Dragana Rogulja

Last updated
Dragana Rogulja
Born
Belgrade, Serbia
Alma materRutgers University
Known forMorphogenic gradients in wing development, CycA regulation of sleep in Drosophila
Awards2016 NIH Director's New Innovator Award Recipient, 2016 Pew Biomedical Scholar, 2015 NYSCF – Robertson Neuroscience Investigator
Scientific career
FieldsNeuroscience
InstitutionsHarvard Medical School

Dragana Rogulja is a Serbian neuroscientist and circadian biologist who is an assistant professor in Neurobiology within the Harvard Medical School Blavatnik Institute of Neurobiology. Rogulja explores the molecular mechanisms governing sleep in Drosophila as well as probing how circadian mechanisms integrate sensory information to drive behavior. Rogulja uses mating behavior in Drosophila to explore the neural circuits linking internal states to motivated behaviors.

Contents

Early life and education

Rogulja was born in Belgrade, Serbia. [1] She pursued an undergraduate education in pharmacy at the University of Belgrade, but was driven to study abroad due to the economic situation in Belgrade. [1] In 1998, midway through her undergraduate degree, Rogulja moved to the United States and finished her undergraduate degree at Rutgers University. [1] She joined the lab of Konstantin Severinov, a Russian molecular biologist, where she worked as an undergraduate researcher and was able to conduct experiments that lead to publications in Science, the Journal of Biological Chemistry, and the Journal of Molecular Biology. [1] Rogulja explored the interactions between the alpha and beta subunits of eukaryotic RNA polymerase in its assembly intermediate state. [2]

Rogulja stayed at Rutgers University to pursue her graduate training in 2000. [3] She joined the lab of Kenneth D. Irvine to study intercellular signalling and regulation of tissue growth by morphogen gradients in drosophila. [3] Rogulja pursued her postdoctoral training under Michael W. Young at Rockefeller University in New York City. [3] Under Young's mentorship, Rogulja began to explore circadian biology and the neural mechanisms regulating sleep in drosophila. [3] She completed her postdoctoral training in 2012. [3]

In her graduate work, Rogulja explored how morphogenic gradients control growth in development. [4] In her first author paper published in Cell in 2005, Rogulja showed, for the first time, that the regulation of wing growth in Drosophila is governed by the morphogenic gradient of Decapentaplegic (DPP). [4] One question that spurred their project was how the wings of Drosophila could have even growth driven by a morphogenic gradient. [4] Going with the hypothesis that slope of the DPP gradient, rather than absolute levels, drives consistent and even growth, Rogulja created a method for controlled gene expression where she could show that signalling between neighboring cells exposed to DPP gradients drives proliferation. [4] Rogulja further proposed a model to explain the morphogen slope dependency on growth, highlighting importantly that her model could account for normal growth despite local variations in morphogen concentration. [4]

Rogulja continued to use Drosophila as a model organism in her postdoctoral studies, but this time to ask question about the molecular mechanisms of sleep. [5] Rogulja found that cyclin A (CycA) and its regulator cyclin A1 promote sleep in Drosophila. [5] Fascinatingly, CycA is only expressed in 40-50 neurons in the fly brain, intermingled with circadian clock neurons suggesting that interactions with their cellular neighbors are important in allowing the circadian cycle to influence sleep. [5] When Rogulja artificially reduced expression of CycA in these neurons, she found that Drosophila had hard times falling asleep and reduced responses to sleep deprivation. [5] Further, since CycA is a cell cycle regulator that is highly conserved across species, Rogulja and her colleagues propose the importance of CycA in sleep regulation beyond drosophila. [5]  In a later paper, Rogulja and a team of researchers used a forward genetic screen to isolate another regulator of CycA called TARA. [6] They found that TARA interacts with CycA to promote sleep and that it acts through inhibiting Cdk1 in the arousal center of the fly brain. [6]

Career and research

In 2013, Rogulja was recruited to Harvard Medical School to become an assistant professor in the Department of Neurobiology. [7] As the principal investigator of the Ragoluja Lab, Rogulja runs a research program with three main focuses: sleep, circadian biology, and motivation. [8] Rogulja uses both Drosophila and rodent models to answer her questions on these topics. [8] Her lab explores the biological basis of sleep from the neural circuits underlying sleep behavior to how sleep deprivation impacts sensory processes such as pain perception. [8] In relation to this work, Rogulja explores how sensory information guides the circadian clock to drive specific behaviors at certain times of day. [8] Lastly, Rogulja collaborates extensively with the Crickmore Lab, led by Michael Crickmore at Harvard, to explore motivated states that drive behavior in animal models, with a specific focus on how sexual behavior is calibrated by internal states. [8] In 2016, Rogulja gave a TEDX Talk in Boston describing the importance of basic science research to understand fundamental mechanisms governing sleep and how our increased exposure to light and dysregulated sleep-wake schedules due to globalization and travel affect our biology. [9]

