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Mark Alkema PhD

TitleProfessor
InstitutionUniversity of Massachusetts Medical School
DepartmentNeurobiology
AddressUniversity of Massachusetts Medical School
364 Plantation Street, LRB
Worcester MA 01605
Phone508-856-6158
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentNeurobiology

    InstitutionUMMS - School of Medicine
    DepartmentNeuroNexus Institute

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentNeuroscience


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    Collapse education and training
    University of Amsterdam, Amsterdam, , NetherlandsBSChemistry
    University of Amsterdam, Amsterdam, , NetherlandsMSChemistry
    University of Amsterdam, Amsterdam, , NetherlandsPHDMedicine

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    Biography


    Mark Alkema received his B. Sc. (1990) from the University of Amsterdam and Ph.D. (1996) from the Netherlands Cancer Institute in Amsterdam. He received a Human Frontiers Science Program fellowship and a Merck / M.I.T. Fellowship to do postdoctoral work at the Massachusetts Institute of Technology in the laboratory of Bob Horvitz. He joined the Department of Neurobiology at the University of Massachusetts Medical School as a faculty member in June, 2005.


    C. elegans behavioral genetics



    University of Massachusetts Medical School UMass Mark Alkema, Ph.D. Our focus is to understand the molecular and cellular basis of behavioral plasticity. We are studying how the environment modulates behavior of the nematode Caenorhabditis elegans. The C. elegans nervous system is very simple and extraordinarily well described. The detailed knowledge  of the C. elegans nervous system combined with its amenability to genetic analysis and laser microsurgery allows us to define neural circuits that control behavior and study behavior at the molecular and cellular level.


    How does the nervous system translate sensory information into behavioral response? Facing the complexity of the mammalian nervous system this fundamental question presents daunting task. Some of the rare cases where we actually know the neural path, from sensory input to motor output, have come from the analyses of escape responses in mollusks, crayfish and goldfish (Korn and Faber, 2005; Edwards et al., 2002; Allen et al., 2006). Defining sensorimotor circuits requires detailed knowledge of the neural connectivity of the nervous system, and the ability to manipulate the functions of the component neurons and to define and quantify the behavioral outputs. The simplicity and completely defined synaptic connectivity of C. elegans nervous system provides unique opportunity to dissect how neural networks control behavior. Moreover, the combination of powerful genetic methods, calcium imaging and electrophysiology allows us to address how the nervous controls behavior with a cellular and molecular resolution that cannot be readily attained in other systems.


    C. elegans escape responseGentle touch elicits an escape response C. elegans where the animal displays characteristic sequence of behaviors to get away from the stimulus. C. elegans moves on its side by propagating a sinusoidal wave of body wall muscle contractions along the length of its body. C. elegans locomotion is accompanied by oscillatory head movements during which the tip of the nose moves rapidly from side to side. First, in response to touch to the anterior half of the body of the animal reverses its direction of locomotion (Chalfie et al., 1985). During this reversal the animals suppresses its lateral head movements (Alkema et al., 2005). Second, the reversal is followed by a deep ventral head bend. Third, the animal makes a sharp turn where it slides the head down the ventral side of the body. This sharp turn (Omega turn) results in approximately 180° change in locomotion anterior. Fourth, the animal resumes forward locomotion and exploratory head movements. Based on the strength of the stimulus the animal has to decide whether to engage in an escape response. Once it does, the animal needs coordinate distinct motor programs, generate asymmetry in its locomotion pattern to allow it to make a sharp turn before it returns to a base state. Our goal is to elucidate what neurons, neurotransmitters and receptors define neural circuits that control these motor programs, and how these motor programs are linked temporally in the execution of the worm escape response.


    C. elegans escape response neural circuitOur previous work and that of others has provided some clues about the neurons that are required for these motor programs. The C. elegans neural wiring diagram and laser ablation experiments support a model in which the touch sensory neurons inhibit the forward locomotion command neurons and activate the backward command neurons causing the animal to move backward away from the stimulus. We have shown that the trace amine, tyramine, plays a crucial role in the coordination of the backing response and the suppression of head oscillations in the escape response. A pair of tyraminergic motorneurons is activated through gap junctions with the backward locomotion command neurons, triggering the release of tyramine (Alkema et al., 2005). Tyramine coordinates two motor programs by inhibiting the forward locomotion command neurons and directly hyperpolarizing neck muscles through the activation of a novel tyramine gated chloride channel, LGC-55 (Pirri et al., 2009).


