Marcos Frank working in Lab

Neuroscience of Sleep

The brain needs sleep. And while all studies show that the brain needs sleep, it is not yet understood why. Faculty within the Department of Translational Medicine and Physiology have set solving this persisting, perplexing question, considering it from all levels—from the molecular and cellular level to model systems and humans.

Regulation and Function of Sleep

One of the central questions in sleep neurobiology is determining the cellular and molecular processes that regulate sleep and confer the positive effects of sleep on the organism. This includes understanding what cell types are influencing sleep and what gene expression is involved in this regulation.

Jonathan Wisor, PhD, research focuses on the regulation of sleep and the consequences of sleep loss. The Wisor Lab applies molecular biology and biochemical techniques to characterize the roles of microglial and neuronal cell types within the cerebral cortex, and specific genes expressed by these cells, in the regulation of sleep.  Using germ-line targeted optogenetic constructs, his lab can modulate the activity of discrete cell types and measure the effects of these manipulations on sleep. Optogenetics is a powerful tool to control the activity of specific cell types in the brain and to determine functional interactions between cell types.

Marcos Frank, Phd, is investigating the role of glial cells in the accumulation and discharge of sleep pressure and synaptic plasticity in vivo. The Frank Lab has shown that astrocytes play a central role in controlling sleepiness through the release of glio-transmitters. Glial cells are known to influence synaptic plasticity and may be key players in both the regulation of sleep and the facilitation of downstream benefits of sleep. Frank’s lab measures brain activity in vivo (electrical and intracellular calcium) and correlates this data to protein levels and gene expression and to quantitative measurements of sleep and wakefulness. This combination of approaches facilitates a robust understanding of how basic neurophysiology correlates to behavioral parameters of sleep.

Sleep is also critically important to brain development in the early postnatal period. Basic processes of neural development have been established in sensory systems making them particularly well suited to study the role of sleep in neurodevelopment. Frank’s lab studies the effect of sleep on the development of the visual system and has shown that critical stages of physiological and neuroanatomical development in the visual cortex are enhanced by sleep. His lab is now working to determine the molecular mechanisms responsible for this effect of sleep.

Christopher Hayworth, PhD, aims to understand the signaling pathways in the brain that are activated in response to stimuli and how they change with sleep deprivation. His work utilizes one and two-photon intracranial brain imaging studies utilizing Adeno-Associated Virus (AAV) directed transgene expression in neurons and glial cells. With these tools, he can optically monitor intracellular calcium signaling in response to visual and other stimuli. AAV-directed genetic models allow manipulation of intracellular regulatory pathways in the brain that can be studied optically and in real-time.

Michael Rempe, PhD, uses his expertise in applied mathematics to develop mathematical models of the neurobiology of sleep. He has developed models that predict sleep behavior and provide useful tools to further quantify experimental results. He also performs data analysis and develops computational tools to complement experimental approaches. He applies his modeling and data analysis techniques to data sets produced by several investigators in the department from basic lab experiments to data collected in the field (i.e. airline pilots), and strengthens theoretical frameworks for data interpretation.

Effects of Sleep and Circadian Rhythms on Behavior and Neurological Disorders

Sleep deprivation and/or the disruption of circadian rhythms has a profound negative impact on cognitive function and on the pathological progression of neurological and neurodegenerative disease.  These changes can be measured at the molecular, cellular, and behavioral levels. Additional factors, such as stress, can compound these negative effects. Understanding the molecular mechanisms by which these effects interact is critical to the development of interventions that may minimize negative outcomes to improve health and/or delay disease progression.

Chris Davis, PhD, investigates the effects of sleep deprivation at the molecular, physiological, and behavioral levels. He demonstrates the consequences of sleep loss on cognitive performance, brain chemistry and slice electrophysiology. He was the first to demonstrate the effects of sleep loss by measuring long-term potentiation in the hippocampus and correlated this physiologic finding with molecular (cortactin, long-noncoding RNAs, microRNAs) and behavioral assays of performance such as a novel floor vibration maze. The Davis Lab has also shown that stress confounds the effects of sleep loss and that the drug Neurexan mitigates stress-induced insomnia in model systems.