One facet of Rogulja's lab explores the neural mechanisms governing mating behavior in drosophila. [10] In 2016, Rogulja and her colleagues discovered the role of dopamine in reflecting the mating need state in males flies and driving the appropriate reproductive behaviors. [10] They found that as males flies participated in copulations, they had increased dopaminergic activity, and decreased mating driving, highlighting the potential of dopamine activity serving as a molecular correlate of mating drive. [10] They further found that the mating drive signal is transmitted by dopamine neurons and integrated with sensory information specific to female perceptions and these neurons further project to motor areas to drive mating behavior. [10] Their circuit mapping exquisitely shows the way in which internal motivational states in drosophila can interact with sensory information and change behavioral output. [10] Following this study, Rogulja and her colleagues explored how dopaminergic signals onto P1 neurons determine courtship probability. [11] They found that a motivational dopamine signal drives the initiation of courtship behavior through interactions with P1 neurons, and the same dopamine signal arriving at P1 following initiation of copulation helps to sustain copulation as well as terminate it. [11] The mechanisms with which the dopaminergic neurons stimulate and terminate copulatory behavior are distinct and the element of chance in plays a role in behavioral outcomes due to the desensitization mechanisms of dopamine neurons pre-copulation. [11] While the element of chance might lead to behavioral inflexibility by the organism itself, it also allows for environmental influences to shape outcomes in novel ways. [11]

Again using mating behavior as a tool to elucidate neural correlates of motivational states, Rogulja and her team probed how motivational dynamics can exist across such large time scales. [12] They identified an excitation loop in Drosophila wherein  increased dopaminergic tone increased the propensity to court but then after copulation, CREB2 generates an inhibitory environment by increasing expression of leaky potassium channels, which helps to stabilize peak motivation in reproductive drive and induce reproductive satiety. [13] They further used computational tools to reproducibly model the observed behavioural and physiological dynamics in mating behavior. [13]

Awards and honors

Select publications

Related Research Articles

Dopamine Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

Circadian rhythm Natural internal process that regulates the 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 and responds to the environment. These 24-hour rhythms are driven by a circadian clock, and they have been widely observed in animals, plants, fungi and cyanobacteria.

The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle.

The Coolidge effect is a biological phenomenon seen in animals, whereby males exhibit renewed sexual interest whenever a new female is introduced, even after sex with prior but still available sexual partners. To a lesser extent, the effect is also seen among females with regard to their mates.

Nucleus accumbens Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

Suprachiasmatic nucleus Part of the brains hypothalamus

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 regulate many different body functions in a 24-hour cycle. The mouse SCN contains approximately 20,000 neurons.

Dopaminergic pathways Projection neurons in the brain that synthesize and release dopamine

Dopaminergic pathways, in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopamine neurons.

Ventral tegmental area Group of neurons on the floor of the midbrain

The ventral tegmental area (VTA), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and other dopamine pathways; it is widely implicated in the drug and natural reward circuitry of the brain. The VTA plays an important role in a number of processes, including reward cognition and orgasm, among others, as well as several psychiatric disorders. Neurons in the VTA project to numerous areas of the brain, ranging from the prefrontal cortex to the caudal brainstem and several regions in between.

Decapentaplegic (Dpp) is a key morphogen involved in the development of the fruit fly Drosophila melanogaster and is the first validated secreted morphogen. It is known to be necessary for the correct patterning and development of the early Drosophila embryo and the fifteen imaginal discs, which are tissues that will become limbs and other organs and structures in the adult fly. It has also been suggested that Dpp plays a role in regulating the growth and size of tissues. Flies with mutations in decapentaplegic fail to form these structures correctly, hence the name. Dpp is the Drosophila homolog of the vertebrate bone morphogenetic proteins (BMPs), which are members of the TGF-β superfamily, a class of proteins that are often associated with their own specific signaling pathway. Studies of Dpp in Drosophila have led to greater understanding of the function and importance of their homologs in vertebrates like humans.