    In predator-prey experiments we have been able to show that the suppression of head movements allows the animal to escape from nematophagous fungi that entrap nematodes. Tyramine signaling mutants that fail to suppress head oscillations on response to touch are more likely to get caught in constricting hyphal rings that inflate upon contact (Maguire et al., 2011). Which neurons are required for the steep ventral head bend, and how the motor neurons in the ventral cord execute an omega turn is largely unknown. Moreover, it is not clear how a long reversal is coupled to an omega turn.

    C. elegans caught by the nematophagous fungus, Drechslerella doedycoidesWhile we have shown that a fast acting ionotropic tyramine receptors is involved in the immediate suppression of head oscillations and reversal upon touch, the slower acting metabotropic tyramine receptors appear to be involved in the execution of the omega turn. We found that the G-protein coupled tyramine receptor, SER-2, is expressed in a subset of inhibitory GABAergic neurons that innervate body wall muscles on the ventral side of the animal. Our genetic and behavioral analyses indicate that SER-2 inhibits GABA release to allow the animal to hypercontract its ventral side during the execution of an omega turn. ser-2 mutants initiate a normal escape response but fail to touch head to tail during an omega turn. This suggests that aminergic modulation of ventral cord motorneurons may allow the animal to generate asymmetry in its locomotion pattern (Donnelly et al., 2013).


    Ultimately, we hope that our studies will teach us more about the basic principles that underlie behavioral plasticity of more complex neural systems.




    Featured Articles



    Video - C. elegans caught by the nematophagous fungus, Drechslerella doedycoidesVIDEO: C. elegans caught by nematophagous fungus
    Video - Invertebrate Research at UMass Medical SchoolVIDEO: Invertebrate Research at UMass Medical School





    Personnel





    University of Massachusetts Medical School UMass Yung-Chi HuangYung-Chi Huang
    Graduate Student
    yung-chi.huang@umassmed.edu


    University of Massachusetts Medical School UMass Jeremy FlormanJeremy Florman
    Graduate Student
    jeremy.florman@umassmed.edu


     


    Lab Alumni


     

    University of Massachusetts Medical School UMass Jennifer PirriJennifer Pirri Ph.D.
    Postdoctoral Fellow - 2013


    University of Massachusetts Medical School UMass Christopher ClarkChristopher Clark
    Graduate Student - 2014


    University of Massachusetts Medical School UMass Diego RayesDiego Rayes, Ph.D.
    Postdoctoral Fellow - 2012


    University of Massachusetts Medical School UMass Jamie Donnelly, Ph.D.
    Jamie Donnelly, Ph.D.
    Graduate Student - 2011


    University of Massachusetts Medical School UMass Jasmin Abraham
    Jasmin Abraham
    Research Technician - 2010


    University of Massachusetts Medical School UMass Sean Maguire
    Sean Maguire
    Research Technician - 2010


    University of Massachusetts Medical School UMass Adam McPherson
    Adam McPherson
    Research Technician - 2008


     


     


     


     


     


     



    Collapse Rotation Projects

    Rotation Projects

    1) Molecular and neuronal characterization of C. elegans escape behavior
    Defining sensorimotor circuits requires detailed knowledge of the neural connectivity of the nervous system, and the ability to manipulate the functions of the component neurons and to define and quantify the behavioral outputs. The simplicity and completely defined synaptic connectivity of C. elegans nervous system provides unique opportunity to dissect how neural networks control behavior.

    2) Identify genes involved in the processing, expression and subunit composition of voltage-gated calcium channels
    The release of neurotransmitter from synaptic vesicles is critical for the propagation of signals that generate behavioral outputs. Voltage-gated calcium channels provide the calcium influx essential for synaptic vesicle exocytosis. We are characterizing mutants to identify new genes involved in the proper assembly, expression and trafficking of functional calcium channels.