Jason Gerstner, PhD, has shown that Fabp7, a glial-enriched transcript, has synchronized circadian expression across all regions of the mouse brain, and is necessary for normal sleep behavior. When Fabp7 is overexpressed in a transgenic fly model, the resulting Fabp7-induced sleep produced enhancement of long-term memory. This Fabp7 overexpression was also shown to rescue a sleep fragmentation phenotype in a fly model of Alzheimer’s disease. He discovered that Fabp7 protein was localized to perisynaptic astrocytic processes, and that this localization may be mediated by local cytoplasmic translation mechanisms. The temporal and spatial expression pattern of Fabp7 may provide mechanistic insight into neural-glial interactions that influence synaptic plasticity in a manner coordinated with sleep and circadian rhythms, which are thought to influence the etiology of neurological disorders and neurodegenerative disease.

Effects of Sleep and Circadian Rhythms on Human Performance and Health

It is well-established that sleep loss and altered circadian rhythms have a profound effect on cognitive function and performance in humans. Alterations in normal sleep and wake cycles can also have a detrimental effect on overall human health. Given the number of people who work extended duty periods or perform shift work, especially in professions that require critical decision-making (pilots, truck drivers, police officers, military service members, etc.), it is critically important to understand the physiological basis of these effects. How best to understand, predict, and mitigate the adverse consequences of sleep loss and circadian disruption is a key focus for several faculty in our department.

In a purpose-built human basic and clinical research facility, research volunteers are subjected to carefully controlled sleep/wake schedules to investigate the effects of sleep loss and circadian misalignment, as well as countermeasures such as napping, recovery sleep, and pharmacological interventions. State-of-the-art sleep monitoring equipment is employed to record the extent, type and quality of sleep, and innovative cognitive tests are used to determine performance and brain function.  The lab is also equipped to measure many different physiological parameters (brain oxygenation, heart rate variability, skin conductance, blood biomarkers, etc.) to determine effects on systemic health and their molecular underpinnings. Furthermore, the facility houses high-fidelity simulators to mimic real-world job performance, including automobile and truck driving as well as law enforcement encounters.  This unique research facility allows our faculty to interrogate the many ways that sleep loss and other stressors impact human performance and health.

Hans Van Dongen, PhD, leads a research program focusing on sleep, sleep deprivation, circadian rhythms, and cognitive performance. He has an extensive track record of experimental and theoretical contributions to sleep research. His research portfolio is broad and, over the past two decades, has included two key focus areas: inter-individual differences in cognitive impairment resulting from sleep deprivation, which he has shown to be both trait-like and task-dependent; and mathematical prediction of performance impairment due to fatigue. More recently, he has broadened his focus to include multi-omics inquiries into the mechanisms by which circadian disruption leads to poor long-term health.

Kimberly Honn, PhD, conducts laboratory sleep and sleep deprivation studies with specially designed computerized or simulated tasks to identify particular cognitive functions that are most vulnerable or most resilient to the effects of sleep loss. She aims to understand the mechanisms by which sleep loss affects the brain such that interventions can be designed to protect against sleep loss-related errors. Honn’s research extends into real-world settings with field research projects studying sleep, shiftwork schedules, and performance in industries including aviation, rail, and long-haul commercial trucking.

Devon Hansen, PhD, uses a combination of highly controlled laboratory- and long-term home-based monitoring studies to examine the impact of sleep loss on cognitive and physiological functioning in healthy normal and sleep-disordered populations, with a particular focus on insomnia. She also oversees the Clinical Sleep Research Facility, which serves to characterize the impact of sleep loss on patients with sleep disorders or other medical conditions involving sleep deficiency; test novel interventions and innovative technologies to advance public health; and increase research training for medical students.

Brieann Satterfield, PhD, aims to understand the complex phenotype-genotype associations between sleep and circadian rhythms, cognition, and health. Her research has shown that at least some inter-individual differences in cognitive impairment due to sleep deprivation can be attributed to genetic differences, which has led to a better understanding of dissociable, differential cognitive effects of sleep deprivation. In a parallel line of research, Satterfield is studying how sleep loss and circadian disruption increase the risk of poor health outcomes such as metabolic syndrome and cancer.

