Douglas G. McMahon

Last updated

Douglas G. McMahon
Douglas McMahon.jpg
Born
Annandale, Virginia
NationalityAmerican
Alma mater University of Virginia
Harvard University
Scientific career
Fields Biology, Neurobiology
Institutions University of Virginia

Douglas G. McMahon is a professor of Biological Sciences and Pharmacology at Vanderbilt University. [1] 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). [2] 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. McMahon helped identifying a retrograde neurotransmission system in the retina involving the melanopsin containing ganglion cells and the retinal dopaminergic amacrine neurons. [3]

Contents

Biography

Education

McMahon earned his Bachelor of Arts in biology from University of Virginia in 1980. Immediately after graduating, McMahon began a Ph.D. program in biology at Northwestern University. However, in 1981, McMahon found himself back at the University of Virginia where he completed his Ph.D. in biology under Gene D. Block. It was during this time that McMahon discovered the basal retinal neurons of the molluscan eye were the clock neurons. From 1986-1990, McMahon conducted his post-doctoral work in neurobiology at Harvard University with John E. Dowling. [4]

Scientific achievements

Neuronal circadian pacemakers

McMahon's work on molluscs with Gene Block led to a better understanding of the daily activity of the oscillating pacemaker cells. [5] Prior to this discovery, the identity of neuron types participating in retinal networks was largely known, but the specific physiological roles of the identified morphological structures were poorly understood. [6] In 2011, McMahon and Block found that retinal neurons in molluscs were active during the day, but inactive at night. Electrical stimulation at the tissue level of the retinal neurons during the day did not affect the organism. However, electrical stimulation at night caused a phase shift in the organism. Because stimulation yielded a phase shift, the results suggested that the retina contained a biological clock. McMahon and Block devised a model explaining these phenomena: light during the day does not have much of an effect on the neurons' activity, as they are already active. Light at night, on the other hand, when these neurons are inactive, stimulates them and causes them to fire action potentials. The change in electrical activity manifests itself as a phase shift within the organism. [5] Further research led them to find that phase shifting is a calcium-dependent process. They found that lowering extracellular levels of calcium actually prevents the organism from phase shifting in response to light without affecting the response of the neurons to light. [7] Around the same time, while Block and McMahon were conducting this experiment, other scientists discovered how to clone the period gene, marking an exciting time in the young field of chronobiology.

Diagram of Basal Retinal Neuron Basal Retinal Neuron.png
Diagram of Basal Retinal Neuron

Retinal research

McMahon contributed to the understanding of retinal neurophysiology alongside his post-doctoral mentor, John E. Dowling. His early research focused on ion channels that mediate transmission at electrical and glutamatergic synapses and the modulatory effects of dopamine and nitric oxide on retinal synapse networks. [9] Through studies with zebrafish he discovered that the neurotransmitter dopamine decreases the electrical coupling within horizontal cells. [10] Further research showed that it was the increase of cAMP within the cell resulting from dopamine binding to AMPA receptor that led to this decrease in coupling. [10] McMahon and his colleagues also demonstrated that exogenous nitric oxide and zinc can modulate AMPA receptor mediated synaptic transmission at gap junctions in hybrid bass retinal neurons. [9]

Isolating the BRN

The work that won McMahon the Donald B. Lindsey Prize for PhD candidates involved locating and isolating specific regions of the eye that possessed circadian rhythms in Bulla gouldiana . Under the mentorship of Gene Block, McMahon recorded from the basal retinal neurons (BRNs), a homogenous group of neurons that are 15-25μm in diameter, of the snail's eye and found that they could entrain to light/dark cycles, and even oscillate in constant darkness with a consistent intrinsic period. [11] The BRN was later shown to entrain to light/dark cycles, and control physiological and behavioral oscillations within the entire organism. [12] McMahon and Block found an increase in firing frequency and depolarization of the BRNs during the day, but the opposite at night. [12] In addition, electrical activity between action potentials in the optic nerve and the firing of the BRNs were shown to share a 1:1 correlation. [13] In 1984, McMahon also demonstrated that the surgical removal of the photoreceptor layer failed to disrupt circadian rhythm in the Bulla eye, while the removal of the BRNs abolished circadian rhythm. His discovery that a fragment of Bulla retina containing as few as six intact BRN somata were sufficient for circadian rhythmogenesis further supported the BRNs as circadian pacemakers. [11] [12] Later work by Dr. Stephan Michel using a surgical reductionist approach provided further evidence that isolated BRNs were capable of circadian oscillations in their conductance. [14]