CLOCK Protein-coding gene in the species Homo sapiens

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is believed to affect both the persistence and period of circadian rhythms.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

Pigment dispersing factor (pdf) is a gene that encodes the protein PDF, which is part of a large family of neuropeptides. Its hormonal product, pigment dispersing hormone (PDH), was named for the diurnal pigment movement effect it has in crustacean retinal cells upon its initial discovery in the central nervous system of arthropods. The movement and aggregation of pigments in retina cells and extra-retinal cells is hypothesized to be under a split hormonal control mechanism. One hormonal set is responsible for concentrating chromatophoral pigment by responding to changes in the organism's exposure time to darkness. Another hormonal set is responsible for dispersion and responds to the light cycle. However, insect pdf genes do not function in such pigment migration since they lack the chromatophore.

mir-279 is a short RNA molecule found in Drosophila melanogaster that belongs to a class of molecules known as microRNAs. microRNAs are ~22nt-long non-coding RNAs that post-transcriptionally regulate the expression of genes, often by binding to the 3' untranslated region of mRNA, targeting the transcript for degradation. miR-279 has diverse tissue-specific functions in the fly, influencing developmental processes related to neurogenesis and oogenesis, as well as behavioral processes related to circadian rhythms. The varied roles of mir-279, both in the developing and adult fly, highlight the utility of microRNAs in regulating unique biological processes.

<i>Cycle</i> (gene)

Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include ARNTL and ARNTL2.

Michael Rosbash American geneticist and chronobiologist (born 1944)

Michael Morris Rosbash is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the Drosophila period gene in 1984 and proposed the Transcription Translation Negative Feedback Loop for circadian clocks in 1990. In 1998, they discovered the cycle gene, clock gene, and cryptochrome photoreceptor in Drosophila through the use of forward genetics, by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to the National Academy of Sciences in 2003. Along with Michael W. Young and Jeffrey C. Hall, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm".

Jeffrey C. Hall American geneticist and chronobiologist

Jeffrey Connor Hall is an American geneticist and chronobiologist. Hall is Professor Emeritus of Biology at Brandeis University and currently resides in Cambridge, Maine.

Douglas G. McMahon

Douglas G. McMahon is a professor of Biological Sciences and Pharmacology at Vanderbilt University. McMahon has contributed several important discoveries to the field of chronobiology and vision. His research focuses on connecting the anatomical location in the brain to specific behaviors. As a graduate student under Gene Block, McMahon identified that the basal retinal neurons (BRNs) of the molluscan eye exhibited circadian rhythms in spike frequency and membrane potential, indicating they are the clock neurons. He became the 1986 winner of the Society for Neuroscience's Donald B. Lindsley Prize in Behavioral Neuroscience for his work. Later, he moved on to investigate visual, circadian, and serotonergic mechanisms of neuroplasticity. In addition, he helped find that constant light can desynchronize the circadian cells in the suprachiasmatic nucleus (SCN). He has always been interested in the underlying causes of behavior and examining the long term changes in behavior and physiology in the neurological modular system. Recently, McMahon helped identify a novel retrograde neurotransmission system in the retina involving the melanopsin ganglion cells in retinal dopaminergic amacrine neurons.

Paul H. Taghert is an American chronobiologist known for pioneering research on the roles and regulation of neuropeptide signaling in the brain using Drosophila melanogaster as a model. He is a professor of neuroscience in the Department of Neuroscience in the School of Medicine at Washington University in St. Louis.

<i>Drosophila</i> circadian rhythm

Drosophila circadian rhythm is a daily 24-hour cycle of rest and activity in the fruit flies of the genus Drosophila. The biological process was discovered and is best understood in the species Drosophila melanogaster. Other than normal sleep-wake activity, D. melanogaster has two unique daily behaviours, namely regular vibration during the process of hatching from the pupa, and during mating. Locomotor activity is maximum at dawn and dusk, while eclosion is at dawn.

Ravi Allada is an Indian-American chronobiologist studying the circadian and homeostatic regulation of sleep primarily in the fruit fly Drosophila. He is the Edward C. Stuntz Distinguished Professor of Neuroscience and Chair of the Department of Neurobiology at Northwestern University. Working with Michael Rosbash, he positionally cloned the Drosophila Clock gene. In his laboratory at Northwestern, he discovered a conserved mechanism for circadian control of sleep-wake cycle, as well as circuit mechanisms that manage levels of sleep.

