Sleep & Circadian Physiology

Lab Director: Irina Zhdanova, Ph.D.

IMG_0059

Overview

Research interests in the Zhdanova laboratory are centered around the role of the intrinsic circadian clock in the synergetic relationship between sleep, cognitive performance, metabolism and adult neurogenesis. By studying these physiological processes and their change with aging, we aim to determine a contribution of circadian desynchrony to human disorders and unsuccessful aging.  We also explore the effects of drugs, both established and those under development, on the circadian mechanisms that could promote healthy synergy between diverse physiological and behavioral functions.

Our lab is conducting circadian studies in human volunteers but also in two animal models, zebrafish and non-human primates. Importantly, all three species are diurnal, i.e., active and feeding during the day but sleep at night. This is critical for translational research. Although the core clock molecular mechanisms, including clock gene expression, nighttime increase in circulating melatonin or entrainment to photoperiod, are highly conserved, the downstream clock-controlled functions in diurnal and nocturnal species occur in antiphase. For example, in humans and mice numerous behavioral, cognitive, genomic, enzymatic, metabolic or neuronal processes have a 12-hour phase difference.

Each of these species contributes unique perspective. In zebrafish model, we focus on adult neurogenesis and role of extracellular proteins and circadian clock on age-related changes in this process. This is because zebrafish have extraordinary active neurogenesis while adults and contribution of this process to cognitive performance at young and old age can be effectively studied in them. Our recent discovery that adult neurogenesis in zebrafish is regulated by the circadian clock paved the way to studying the role of clock factors in cognitive performance, normal brain aging and neurodegenerative disorders.

The sophistication of the non-human primate model allows us to use non-invasive methods to explore how the intrinsic circadian clock, so difficult to assess in humans, affects sleep, cognitive performance and metabolism.  Using non-invasive methods and highly enriched environment, we reveal each animal’s unique chronotype and determine its impact on cognition and metabolism.

In human studies, we explore which circadian measures can be predictive of sleep quantity and quality, mood and cognitive performance, and their change with age. We also evaluate portable electronic devices that could help to reliably document chronotype in clinical trials and field studies.

Methodology

PRIMATES

Documenting intrinsic and entrained circadian rhythms of activity, sleep, food intake, food preference (solid and fluid), water intake, urine excretion, cognitive performance (memory, reaction time, attention), blood- and urine-born factors, and self-enrichment (toy manipulation, self-selection of “movies” and videogames). These studies are conducted in 28 specially designed spacious circadian chambers, equipped with touch screen laptop, multiple feeders for self-administration of food via simple manipulations or while conducting cognitive tests.

ZEBRAFISH

High throughput locomotor activity assays, using image analysis system allows us to study the sleep-like state and circadian rhythms. Each of our 9 behavioral systems allows us to record up to 80 larval or 24 adult fish at a time.

High-speed video camera recordings (1000 frames per second) document detailed locomotor patterns in larval and adult zebrafish.

Confocal calcium imaging of neuronal activity in behaving zebrafish helps in our search of the specific neuronal structures involved in the behaviors of interest.

Adult neurogenesis and molecular mechanisms of the clock are  addressed using immunohistochemistry and real-time RT-PCR.

GENERAL METHODS

Immunoassays for melatonin, cortisol, cAMP and cGMP in human and animal body fluids and tissues.

People

Irina Zhdanova, MD, PhD. is the Director of the laboratory. Her clinical and experimental research has contributed to a better understanding of the role the pineal hormone melatonin plays in normal sleep regulation in diurnal species. Her discovery of the first known familial circadian disorder in non-human primates opened new opportunities to studying the role of circadian desynchrony in health and disease.

Lili Yu, MD, specializes in genetics and endocrinology of circadian rhythms. Her research is focused on gene expression analysis and endocrine functions in zebrafish, non-human primates and humans.

Alex Stankiewicz, PhD candidate (defense 5/2017), with specialization in circadian biology of adult neurogenesis. His research is focused on circadian patterns of adult neurogenesis, its changes with aging and nutritional states, and in response to drugs of abuse, using zebrafish model.

Valerie Maymi, BS, Biology, specializes in circadian rhythms of non-human primates. Her focus is on circadian patterns of sleep/activity, feeding and cognitive functions, and effects of drugs modulating metabolism.

Victor Pasols, MS, Electrical Engineering  & Computer science.  Specialization in the development and maintenance of software and hardware for circadian rhythm research, using NHP and zebrafish models.

Erin McGowan, MS candidate, with specialization in circadian rhythms of adult neurogenesis in zebrafish model, and role of age and nutrition in this process.

Andrew Fraine, PhD, Physics, with specialization is in the development of custom hardware and software for high-resolution confocal imaging to study circadian rhythms of molecular processes in live zebrafish.

Recent Publications

Riley E, Kopotiyenko K, Zhdanova I. Prenatal and acute cocaine exposure affects neural responses and habituation to visual stimuli. Front Neural Circuits. 2015 Aug 25;9:41

Zhdanova IV, Rogers J, González-Martínez J, Farrer LA. The ticking clock of Cayo Santiago macaques and its implications for understanding human circadian rhythm disorders. Am J Primatol. 2015 May 1 doi: 10.1002/ajp.22413.

Hartsough EJ, Meyer RD, Chitalia V, Jiang Y, Marquez VE, Zhdanova IV, Weinberg J, Costello CE, Rahimi N. (2013) Lysine methylation promotes VEGFR-2 activation and angiogenesis. Science Signal. Dec 3;6(304):ra104.

Zhdanova IV Melatonin (2013) In: Encyclopedia of Neurological Sciences. Elsevier (Eds. Drs Aminoff and Daroff)

Zhdanova IV, Masuda K, Bozhokin SV, Rosene DL,Gonzalez-Martinez J, Schettler S, Samorodnitsky E. (2012) Familial Circadian Rhythm Disorder in the Diurnal Primate, Macaca Mulatta. PloS One. 7(3):e33327.

For more publications, see Dr. Zhdanova’s faculty page.