Recent research

McMahon's lab is currently interested in three areas of research: the role of dopamine on visual function and retinal physiology, links between molecular, intracellular, electrical, and behavioral rhythms in the brain's biological clock, and how perinatal photoperiod affects the serotonergic system and anxious/depressive behavior. [15] Alongside Dao-Qi Zhang, the lab has made significant contributions to the understanding of retinal neural network adaptation by dopaminergic amacrine neurons (DA neurons), revealing a retrograde neurotransmission pathway in the retina specifically involving melanopsin containing ganglion cells. McMahon's lab developed mouse models, which enable in situ electrophysiological recording from DA neurons. [3]

In early 2015, McMahon and his graduate students, Jeff Jones and Michael Tackenberg, found that circadian rhythms in mice could be shifted by artificial stimulus to the suprachiasmatic nucleus (SCN) using a laser and optical fiber. [16] Using optogenetics, the Vanderbilt researchers were able to change the firing rate of neurons in the SCN so that their firing resembled their normal day and night activity levels. Subsequently, altering the firing rate of the SCN neurons reset the biological clocks of the mice. Prior to this experiment, firing rate was thought to be strictly an output of the SCN. However, the results from this experiment suggest that firing rate is a more complex mechanism that is yet to be fully understood. Although not ready for direct human use, optogenetic stimulation techniques such as the one used by McMahon could potentially be used to treat seasonal affective disorder, reduce the adverse health effects of working a night shift, and even alleviate the symptoms of jet lag. [16]

In 2014, McMahon, along with Chad Jackson, Megan Capozzi, and Heng Dai, found that mice exposed to short, winter-like, light cycles showed enduring deficits in photopic retinal light responses and visual contrast sensitivity. Additionally, dopamine levels were significantly lower in short photoperiod mice. These findings suggest that seasonal light cycles experienced during retinal development and maturation have lasting influences on retinal and visual function, likely through developmental programming of retinal dopamine. [17]

Procedural Contributions

McMahon's lab generated transgenic Per1::GFP mice in which a degradable form of recombinant jellyfish GFP reporter is driven by the mouse Per1 gene promoter. mPer1‐driven GFP fluorescence intensity reports light‐induction and circadian rhythmicity in neural structures of the SCN. The Per1::GFP transgenic mouse allows for the simultaneous quantification of molecular clock state and the firing rate of SCN neurons. Thus, this circadian reporter transgene depicts gene expression dynamics of biological clock neurons, giving a new view of this brain function. [18]

Honors and awards

Positions

McMahon has held multiple positions in academia:

Affiliations

McMahon has also been a member of many scientific communities. The most recent are listed below.

See also

Related Research Articles

<span class="mw-page-title-main">Circadian rhythm</span> Natural internal process that regulates the sleep-wake cycle

A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximise the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.

<span class="mw-page-title-main">Suprachiasmatic nucleus</span> Part of the brains hypothalamus

The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. The SCN is the principal circadian pacemaker in mammals, responsible for generating circadian rhythms. Reception of light inputs from photosensitive retinal ganglion cells allow the SCN to coordinate the subordinate cellular clocks of the body and entrain to the environment. The neuronal and hormonal activities it generates regulate many different body functions in an approximately 24-hour cycle.

<span class="mw-page-title-main">Melanopsin</span> Mammalian protein found in Homo sapiens

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 formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.

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 of ipRGCs was first suspected in 1927 when rodless, coneless mice still responded to a light stimulus through pupil constriction, This implied that rods and cones are not the only light-sensitive neurons in the retina. Yet research on these cells did not advance until the 1980s. Recent research has shown that these retinal ganglion cells, unlike other retinal ganglion cells, are intrinsically photosensitive due to the presence of melanopsin, a light-sensitive protein. Therefore, they constitute a third class of photoreceptors, in addition to rod and cone cells.