References

  1. 1 2 3 4 Wald, Chelsea (2010-02-05). "A Husband and Wife Play Science on the Same Team". Science | AAAS. Retrieved 2020-05-01.
  2. ↑ Naryshkina, Tatyana; Rogulja, Dragana; Golub, Larisa; Severinov, Konstantin (2000-10-06). "Inter- and Intrasubunit Interactions during the Formation of RNA Polymerase Assembly Intermediate". Journal of Biological Chemistry. 275 (40): 31183–31190. doi: 10.1074/jbc.M003884200 . ISSN   0021-9258. PMID   10906130.
  3. 1 2 3 4 5 "Neurotree - Dragana Rogulja". neurotree.org. Retrieved 2020-05-01.
  4. 1 2 3 4 5 Rogulja, Dragana; Irvine, Kenneth D. (2005-11-04). "Regulation of cell proliferation by a morphogen gradient". Cell. 123 (3): 449–461. doi: 10.1016/j.cell.2005.08.030 . ISSN   0092-8674. PMID   16269336.
  5. 1 2 3 4 5 6 Rogulja, Dragana; Young, Michael W. (2012-03-30). "Control of Sleep by Cyclin A and Its Regulator". Science. 335 (6076): 1617–1621. Bibcode:2012Sci...335.1617R. doi:10.1126/science.1212476. ISSN   0036-8075. PMC   3380085 . PMID   22461610.
  6. 1 2 Afonso, Dinis J. S.; Liu, Die; Machado, Daniel R.; Pan, Huihui; Jepson, James E. C.; Rogulja, Dragana; Koh, Kyunghee (2015-06-29). "TARANIS Functions with Cyclin A and Cdk1 in a Novel Arousal Center to Control Sleep in Drosophila". Current Biology. 25 (13): 1717–1726. doi:10.1016/j.cub.2015.05.037. ISSN   1879-0445. PMC   4559600 . PMID   26096977.
  7. ↑ "NIH Director's New Innovator Award Program - 2016 Award Recipients | NIH Common Fund". commonfund.nih.gov. Retrieved 2020-05-01.
  8. 1 2 3 4 5 "Research". Rogulja Lab. Retrieved 2020-05-01.
  9. ↑ The Dark Side of Light | Dragana Rogulja | TEDxYouth@BeaconStreet , retrieved 2020-05-01
  10. 1 2 3 4 5 6 Zhang, Stephen X.; Rogulja, Dragana; Crickmore, Michael A. (2016-07-06). "Dopaminergic Circuitry Underlying Mating Drive". Neuron. 91 (1): 168–181. doi: 10.1016/j.neuron.2016.05.020 . ISSN   0896-6273. PMID   27292538.
  11. 1 2 3 4 5 Zhang, Stephen X.; Miner, Lauren E.; Boutros, Christine L.; Rogulja, Dragana; Crickmore, Michael A. (2018-07-25). "Motivation, Perception, and Chance Converge to Make a Binary Decision". Neuron. 99 (2): 376–388.e6. doi: 10.1016/j.neuron.2018.06.014 . ISSN   0896-6273. PMID   29983326.
  12. 1 2 Zhang, Stephen X.; Rogulja, Dragana; Crickmore, Michael A. (2019-10-07). "Recurrent Circuitry Sustains Drosophila Courtship Drive While Priming Itself for Satiety". Current Biology. 29 (19): 3216–3228.e9. doi:10.1016/j.cub.2019.08.015. ISSN   0960-9822. PMC   6783369 . PMID   31474539.
  13. 1 2 Zhang, Stephen X.; Rogulja, Dragana; Crickmore, Michael A. (2019-10-07). "Recurrent Circuitry Sustains Drosophila Courtship Drive While Priming Itself for Satiety". Current Biology. 29 (19): 3216–3228.e9. doi:10.1016/j.cub.2019.08.015. ISSN   0960-9822. PMC   6783369 . PMID   31474539.
  14. ↑ "NIH Director's New Innovator Award Program - 2016 Award Recipients | NIH Common Fund". commonfund.nih.gov. Retrieved 2020-05-01.
  15. ↑ "Awards & Recognition: June 2016". hms.harvard.edu. Retrieved 2020-05-01.
  16. ↑ "Dragana Rogulja, PhD". New York Stem Cell Foundation. Retrieved 2020-05-01.
  17. ↑ Rogulja, Dragana; Rauskolb, Cordelia; Irvine, Kenneth D. (2008-08-12). "Morphogen Control of Wing Growth through the Fat Signaling Pathway". Developmental Cell. 15 (2): 309–321. doi:10.1016/j.devcel.2008.06.003. ISSN   1534-5807. PMC   2613447 . PMID   18694569.
  18. ↑ Rogulja, Dragana; Irvine, Kenneth D. (2005-11-04). "Regulation of Cell Proliferation by a Morphogen Gradient". Cell. 123 (3): 449–461. doi: 10.1016/j.cell.2005.08.030 . ISSN   0092-8674. PMID   16269336.
  19. ↑ Kuznedelov, Konstantin; Minakhin, Leonid; Niedziela-Majka, Anita; Dove, Simon L.; Rogulja, Dragana; Nickels, Bryce E.; Hochschild, Ann; Heyduk, Tomasz; Severinov, Konstantin (2002-02-01). "A Role for Interaction of the RNA Polymerase Flap Domain with the σ Subunit in Promoter Recognition". Science. 295 (5556): 855–857. Bibcode:2002Sci...295..855K. doi:10.1126/science.1066303. ISSN   0036-8075. PMID   11823642.
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