Karen L Gamble

University of Alabama at Birmingham | UAB · Department of Psychiatry and Behavioral Neurobiology

Parkinsons disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, beh...

The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm driven by molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery, but whether these molecular programs generate...

The timing of food intake is vital for metabolic health in obesity. A recent study in mice from Hepler et al. in Science shows the importance of the adipocyte circadian clock in metabolic health, highlighting the creatine pathway and thermogenesis with the alignment of the timing of high-fat feeding.

Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the...

Circadian rhythms are biological processes that cycle across 24 h and regulate many facets of neurophysiology, including learning and memory. Circadian variation in spatial memory task performance is well documented; however, the effect of sex across circadian time (CT) remains unclear. Additionally, little is known regarding the impact of time-of-...

Insomnia is a common sleep disorder associated with poor health outcomes. Individuals from racially underrepresented groups as well as women tend to report more severe insomnia symptoms, and frequent experiences of discrimination have been found to drive such disparities. Smokers commonly experience sleep problems since nicotine can alter the sleep...

The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm that is driven by intrinsic activity of molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery but whether thes...

Introduction Cigarette smoking is known to have a negative effect on individuals’ sleep quality. Specifically, evidence shows that smoking can exacerbate sleep disorders such as obstructive sleep apnea (OSA) by increasing irritation and inflammation of the upper respiratory conducts. Furthermore, previous research highlights a complex bidirectional...

Background Circadian misalignment between behaviors such as feeding and endogenous circadian rhythms, particularly in the context of shiftwork, is associated with poorer cardiometabolic health. We examined whether insulin and leptin levels differ between dayshift versus nightshift nurses, as well as explored whether the timing of food intake modula...

Age-related cognitive decline and disruptions in circadian rhythms are growing problems as the average human life span increases. Multiple strains of the senescence-accelerated mouse (SAM) show reduced life span, and the SAMP8 strain in particular has been well documented to show cognitive deficits in behavior as well as a bimodal pattern of circad...

Circadian rhythms are biological processes that cycle across 24 hours and regulate many facets of neurophysiology, including learning and memory. Circadian variation in performance on spatial memory tasks is well-documented; however, the effect of sex across circadian time remains unclear. Additionally, little is known regarding the impact of time-...

Night shift work increases risk of cardiovascular disease associated with an irregular eating schedule. Elevating this risk is the high level of salt intake observed in the typical Western diet. Renal Na+ excretion has a distinct diurnal pattern, independent of time of intake, yet the interactions between the time of intake and the amount of salt i...

Aims/hypothesisHypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribu...

Diet-induced obesity is associated with an increased risk of developing cardiovascular disease (CVD) . Aortic damage and stiffness are critical risk factors for CVD progression, especially with chronic high fat diet (HFD). Mice fed HFD ad libitum have increased food intake during the inactive period. We previously showed that HFD leads to significa...

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 tha...

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...

Feeding rodents a high fat diet (HFD) disrupts normal behavioral rhythms, particularly meal timing. Within the brain, mis-timed feeding shifts molecular rhythms in the hippocampus and impairs memory. We hypothesize that altered meal timing induced by HFD leads to cognitive impairment and that restricting HFD access to the ‘active period’ (i.e., nig...

Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunologic pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypoth...

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 cir...

Patients with Alzheimers 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...

Glucagon regulates glucose and lipid metabolism and also 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 Facto...

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 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 th...

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 t...

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 alcoh...

Irregular timing of food intake increases hypertension and cardiometabolic disease risk. A chronic high fat diet (HFD) also disrupts circadian rhythms. We hypothesized that active period time restricted feeding (TRF) during the last 2 weeks in mice on a chronic HFD will improve blood pressure rhythm, diurnal variation of circulating plasma factors,...

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 st...

Irregular timing of food intake is known to influence risk for cardiometabolic disease. Studies in humans and animals demonstrate that a chronic high fat diet (HFD) leads to endothelial dysfunction and cardiovascular disease. We hypothesized that restricting food availability to the active period with a HFD leads to reduced vascular damage, increas...

The Nobel Prize in Physiology or Medicine in 2017 was awarded for the study of the molecular/cellular basis of circadian rhythms in flies. The work was on flies is an example of a principle, repeated in subsequent decades, that simple model systems can uncover universal cellular and subcellular events. We briefly trace how this work opened new fiel...

Irregular timing of food intake increases cardiometabolic disease and hypertension risk. A chronic high fat diet (HFD) leads to loss of endothelial function and reduced activation of endothelial NO synthase (NOS3). We hypothesized that restricting food availability to the active period in mice on HFD will restore the blood pressure rhythm and NOS3...

Introduction Circadian rhythms greatly influence 24-h variation in cognition in nearly all organisms, including humans. Circadian clock impairment and sleep disruption are detrimental to cognition and negatively influence the acquisition and recall of learned behaviors. The circadian clock can become out of sync with the environment during circadia...

Introduction Social jetlag, characterized by later bedtimes and waketimes on off days compared with work days, is associated with adverse mental and physical health outcomes. Given the common use of three 12-hour shifts in nursing schedules, we hypothesized that day shift nurses with a later chronotype would exhibit greater social jetlag and associ...

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 ci...

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 e...

Timing of food intake increases the risk for cardiometabolic disease. A chronic high fat diet (HFD) leads to endothelial dysfunction with loss of nitric oxide (NO) signaling in mice. Both endothelial function and vascular resistance display circadian variation with endothelial‐dependent relaxation and NO signaling peaking during the active period,...

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...

Night shift work and salt intake are each independent risk factors for cardiovascular disease and possibly insulin resistance. Rhythms in renal sodium excretory function are observed regardless of the time of intake suggesting that salt ingested during the typical inactive period is retained until the following active period. Thus, we hypothesized...

