Johanna H. Meijer (born 26 March 1959) is a Dutch scientist who has contributed significantly to the field of

chronobiology Chronobiology is a field of biology that examines timing processes, including periodic (cyclic) phenomena in living organisms, such as their adaptation to solar- and lunar-related rhythms. These cycles are known as biological rhythms. Chronobi ...

. Meijer has made notable contributions to the understanding of the neural and molecular mechanisms of circadian pacemakers. She is known for her extensive studies of photic and non-photic effects on the mammalian circadian clocks. Notably, Meijer is the 2016 recipient of the Aschoff and Honma Prize, one of the most prestigious international prizes in the circadian research field. In addition to still unraveling neuronal mechanisms of circadian clocks and their applications to health, Meijer's lab now studies the effects of modern lifestyles on our circadian rhythm and bodily functions.

Life

Academic career

Meijer attended

Leiden University Leiden University (abbreviated as ''LEI''; nl, Universiteit Leiden) is a Public university, public research university in Leiden, Netherlands. The university was founded as a Protestant university in 1575 by William the Silent, William, Prince o ...

in the

Netherlands ) , anthem = ( en, "William of Nassau") , image_map = , map_caption = , subdivision_type = Sovereign state , subdivision_name = Kingdom of the Netherlands , established_title = Before independence , established_date = Spanish Netherl ...

, where she obtained her master's degree in the Department of Biology, Physics, and Medicine and her

Ph.D. A Doctor of Philosophy (PhD, Ph.D., or DPhil; Latin: or ') is the most common degree at the highest academic level awarded following a course of study. PhDs are awarded for programs across the whole breadth of academic fields. Because it is ...

Physiology Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...

. After completing her Ph.D. in 1989, Meijer became an assistant professor in the Department of Physiology at Leiden University in 1992. Here, Meijer began her work on

circadian rhythms A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

alongside Ben Rusak. In 2001, Meijer became an associate professor at Leiden University. Meijer continues her study of circadian rhythms and

today as a Professor and Head of Neurophysiology Group at the Leiden University Medical Center in the Netherlands and a visiting professor in the Department of

Ophthalmology Ophthalmology ( ) is a surgical subspecialty within medicine that deals with the diagnosis and treatment of eye disorders. An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a medic ...

at the

University of Oxford , mottoeng = The Lord is my light , established = , endowment = £6.1 billion (including colleges) (2019) , budget = £2.145 billion (2019–20) , chancellor ...

in the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the continental mainland. It comprises England, Scotland, Wales and North ...

Scientific contributions

Neuronal network organization of the circadian clock

Meijer is a major contributor to the topic of circadian clocks and neuronal organization. She discovered that synaptic and

neural plasticity Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that differs from how it ...

in the neuronal network of the

suprachiasmatic nucleus The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...

(SCN) is required for regular seasonal adaptation of the circadian clock in animals. It was shown that in mammals, the functional integrity of the SCN is crucial to health, well-being, cognitive performance, and alertness. Aging and sleep deprivation both result in a decrease in circadian amplitude, while activities such as exercise result in an increase in the circadian amplitude. This paper discusses how the effects of aging and sleep deprivation negatively impact the SCN and work to degrade its functional integrity. Additionally, Meijer and colleagues demonstrated the mechanisms behind synchronization and plasticity of the SCN circadian pacemaker which allows the circadian clock to respond to changes in the length of day. Meijer found that SCN synchronization improves with exercise and worsens with age and sleep deprivation. Studying plasticity further, Meijer and other scientists discovered that plasticity has effects on metabolism. Specifically, they found that a phase shift in one's circadian clock due to different patterns of light exposure results in metabolic disorders and obesity. Meijer's studies of

cryptochrome Cryptochromes (from the Greek κρυπτός χρώμα, "hidden colour") are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields i ...

-deficient mice (a photoreceptor which regulates entrainment by light) revealed that they show no neuronal activity in the SCN because the circadian rhythm is generated from a transcription-translation feedback loop, which includes both positive and negative feedback via certain circadian clock genes.