    3) Investigate the evolutionary origins of escape behavior
    Nematophagous fungi employ a variety of strategies to capture worms. In predator-prey experiments, we have been able to show that the suppression of head movements allows the animal to escape from constricting traps. Further investigation of the neurobiology behind the escape from predation may provide insight into how this behavior evolves.

    Contact Information:
    Mark Alkema, Ph.D.
    University of Massachusetts Medical School
    Department of Neurobiology, LRB 717
    364 Plantation Street
    Worcester, MA 01605 USA
    phone: 508-856-6158 (office)
    phone: 508-856-8541 (lab)
    e-mail: mark.alkema@umassmed.edu




    Collapse Post Docs

    A postdoctoral position is available to study in this laboratory. Contact Dr. Mark Alkema for additional details.


    Contact Information:
    Mark Alkema, Ph.D.
    University of Massachusetts Medical School
    Department of Neurobiology, LRB 717
    364 Plantation Street
    Worcester, MA 01605 USA
    phone: 508-856-6158 (office)
    phone: 508-856-8541 (lab)
    e-mail: mark.alkema@umassmed.edu





    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Romanelli-Cedrez L, Carrera I, Otero L, Miranda-Vizuete A, Mariotti M, Alkema MJ, Salinas G. Selenoprotein T is required for pathogenic bacteria avoidance in Caenorhabditis elegans. Free Radic Biol Med. 2017 Mar 24. PMID: 28347729.
      View in: PubMed
    2. Cook DE, Zdraljevic S, Tanny RE, Seo B, Riccardi DD, Noble LM, Rockman MV, Alkema MJ, Braendle C, Kammenga JE, Wang J, Kruglyak L, FĂ©lix MA, Lee J, Andersen EC. The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length. Genetics. 2016 Sep; 204(1):371-83. PMID: 27449056.
      View in: PubMed
    3. Rayes D, Alkema MJ. Imprinting: When Early Life Memories Make Food Smell Bad. Curr Biol. 2016 May 9; 26(9):R362-4. PMID: 27166694.
      View in: PubMed
    4. Venkatachalam V, Ji N, Wang X, Clark C, Mitchell JK, Klein M, Tabone CJ, Florman J, Ji H, Greenwood J, Chisholm AD, Srinivasan J, Alkema M, Zhen M, Samuel AD. Pan-neuronal imaging in roaming Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2016 Feb 23; 113(8):E1082-8. PMID: 26711989.
      View in: PubMed
    5. Nagy S, Huang YC, Alkema MJ, Biron D. Caenorhabditis elegans exhibit a coupling between the defecation motor program and directed locomotion. Sci Rep. 2015 Nov 24; 5:17174. PMID: 26597056.
      View in: PubMed
    6. Fang-Yen C, Alkema MJ, Samuel AD. Illuminating neural circuits and behaviour in Caenorhabditis elegans with optogenetics. Philos Trans R Soc Lond B Biol Sci. 2015 Sep 19; 370(1677):20140212. PMID: 26240427.
      View in: PubMed
    7. Pirri JK, Rayes D, Alkema MJ. A Change in the Ion Selectivity of Ligand-Gated Ion Channels Provides a Mechanism to Switch Behavior. PLoS Biol. 2015; 13(9):e1002238. PMID: 26348462.
      View in: PubMed
    8. Gao S, Xie L, Kawano T, Po MD, Pirri JK, Guan S, Alkema MJ, Zhen M. Corrigendum: The NCA sodium leak channel is required for persistent motor circuit activity that sustains locomotion. Nat Commun. 2015; 6:7191. PMID: 25995025.
      View in: PubMed
    9. Oh KH, Abraham LS, Gegg C, Silvestri C, Huang YC, Alkema MJ, Furst J, Raicu D, Kim H. Presynaptic BK channel localization is dependent on the hierarchical organization of alpha-catulin and dystrobrevin and fine-tuned by CaV2 calcium channels. BMC Neurosci. 2015 Apr 24; 16:26. PMID: 25907097.
      View in: PubMed
