.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225159PMC
January 2017

Regulation of persistent sodium currents by glycogen synthase kinase 3 encodes daily rhythms of neuronal excitability.

Nat Commun 2016 11 14;7:13470. Epub 2016 Nov 14.

Department of Psychiatry, University of Alabama at Birmingham, 1720 7th Avenue South, Birmingham, Alabama 35294, USA.

How neurons encode intracellular biochemical signalling cascades into electrical signals is not fully understood. Neurons in the central circadian clock in mammals provide a model system to investigate electrical encoding of biochemical timing signals. Here, using experimental and modelling approaches, we show how the activation of glycogen synthase kinase 3 (GSK3) contributes to neuronal excitability through regulation of the persistent sodium current (I). I exhibits a day/night difference in peak magnitude and is regulated by GSK3. Using mathematical modelling, we predict and confirm that GSK3 activation of I affects the action potential afterhyperpolarization, which increases the spontaneous firing rate without affecting the resting membrane potential. Together, these results demonstrate a crucial link between the molecular circadian clock and electrical activity, providing examples of kinase regulation of electrical activity and the propagation of intracellular signals in neuronal networks.
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http://dx.doi.org/10.1038/ncomms13470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114562PMC
November 2016

Altered myocardial metabolic adaptation to increased fatty acid availability in cardiomyocyte-specific CLOCK mutant mice.

Biochim Biophys Acta 2016 10 22;1861(10):1579-95. Epub 2015 Dec 22.

Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

A mismatch between fatty acid availability and utilization leads to cellular/organ dysfunction during cardiometabolic disease states (e.g., obesity, diabetes mellitus). This can precipitate cardiac dysfunction. The heart adapts to increased fatty acid availability at transcriptional, translational, post-translational and metabolic levels, thereby attenuating cardiomyopathy development. We have previously reported that the cardiomyocyte circadian clock regulates transcriptional responsiveness of the heart to acute increases in fatty acid availability (e.g., short-term fasting). The purpose of the present study was to investigate whether the cardiomyocyte circadian clock plays a role in adaptation of the heart to chronic elevations in fatty acid availability. Fatty acid availability was increased in cardiomyocyte-specific CLOCK mutant (CCM) and wild-type (WT) littermate mice for 9weeks in time-of-day-independent (streptozotocin (STZ) induced diabetes) and dependent (high fat diet meal feeding) manners. Indices of myocardial metabolic adaptation (e.g., substrate reliance perturbations) to STZ-induced diabetes and high fat meal feeding were found to be dependent on genotype. Various transcriptional and post-translational mechanisms were investigated, revealing that Cte1 mRNA induction in the heart during STZ-induced diabetes is attenuated in CCM hearts. At the functional level, time-of-day-dependent high fat meal feeding tended to influence cardiac function to a greater extent in WT versus CCM mice. Collectively, these data suggest that CLOCK (a circadian clock component) is important for metabolic adaption of the heart to prolonged elevations in fatty acid availability. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
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http://dx.doi.org/10.1016/j.bbalip.2015.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917492PMC
October 2016

Cortical PGC-1α-Dependent Transcripts Are Reduced in Postmortem Tissue From Patients With Schizophrenia.

Schizophr Bull 2016 07 17;42(4):1009-17. Epub 2015 Dec 17.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL;

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) has been linked to multiple neurological and psychiatric disorders including schizophrenia, but its involvement in the pathophysiology of these disorders is unclear. Experiments in mice have revealed a set of developmentally-regulated cortical PGC-1α-dependent transcripts involved in calcium buffering (parvalbumin, PV), synchronous neurotransmitter release (synaptotagmin 2, Syt2; complexin 1, Cplx1) and axonal integrity (neurofilamaent heavy chain, Nefh). We measured the mRNA expression of PGC-1α and these transcripts in postmortem cortical tissue from control and schizophrenia patients and found a reduction in PGC-1α-dependent transcripts without a change in PGC-1α. While control subjects with high PGC-1α expression exhibited high PV and Nefh expression, schizophrenia subjects with high PGC-1α expression did not, suggesting dissociation between PGC-1α expression and these targets in schizophrenia. Unbiased analyses of the promoter regions for PGC-1α-dependent transcripts revealed enrichment of binding sites for the PGC-1α-interacting transcription factor nuclear respiratory factor 1 (NRF-1). NRF-1 mRNA expression was reduced in schizophrenia, and its transcript levels predicted that of PGC-1α-dependent targets in schizophrenia. Interestingly, the positive correlation between PGC-1α and PV, Syt2, or Cplx1 expression was lost in schizophrenia patients with low NRF-1 expression, suggesting that NRF-1 is a critical predictor of these genes in disease. These data suggest that schizophrenia involves a disruption in PGC-1α and/or NRF-1-associated transcriptional programs in the cortex and that approaches to enhance the activity of PGC-1α or transcriptional regulators like NRF-1 should be considered with the goal of restoring normal gene programs and improving cortical function.
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http://dx.doi.org/10.1093/schbul/sbv184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903048PMC
July 2016

Synchronized time-keeping is key to healthy mood regulation (Commentary on Landgraf et al.).