Light responses of the mammalian circadian system

Applying techniques in neurophysiology to the study of circadian systems, Meijer pioneered the use of ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

'' and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

electrophysiological Electrophysiology (from Greek , ''ēlektron'', "amber" etymology of "electron"">Electron#Etymology">etymology of "electron" , ''physis'', "nature, origin"; and , ''-logia'') is the branch of physiology that studies the electrical properties of bi ...

recordings to characterize the neural basis of circadian light responses in the mammalian SCN. Meijer's early studies in rodents used direct electrical recordings to map the prevalence and properties of visual SCN neurons in response to retinal light exposure. Meijer went on to characterize the baseline and light-induced activity of the mammalian SCN through long-term recordings in freely moving rats, which established the ability of the SCN to produce circadian rhythms in neural activity ''in vivo''. Studying pathways for light input to the SCN, Meijer found that

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

injections in the SCN produce phase shifts in the circadian activity rhythms of hamsters similar to those induced by light exposure, providing evidence that glutamate transmission mediates photic

entrainment Entrainment may refer to: * Air entrainment, the intentional creation of tiny air bubbles in concrete * Brainwave entrainment, the practice of entraining one's brainwaves to a desired frequency * Entrainment (biomusicology), the synchronization o ...

. Building upon this finding, Meijer later demonstrated the presence of

glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system a ...

s within the

retinohypothalamic tract In neuroanatomy, the retinohypothalamic tract (RHT) is a photic neural input pathway involved in the circadian rhythms of mammals. The origin of the retinohypothalamic tract is the intrinsically photosensitive retinal ganglion cells (ipRGC), whi ...

of brown Norwegian rats through the use of

immunogold labeling Immunogold labeling or Immunogold staining (IGS) is a staining technique used in electron microscopy. This staining technique is an equivalent of the indirect immunofluorescence technique for visible light. Colloidal gold particles are most ofte ...

, providing molecular evidence that glutamate acts as a neurotransmitter in the transduction of photic signals to the circadian clock. Probing the role of classical photoreceptors in photic entrainment, Meijer's lab demonstrated that light-dependent activation of the SCN was retained in mice lacking the photopigment

melanopsin Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene ''Opn4''. In the mammalian retina, there are two additional categories of opsins, both involved in the for ...

(''Opn4-/-'') but strongly attenuated in mice lacking

rods and cones A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light (visible electromagnetic radiati ...

(''rd/rd cl''). Previously, melanopsin expressed in

intrinsically photosensitive retinal ganglion cell Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye. The presence ...

s was thought to be the primary photopigment involved in light input to the circadian clock. As such, these results offered evidence for the role of classical photoreceptors in transmitting light information to the SCN, which showed that the mammalian circadian clock receives input from photopigments beyond melanopsin.

Clinical implications of circadian biology

Mood, aging, and metabolism

Meijer's current research aims to understand circadian disruptions associated with a wide range of health concerns, including aging, mental health, metabolic disorders, and sleep deprivation. In this domain, Meijer contributed to studies demonstrating that

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

degradation by

monoamine oxidase A Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, s ...

is regulated by the circadian clock proteins

BMAL1 Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the gene on chromosome 11, region p15.3. It's also known as ''BMAL1'', ''MOP3'', and, less com ...

NPAS2 Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the ''NPAS2'' gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenan ...

, and

PER2 PER2 is a protein in mammals encoded by the ''PER2'' gene. ''PER2'' is noted for its major role in circadian rhythms. Discovery The ''per ''gene'' ''was first discovered using forward genetics in ''Drosophila melanogaster, Drosophilla melanoga ...

in mice. This finding points to a molecular connection between circadian rhythms, dopamine metabolism, and mood-related behaviors, which may suggest that circadian disruptions play a role in mood regulation. Studies conducted by the Meijer lab helped link differences in SCN activity to age-related changes in sleep and circadian function. Through longitudinal electrical recordings in mice, Meijer's group showed that circadian rhythms in the SCN become weaker and desynchronized with increasing age, which has been associated with

amyloid Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a beta sheet (β-sheet) Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Staining, ...