    10. Gao S, Xie L, Kawano T, Po MD, Guan S, Zhen M, Pirri JK, Alkema MJ. The NCA sodium leak channel is required for persistent motor circuit activity that sustains locomotion. Nat Commun. 2015; 6:6323. PMID: 25716181.
      View in: PubMed
    11. Sun L, Shay J, McLoed M, Roodhouse K, Chung SH, Clark CM, Pirri JK, Alkema MJ, Gabel CV. Neuronal regeneration in C. elegans requires subcellular calcium release by ryanodine receptor channels and can be enhanced by optogenetic stimulation. J Neurosci. 2014 Nov 26; 34(48):15947-56. PMID: 25429136.
      View in: PubMed
    12. Bhattacharya R, Touroutine D, Barbagallo B, Climer J, Lambert CM, Clark CM, Alkema MJ, Francis MM. A conserved dopamine-cholecystokinin signaling pathway shapes context-dependent Caenorhabditis elegans behavior. PLoS Genet. 2014 Aug; 10(8):e1004584. PMID: 25167143.
      View in: PubMed
    13. Shipley FB, Clark CM, Alkema MJ, Leifer AM. Simultaneous optogenetic manipulation and calcium imaging in freely moving C. elegans. Front Neural Circuits. 2014; 8:28. PMID: 24715856.
      View in: PubMed
    14. Homberg U, Seyfarth J, Binkle U, Monastirioti M, Alkema MJ. Identification of distinct tyraminergic and octopaminergic neurons innervating the central complex of the desert locust, Schistocerca gregaria. J Comp Neurol. 2013 Jun 15; 521(9):2025-41. PMID: 23595814.
      View in: PubMed
    15. Donnelly JL, Clark CM, Leifer AM, Pirri JK, Haburcak M, Francis MM, Samuel AD, Alkema MJ. Monoaminergic orchestration of motor programs in a complex C. elegans behavior. PLoS Biol. 2013; 11(4):e1001529. PMID: 23565061.
      View in: PubMed
    16. Schumacher JA, Hsieh YW, Chen S, Pirri JK, Alkema MJ, Li WH, Chang C, Chuang CF. Intercellular calcium signaling in a gap junction-coupled cell network establishes asymmetric neuronal fates in C. elegans. Development. 2012 Nov; 139(22):4191-201. PMID: 23093425.
      View in: PubMed
    17. Pirri JK, Alkema MJ. The neuroethology of C. elegans escape. Curr Opin Neurobiol. 2012 Apr; 22(2):187-93. PMID: 22226513.
      View in: PubMed
    18. Maguire SM, Clark CM, Nunnari J, Pirri JK, Alkema MJ. The C. elegans touch response facilitates escape from predacious fungi. Curr Biol. 2011 Aug 9; 21(15):1326-30. PMID: 21802299.
      View in: PubMed
    19. Leifer AM, Fang-Yen C, Gershow M, Alkema MJ, Samuel AD. Optogenetic manipulation of neural activity in freely moving Caenorhabditis elegans. Nat Methods. 2011 Feb; 8(2):147-52. PMID: 21240279.
      View in: PubMed
    20. Koon AC, Ashley J, Barria R, DasGupta S, Brain R, Waddell S, Alkema MJ, Budnik V. Autoregulatory and paracrine control of synaptic and behavioral plasticity by octopaminergic signaling. Nat Neurosci. 2011 Feb; 14(2):190-9. PMID: 21186359.
      View in: PubMed
    21. Grove CA, De Masi F, Barrasa MI, Newburger DE, Alkema MJ, Bulyk ML, Walhout AJ. A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors. Cell. 2009 Jul 23; 138(2):314-27. PMID: 19632181.
      View in: PubMed
    22. Pirri JK, McPherson AD, Donnelly JL, Francis MM, Alkema MJ. A tyramine-gated chloride channel coordinates distinct motor programs of a Caenorhabditis elegans escape response. Neuron. 2009 May 28; 62(4):526-38. PMID: 19477154.
      View in: PubMed
    23. Alkema MJ. Oxygen sensation: into thick air. Curr Biol. 2009 May 26; 19(10):R407-9. PMID: 19467207.
      View in: PubMed
    24. Alkema MJ, Hunter-Ensor M, Ringstad N, Horvitz HR. Tyramine Functions independently of octopamine in the Caenorhabditis elegans nervous system. Neuron. 2005 Apr 21; 46(2):247-60. PMID: 15848803.
      View in: PubMed
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