Steve James, PhD, focuses his research on the interaction between physical stressors, including sleep deprivation, and operational performance in high-consequence occupations such as the military, law enforcement, and patient care. He utilizes the research facility’s simulation technology, coupled with neurophysiological measurements, to evaluate the training and performance of military and law enforcement personnel as well as other occupations where critical decision-making has far-reaching consequences for performance and safety outcomes.

Amanda Lamp, PhD, researches sleep, fatigue, and cognitive performance in occupational settings, with a current emphasis on Fatigue Risk Management Systems (FRMS) in the aviation industry. Her work is based on data collected by field studies measuring operator sleep, fatigue, sleepiness, and performance.  Her group is currently studying pilot fatigue and sleepiness, sleep duration and quality, and effects on cognitive performance during commercial flights of various lengths, from short to ultra-long-range operations. She hopes to understand the various factors that impact pilot sleep and cognitive performance during flight operations to increase pilot alertness, mitigate risk and enhance safety. Her lab is at the forefront of applying evidence-based science to the aviation industry.

Courtney Kurinec, PhD, researches situational and individual factors that influence cognitive processes involved in memory and decision-making. Her primary line of research examines how sleep deprivation or cognitive load affects the way people learn and remember information, and how this affects subsequent decision-making. This work is carried out in a controlled laboratory environment where the effect of factors like sleep loss and cognitive load can be measured with computer-based cognitive tasks. Kurinec also investigates how sleep loss and cognitive load impact the processing of affective or emotional information, as well as how individual differences in cognitive ability or personality traits moderate these effects in the context of cognitive and affective tasks.

Matt Layton, MD, PhD research interests include physiological and behavioral aspects of substance use disorders and their treatment, including hyperbaric oxygen use in opioid addiction, and the interactions of natural products and drugs. Asthe physician of record for the Sleep and Performance Research Center, and Medical Director for the Program of Excellence in Addictions Research, he studies how substance use and mental disorders impact sleep architecture and sleep-related behaviors, and he is a co-investigator with many other faculty members in the department.

Interaction of Sleep and Metabolism

It is generally accepted that circadian rhythms and the duration of the waking period largely determine when and how much we sleep. The research conducted in the labs of Éva Szentirmai, MD, PhD, and Levente Kapás, MD, PhD, broadens this framework to include other systemic factors that affect sleep.

Szentirmai’s research is focused on how aspects of metabolism impinge on neuronal circuits that are involved in regulating sleep-wake activity. Szentirmai is working to understand how endocrine and metabolic signals from organs such as the liver, the gastrointestinal tract, and adipose tissue communicate with the hypothalamus to control sleep and coordinate metabolism and vigilance. Her laboratory uses a wide range of experimental approaches that include molecular neuroscience, whole animal physiology and behavior.

The Kapás Lab is also investigating aspects of systemic physiology and their interaction with sleep. He has shown that there is communication between the gastrointestinal system and the brain via the vagus nerve (CN X) that impacts sleep. He is also interested in the interaction of the microbiome as well as immune responses in controlling the quality, timing and amount of sleep.

Sleep and Gene Expression

Sleep, and sleep deprivation, induce specific patterns of gene expression.  Lucia Peixoto, PhD, uses genomic approaches to understand fundamental properties of sleep and other neurologic functions such as learning and memory. Her lab demonstrated specific patterns of gene expression, and its epigenetic regulation, in response to sleep deprivation. This work requires a combination of experimental approaches including behavioral paradigms in autism model systems, molecular biology, and the analysis of high-throughput sequence data. The Peixoto Lab also uses genomic and candidate gene approaches to study neurodevelopmental disabilities, in particular Autism Spectrum Disorder (ASD).  They are currently using several models of human genetic disorders with a high prevalence of ASD to study the mechanism by which sleep and development interact in ASD with a focus on epigenetic and transcriptional regulation.