Gene David Block is an American biologist who has served as the current and 6th chancellor of the University of California, Los Angeles since August 2007.

<span class="mw-page-title-main">Retinohypothalamic tract</span> Neural pathway involved with circadian rhythms

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), which contain the photopigment melanopsin. The axons of the ipRGCs belonging to the retinohypothalamic tract project directly, monosynaptically, to the suprachiasmatic nuclei (SCN) via the optic nerve and the optic chiasm. The suprachiasmatic nuclei receive and interpret information on environmental light, dark and day length, important in the entrainment of the "body clock". They can coordinate peripheral "clocks" and direct the pineal gland to secrete the hormone melatonin.

<span class="mw-page-title-main">PER3</span> Protein and coding gene in humans

The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associated with delayed sleep phase syndrome in humans.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

<span class="mw-page-title-main">Russell Foster</span>

Russell Grant Foster, CBE, FRS FMedSci is a British professor of circadian neuroscience, the Director of the Nuffield Laboratory of Ophthalmology and the Head of the Sleep and Circadian Neuroscience Institute (SCNi). He is also a Nicholas Kurti Senior Fellow at Brasenose College at the University of Oxford. Foster and his group are credited with key contributions to the discovery of the non-rod, non-cone, photosensitive retinal ganglion cells (pRGCs) in the mammalian retina which provide input to the circadian rhythm system. He has written and co-authored over a hundred scientific publications.

Steven M. Reppert is an American neuroscientist known for his contributions to the fields of chronobiology and neuroethology. His research has focused primarily on the physiological, cellular, and molecular basis of circadian rhythms in mammals and more recently on the navigational mechanisms of migratory monarch butterflies. He was the Higgins Family Professor of Neuroscience at the University of Massachusetts Medical School from 2001 to 2017, and from 2001 to 2013 was the founding chair of the Department of Neurobiology. Reppert stepped down as chair in 2014. He is currently distinguished professor emeritus of neurobiology.

Michael Menaker, was an American chronobiology researcher, and was Commonwealth Professor of Biology at University of Virginia. His research focused on circadian rhythmicity of vertebrates, including contributing to an understanding of light input pathways on extra-retinal photoreceptors of non-mammalian vertebrates, discovering a mammalian mutation for circadian rhythmicity, and locating a circadian oscillator in the pineal gland of bird. He wrote almost 200 scientific publications.

Arnold Eskin was a professor of chronobiology at the University of Houston in Houston, Texas. He attended Vanderbilt University, where he received a degree in physics. He later attended University of Texas at Austin, where he received his Ph.D. in zoology in 1969. He is recognized in the term Eskinogram, and has been a leader in the discovery of mechanisms underlying entrainment of circadian clocks.

Hitoshi Okamura is a Japanese scientist who specializes in chronobiology. He is currently a professor of Systems Biology at Kyoto University Graduate School of Pharmaceutical Sciences and the Research Director of the Japan Science Technology Institute, CREST. Okamura's research group cloned mammalian Period genes, visualized clock oscillation at the single cell level in the central clock of the SCN, and proposed a time-signal neuronal pathway to the adrenal gland. He received a Medal of Honor with Purple Ribbon in 2007 for his research and was awarded Aschoff's Ruler for his work on circadian rhythms in rodents. His lab recently revealed the effects of m6A mRNA methylation on the circadian clock, neuronal communications in jet lag, and the role of dysregulated clocks in salt-induced hypertension.

Hajime Tei is a Japanese neuroscientist specializing in the study of chronobiology. He currently serves as a professor at the Kanazawa University Graduate School of Natural Science & Technology. He is most notable for his contributions to the discovery of the mammalian period genes, which he discovered alongside Yoshiyuki Sakaki and Hitoshi Okamura.