aggregation in

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

. These findings suggest that the deterioration of SCN activity may contribute to the circadian dysfunctions observed in Alzheimer's disease. Research on circadian energy metabolism in the Meijer lab helped establish the detrimental effects of a high-fat diet on metabolic gene expression in liver and adipose tissue, supporting the role of circadian alterations in the development of

insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...

and

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

. Additionally, mouse SCN lesion experiments performed in the Meijer lab identified disruptions in circadian glucose homeostasis rhythms, corroborating observations in whole-animal

knockout studies A gene knockout (abbreviation: KO) is a genetic technique in which one of an organism's genes is made inoperative ("knocked out" of the organism). However, KO can also refer to the gene that is knocked out or the organism that carries the gene kno ...

of circadian genes.

Chronopharmacology

Meijer has also been influential in understanding how medications interact with and affect the daily

circadian rhythm A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...

of patients. She has studied how

methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, ...

delays the circadian clock and investigated how some medications move throughout the body following a 24-hour variation. In addition, she has explored the relationship between the time of day medications are administered, such as

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...

and

levofloxacin Levofloxacin, sold under the brand name Levaquin among others, is an antibiotic medication. It is used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, H. pylori (in combination with other medications), ...

, and how the body reacts differently depending on those administration times. With this understanding, she researched how certain receptors in the brain also follow a 24-hour rhythm, and specifically how medications could be more effective by taking into account the efflux of the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

through the

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...

Sleep and non-photic effects on the circadian pacemaker

Meijer made significant contributions to understanding the non-photic effects on the SCN pacemaker. She found that mammalian's sleep-wake timing is regulated by the SCN pacemaker. Meijer also studied the long-term effects of sleep deprivation in mammals. Studying the circadian response to

sleep deprivation Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either chronic or acute and may vary ...

, Meijer's group obtained the first evidence that sleep centers in the brain directly regulates activity of the SCN. By live-monitoring the SCN activity and sleep phase in rats, Meijer and colleagues demonstrated that slow-wave activity during non-rapid eye movement (NREM) sleep was associated with reduced SCN activity, whereas rapid eye movement (REM) sleep was correlated with increased SCN activity. Furthermore, the transition between NREM and REM sleep was shown to correspond to sharp alterations in SCN firing patterns. In subsequent sleep deprivation experiments, the disruption of slow-wave NREM sleep resulted in increased activity in the SCN, while REM sleep disruption decreased SCN activity. These results indicated that the SCN receives and responds to information on sleep states, although the physiological mechanisms underlying this phenomenon remain to be elucidated. Additional to Meijer's interests in sleep, she also conducted a study on the effects of chronic

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...

consumption in mice. Her studies showed that unlike traditional conventions of how caffeine may affect sleep, chronic caffeine intake seemed to increase the amplitude of the daily

sleep-wake cycle A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

and elevate sleep pressure in mice.

Practical applications of circadian rhythms

Meijer has also been an advocate for understanding how

can affect various fields of study. For preterm children being held in the

neonatal intensive care unit A neonatal intensive care unit (NICU), also known as an intensive care nursery (ICN), is an intensive care unit (ICU) specializing in the care of ill or premature newborn infants. Neonatal refers to the first 28 days of life. Neonatal care, as kn ...

, she hopes to expand the connection between consistent light-dark cycles and how they could potentially improve the outcome of their health. She also studied how the effect of light dark cycles can affect the temporal behavior,

population dynamics Population dynamics is the type of mathematics used to model and study the size and age composition of populations as dynamical systems. History Population dynamics has traditionally been the dominant branch of mathematical biology, which has ...

and

social hierarchy Social stratification refers to a society's categorization of its people into groups based on socioeconomic factors like wealth, income, race, education, ethnicity, gender, occupation, social status, or derived power (social and political). As su ...

in mice. In

zebrafish The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family ( Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...