Eur J Neurosci 2016 05 13;43(10):1307-8. Epub 2016 Jan 13.

Division of Behavioral Neurobiology, Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL, USA.

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http://dx.doi.org/10.1111/ejn.13147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874851PMC
May 2016

GIRK Channels Mediate the Nonphotic Effects of Exogenous Melatonin.

J Neurosci 2015 Nov;35(45):14957-65

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, and

Unlabelled: Melatonin supplementation has been used as a therapeutic agent for several diseases, yet little is known about the underlying mechanisms by which melatonin synchronizes circadian rhythms. G-protein signaling plays a large role in melatonin-induced phase shifts of locomotor behavior and melatonin receptors activate G-protein-coupled inwardly rectifying potassium (GIRK) channels in Xenopus oocytes. The present study tested the hypothesis that melatonin influences circadian phase and electrical activity within the central clock in the suprachiasmatic nucleus (SCN) through GIRK channel activation. Unlike wild-type littermates, GIRK2 knock-out (KO) mice failed to phase advance wheel-running behavior in response to 3 d subcutaneous injections of melatonin in the late day. Moreover, in vitro phase resetting of the SCN circadian clock by melatonin was blocked by coadministration of a GIRK channel antagonist tertiapin-q (TPQ). Loose-patch electrophysiological recordings of SCN neurons revealed a significant reduction in the average action potential rate in response to melatonin. This effect was lost in SCN slices treated with TPQ and SCN slices from GIRK2 KO mice. The melatonin-induced suppression of firing rate corresponded with an increased inward current that was blocked by TPQ. Finally, application of ramelteon, a potent melatonin receptor agonist, significantly decreased firing rate and increased inward current within SCN neurons in a GIRK-dependent manner. These results are the first to show that GIRK channels are necessary for the effects of melatonin and ramelteon within the SCN. This study suggests that GIRK channels may be an alternative therapeutic target for diseases with evidence of circadian disruption, including aberrant melatonin signaling.

Significance Statement: Despite the widespread use of melatonin supplementation for the treatment of sleep disruption and other neurological diseases such as epilepsy and depression, no studies have elucidated the molecular mechanisms linking melatonin-induced changes in neuronal activity to its therapeutic effects. Here, we used behavioral and electrophysiological techniques to address this scientific gap. Our results show that melatonin and ramelteon, a potent and clinically relevant melatonin receptor agonist, significantly affect the neurophysiological function of suprachiasmatic nucleus neurons through activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels. Given the importance of GIRK channels for neuronal excitability (with >600 publications on these channels to date), our study should generate broad interest from neuroscientists in fields such as epilepsy, addiction, and cognition.
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http://dx.doi.org/10.1523/JNEUROSCI.1597-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642232PMC
November 2015

The Molecular Circadian Clock and Alcohol-Induced Liver Injury.

Biomolecules 2015 Oct 14;5(4):2504-37. Epub 2015 Oct 14.

Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.

Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.
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http://dx.doi.org/10.3390/biom5042504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4693245PMC
October 2015

Chronic ethanol consumption disrupts diurnal rhythms of hepatic glycogen metabolism in mice.

Am J Physiol Gastrointest Liver Physiol 2015 Jun 9;308(11):G964-74. Epub 2015 Apr 9.

Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama;

Chronic ethanol consumption has been shown to significantly decrease hepatic glycogen content; however, the mechanisms responsible for this adverse metabolic effect are unknown. In this study, we examined the impact chronic ethanol consumption has on time-of-day-dependent oscillations (rhythms) in glycogen metabolism processes in the liver. For this, male C57BL/6J mice were fed either a control or ethanol-containing liquid diet for 5 wk, and livers were collected every 4 h for 24 h and analyzed for changes in various genes and proteins involved in hepatic glycogen metabolism. Glycogen displayed a robust diurnal rhythm in the livers of mice fed the control diet, with the peak occurring during the active (dark) period of the day. The diurnal glycogen rhythm was significantly altered in livers of ethanol-fed mice, with the glycogen peak shifted into the inactive (light) period and the overall content of glycogen decreased compared with controls. Chronic ethanol consumption further disrupted diurnal rhythms in gene expression (glycogen synthase 1 and 2, glycogenin, glucokinase, protein targeting to glycogen, and pyruvate kinase), total and phosphorylated glycogen synthase protein, and enzyme activities of glycogen synthase and glycogen phosphorylase, the rate-limiting enzymes of glycogen metabolism. In summary, these results show for the first time that chronic ethanol consumption disrupts diurnal rhythms in hepatic glycogen metabolism at the gene and protein level. Chronic ethanol-induced disruption in these daily rhythms likely contributes to glycogen depletion and disruption of hepatic energy homeostasis, a recognized risk factor in the etiology of alcoholic liver disease.
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http://dx.doi.org/10.1152/ajpgi.00081.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451320PMC
June 2015
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