In the field of chronobiology, the dual circadian oscillator model refers to a model of entrainment initially proposed by Colin Pittendrigh and Serge Daan. The dual oscillator model suggests the presence of two coupled circadian oscillators: E (evening) and M (morning). The E oscillator is responsible for entraining the organism’s evening activity to dusk cues when the daylight fades, while the M oscillator is responsible for entraining the organism’s morning activity to dawn cues, when daylight increases. The E and M oscillators operate in an antiphase relationship. As the timing of the sun's position fluctuates over the course of the year, the oscillators' periods adjust accordingly. Other oscillators, including seasonal oscillators, have been found to work in conjunction with circadian oscillators in order to time different behaviors in organisms such as fruit flies.

<span class="mw-page-title-main">Sato Honma</span>

Sato Honma is a Japanese chronobiologist who researches the biological mechanisms of circadian rhythms. She mainly collaborates with Ken-Ichi Honma on publications, and both of their primary research focuses are the human circadian clock under temporal isolation and the mammalian suprachiasmatic nucleus (SCN), its components, and associates. Honma is a retired professor at the Hokkaido University School of Medicine in Sapporo, Japan. She received her Ph.D. in physiology from Hokkaido University. She taught physiology at the School of Medicine and then at the Research and Education Center for Brain Science at Hokkaido University. She is currently the director at the Center for Sleep and Circadian Rhythm Disorders at Sapporo Hanazono Hospital and works as a somnologist.

Johanna H. Meijer is a Dutch scientist who has contributed significantly to the field of chronobiology. 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.

The food-entrainable oscillator (FEO) is a circadian clock that can be entrained by varying the time of food presentation. It was discovered when a rhythm was found in rat activity. This was called food anticipatory activity (FAA), and this is when the wheel-running activity of mice decreases after feeding, and then rapidly increases in the hours leading up to feeding. FAA appears to be present in non-mammals (pigeons/fish), but research heavily focuses on its presence in mammals. This rhythmic activity does not require the suprachiasmatic nucleus (SCN), the central circadian oscillator in mammals, implying the existence of an oscillator, the FEO, outside of the SCN, but the mechanism and location of the FEO is not yet known. There is ongoing research to investigate if the FEO is the only non-light entrainable oscillator in the body.

Elizabeth Maywood is an English researcher who studies circadian rhythms and sleep in mice. Her studies are focused on the suprachiasmatic nucleus (SCN), a small region of the brain that controls circadian rhythms.

Martin R. Ralph is a circadian biologist who serves as a professor in the Psychology Department at the University of Toronto. His research primarily focuses on circadian rhythmicity in the fields of neuroscience, psychology, and endocrinology. His most notable work was has been on the suprachiasmatic nucleus, now recognized as the central circadian pacemaker in mammals, but has also investigated circadian rhythms in the context of time, memory, and light.