, she expanded on how having either a proactive or reactive personality types can be connected to individual clock

gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...

rhythms. She found that individuals with the proactive personality type, characterized as being more aggressive and a higher baseline metabolic rate, had a significant distinct diurnal rhythmicity in clock gene expression. In contrast, individuals with the reactive trait showed a significant lack of diurnal or nocturnal rhythmicity in those same genes. Additionally, she has researched whether or not the action of wheel-running, commonly used in many areas of research, is stereotyped or a natural behavior. Stereotyped behaviors are characterized as repetitive, invariant, and lack a goal or function. By comparing the activity of mice in a lab, sand dunes, and an urban environment, she found that

wheel running A hamster wheel or running wheel is an exercise device used primarily by hamsters and other rodents, but also by other cursorial animals when given the opportunity. Most of these devices consist of a runged or ridged wheel held on a stand by ...

was intentional and occurred in similar rates regardless of captivity. This was confirmed even when a rewarding stimulus was removed from the experiment, as there was an increase in the fraction of mice visits versus wheel activity in non-captivity. This indicated that wheel-running is a rewarding action that mice undertake regardless of the environment they are located in.

The circadian clock in modern society

Meijer currently leads the large nation-wide research consortiu
BioClock
to investigate the biological clock in day-to-day life. This BioClock consortium is a joint collaboration between 13 Dutch Universities and Universities of Applied Sciences together with governmental, semi-governmental and commercial parties. In 2020, BioClock was awarded 9.7 million Euros from the Dutch Research Council (NWO) for the Dutch National Research Agenda program (NWA). Across 25 projects, Meijer and colleagues investigate a unique coverage of the effects of modern daily life on health. Since 80% of the world lives in a light-polluted sky and one in five works in Europe is currently engaged in some form of shift work, important cues for the biological clock have drastically and abruptly changed in the past years. These changes lead to circadian disruption of humans and animals, with large consequences for mental and physical human health, as well as fitness and the chance of survival for many species. Meijer investigates with the BioClock consortium how these challenges can be overcome by uniting experts from different disciplines with the ultimate goal to protect or even strengthen the clock to promote health, quality of life and biodiversity.

Positions and honors

Academic positions

* 2007–Present: Full Professor, Department of Physiology, LUMC, Leiden, The Netherlands. * 2013–Present: Visiting professor, Nuffield Department of Ophthalmology and Clinical Neuroscience,

Oxford University Oxford () is a city in England. It is the county town and only city of Oxfordshire. In 2020, its population was estimated at 151,584. It is north-west of London, south-east of Birmingham and north-east of Bristol. The city is home to the ...

, GB. * 2001-2007: Associate Professor, Department of Physiology, LUMC, Leiden, The Netherlands. * 1992-2001: Assistant Professor, Department of Physiology, LUMC, Leiden, The Netherlands. * 2014–Present: Member of the Royal Dutch Society of Sciences. * 2012: Elected Member at Large of the

Society for Research on Biological Rhythms The Society for Research on Biological Rhythms (SRBR) is an international chronobiological research society with three key goals: (1) to promote the advancement and dissemination of basic and applied research in all aspects of biological rhythms ( ...

. * 1989: Fellowship of the

Royal Dutch Academy of Sciences The Royal Netherlands Academy of Arts and Sciences ( nl, Koninklijke Nederlandse Akademie van Wetenschappen, abbreviated: KNAW) is an organization dedicated to the advancement of science and literature in the Netherlands. The academy is housed ...

Honors and awards

* 2020: Dutch National Research Agenda grant – “BioClock Consortium”. website: www.bioclockconsortium.org * 2019: European Advanced Research Grant, ERC: “The circadian clock in day-active species: preserving our health in modern society” * 2016: Aschoff and Honma Prize in Biological Rhythm Research. * 1993: “Aschoff’s Rule, a prize for eminent contributions in Chronobiology supporting the interdisciplinary spirit of the field”.

References

{{DEFAULTSORT:Meijer, Johanna 21st-century Dutch biologists Chronobiologists Leiden University alumni Academic staff of Leiden University 1959 births Scientists from The Hague Living people