Both human and animal studies demonstrate that a chronic high fat diet (HFD) leads to endothelial dysfunction. Timing of feeding and fasting is known to influence risk for cardiometabolic disease. Ad libitum chronic HFD disrupts the normal circadian rhythm in metabolism and peripheral molecular clock gene rhythm in mice. However, specific circadian...

Kidney function follows a strong circadian rhythm that is tightly regulated by clock genes. We previously reported that high salt diet induced dyssynchrony in renal clock gene expression in the cortex and medulla. However, whether changes in other dietary factors pose threats to renal circadian rhythms remain largely unknown. The current study was...

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 report...

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. Herein, we sought to determine whether genetic disruption of the hepatocyte...

Dyssynchrony of circadian rhythms are 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 lab recently reported that t...

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...

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 sy...

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 24h day. We have recently shown that GSK3 is capa...

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...

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 synthas...

Supplementary Figures 1-6 and Supplementary Table 1

Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extra-cellular 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 GABAA receptors that respond to both phasic and t...

Objectives: This article presents the consensus findings of the National Sleep Foundation Drowsy Driving Consensus Working Group, which was an expert panel assembled to establish a consensus statement regarding sleep-related driving impairment. Methods: The National Sleep Foundation assembled a expert panel comprised of experts from the sleep co...

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 corti...

Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BP), are relatively common, affecting up to 20% of the adult population. However, despite the frequency of these disorders, there is much that we still do not understand about the underlying physiological mechanism of these diseases. The difficulty in understanding the...

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 a...

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 inw...

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...

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 thi...

Shift work misaligns the environment and the body's internal clock. A new study suggests that this 'social jet lag' can be remedied by a 'personalized schedule', an intervention that may help reduce circadian misalignment and pathologies in shift workers. Copyright © 2015 Elsevier Ltd. All rights reserved.

The suprachiasmatic nucleus (SCN) drives and synchronizes daily rhythms at the cellular level via transcriptional-translational feedback loops comprising clock genes such as Bmal1 and Period (Per). Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, phosphorylates at least 5 core clock proteins and shows diurnal variation in phosphorylati...

Objectives: To determine the off-shift sleep strategies of bi-ethnic night-shift nurses, the relationship between these sleep strategies and adaptation to shift work, and identify the participant-level characteristics associated with a given sleep strategy. Methods: African-American and non-Hispanic White female, night-shift nurses from an academic...

Hepatic lipid metabolism is controlled by integrated metabolic pathways. Excess accumulation of hepatic triglyceride (TG) is a hallmark of nonalcoholic fatty liver disease which is associated with obesity and insulin resistance. Here, we show that KSRP ablation reduces hepatic TG levels and diet-induced hepatosteatosis. Expression of Per2 is increa...

To evaluate pedestrian behavior, including reaction time, impulsivity, risk-taking, attention, and decision-making, in children with obstructive sleep apnea syndrome (OSAS) compared with healthy controls. Using a case control design, 8- to 16-year-olds (n = 60) with newly diagnosed and untreated OSAS engaged in a virtual reality pedestrian environm...

Aggregates of α-synuclein (α-syn) accumulate in neurons in Parkinson's Disease and other synucleinopathies. These inclusions predominantly localize to axons even in the early stages of the disease, but their impact on axon function has remained unknown. Previously, we established a model in which the addition of pre-formed α-syn fibrils to primary...

Key points Many time‐of‐day cues are mediated by G protein‐coupled signals within the clock centre (the suprachiasmatic nucleus, SCN) of the mammalian brain. The role of G protein‐coupled inwardly rectifying potassium (GIRK) channels in SCN function and entrainment has yet to be determined. GIRK channels are necessary for proper day‐time SCN neuron...

Circadian clocks are cell autonomous, transcriptionally based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a temporally appropriate manner. Critical to circadian clock function are 2 transcription factors, CLOCK and BMAL1. The purpose of the present study was...

Organisms experience dramatic fluctuations in demands and stresses over the course of the day. In order to maintain biological processes within physiological boundaries, mechanisms have evolved for anticipation of, and adaptation to, these daily fluctuations. Endocrine factors have an integral role in homeostasis. Not only do circulating levels of...

Many cognitive factors contribute to unintentional pedestrian injury, including reaction time, impulsivity, risk-taking, attention, and decision-making. These same factors are negatively influenced by excessive daytime sleepiness (EDS), which may place children with EDS at greater risk for pedestrian injury. Using a case-control design, 33 children...

Circadian clocks are temporal interfaces that organize biological systems and behavior to dynamic external environments. Components of the molecular clock are expressed throughout the brain and are centrally poised to play an important role in brain function. This paper focuses on key issues concerning the relationship among circadian clocks, brain...

Chronic ethanol consumption disrupts several metabolic pathways including β-oxidation and lipid biosynthesis, facilitating the development of alcoholic fatty liver disease. Many of these same metabolic pathways are directly regulated by cell autonomous circadian clocks, and recent studies suggest that disruption of daily rhythms in metabolism contr...

Two-way ANOVA results of metabolic gene expression in liver. (XLSX)

Weekly body weights. Body weight was monitored in A) C57BL/6J mice and B) Per2Luc mice throughout the course of the ethanol-feeding protocol. Differences in body weight between control (♦) and ethanol-fed (▪) mice were determined using two-way repeated measures ANOVA. Data are presented as mean ± SEM for n = 33 control and ethanol C57BL/6J mice or...

Two-way ANOVA results of clock gene expression in liver. (XLSX)

Genes examined in suprachiasmatic nucleus and/or liver of C57BL/6 mice. (XLSX)