References

  1. ↑ "Douglas G. McMahon, Ph.D." vanderbilt.edu.
  2. ↑ Liu, AC; Welsh, DK; Ko, CH; Tran, HG; Zhang, EE; Priest, AA; Buhr, ED; Singer, O; Meeker, K; Verma, IM; Doyle, FJ 3rd; Takahashi, JS; Kay, SA (2007). "Intercellular Coupling Confers Robustness against Mutations in the SCN Circadian Clock Network". Cell. 129 (3): 605–616. doi:10.1016/j.cell.2007.02.047. PMC   3749832 . PMID   17482552.
  3. 1 2 Zhang, Dao-Qi; Wong, Kwoon Y.; Sollars, Patricia J.; Berson, David M.; Pickard, Gary E.; McMahon, D.G (2008). "Intraretinal signaling by ganglion cell photoreceptors to dopaminergic amacrine neurons". Proceedings of the National Academy of Sciences. 105 (37): 14181–14186. Bibcode:2008PNAS..10514181Z. doi: 10.1073/pnas.0803893105 . PMC   2544598 . PMID   18779590.
  4. 1 2 3 4 "McMahon Biographical Sketch" (PDF). Vkc.mc.vanderbilt.edu. Retrieved 8 April 2015.
  5. 1 2 Colwell, CS (2011). "Linking neural activity and molecular oscillations in the SCN". Nature Reviews Neuroscience. 12 (10): 553–569. doi:10.1038/nrn3086. PMC   4356239 . PMID   21886186.
  6. ↑ Tosini, Gianluca; Pozdeyev, Nikita; Sakamoto, Katsuhiko; Iuvone, P. Michael (2008). "The circadian clock system in the mammalian retina". BioEssays. 30 (7): 624–633. doi:10.1002/bies.20777. PMC   2505342 . PMID   18536031.
  7. ↑ Lundkvist, Gabriella B.; Kwak, Yongho; Davis, Erin K.; Tei, Hajime; Block, Gene D. (17 August 2005). "A Calcium Flux Is Required for Circadian Rhythm Generation in Mammalian Pacemaker Neurons". The Journal of Neuroscience. 25 (33): 7682–7686. doi:10.1523/JNEUROSCI.2211-05.2005. ISSN   0270-6474. PMC   6725395 . PMID   16107654.
  8. ↑ Jacklet, Jon W. (1985). "Neurobiology of circadian rhythms generators". Trends in Neurosciences. 8: 69–73. doi:10.1016/0166-2236(85)90029-3. S2CID   53192143.
  9. 1 2 Kolb, Helga; Ripps, Harris; Wu, Samuel (2004). Concepts and Challenges in Retinal Biology . Elsevier Science B.V. pp.  419–436. ISBN   978-0444514844.
  10. 1 2 Baldridge, William H.; Vaney, David I.; Weiler, Reto (1998). "The modulation of intercellular coupling in the retina". Seminars in Cell & Developmental Biology. 9 (3): 311–318. doi:10.1006/scdb.1998.0235. PMID   9665867.
  11. 1 2 Blumenthal, Edward M.; Block, Gene D.; Eskin, Arnold (30 September 2001). "Chapter 14: Cellular and Molecular Analysis of Molluscan Circadian Pacemakers". In Takahashi, Joseph S.; Turek, Fred W.; Moore, Robert Y. (eds.). Circadian Clocks. Springer Science & Business Media. pp. 371–400. ISBN   978-1-4615-1201-1.
  12. 1 2 3 Herzog, Erik D. (October 2007). "Neurons and networks in daily rhythms". Nature Reviews Neuroscience. 8 (10): 790–802. doi:10.1038/nrn2215. ISSN   1471-003X. PMID   17882255. S2CID   33687097.
  13. ↑ Aronson, B. (1993). "Circadian rhythms" (PDF). Brain Research Reviews. 18 (3): 315–333. doi:10.1016/0165-0173(93)90015-R. hdl: 2027.42/60639 . PMID   8401597. S2CID   20418410.
  14. ↑ Michel, S.; Geusz, M. E.; Zaritsky, J. J.; Block, G. D. (8 January 1993). "Circadian rhythm in membrane conductance expressed in isolated neurons". Science. 259 (5092): 239–241. Bibcode:1993Sci...259..239M. doi:10.1126/science.8421785. ISSN   0036-8075. PMID   8421785 . Retrieved 23 April 2015.
  15. ↑ "mcmahonlab". Mcmahonlab.wix.com. Retrieved 8 April 2015.
  16. 1 2 David Salisbury (2 February 2015). "New 'reset' button discovered for circadian clock | Research News @ Vanderbilt | Vanderbilt University". News.vanderbilt.edu. Retrieved 8 April 2015.
  17. ↑ Jackson, C. R.; Capozzi, M; Dai, H; McMahon, D. G. (2014). "Circadian Perinatal Photoperiod has Enduring Effects on Retinal Dopamine and Visual function". Journal of Neuroscience. 34 (13): 4627–4633. doi:10.1523/JNEUROSCI.4887-13.2014. PMC   3965786 . PMID   24672008.
  18. ↑ Kuhlman, S. J.; Quintero, J. E.; McMahon, D. G. (2000). "GFP fluorescence reports Period 1 circadian gene regulation in the mammalian biological clock". NeuroReport. 11 (7): 1479–1482. doi:10.1097/00001756-200005150-00024. PMID   10841361. S2CID   2843191.
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