The document discusses how biological systems evolve complex gene interactions and networks in response to environmental pressures, rather than being engineered like machines, using examples from neuroscience research on fruit flies, squid, and fish to illustrate how neural systems respond to stimuli in variable and adaptive ways. It also examines theories of how biological systems achieve robustness through degeneracy and maintain behavioral variability through multiple learning systems that balance exploitation and exploration.

1. Evolved not engineered: a systemsneurobiologyBjörn Brembshttp://brembs.netFreie Universität Berlin, Institut für Biologie – NeurobiologieKönigin-Luise Str. 28/30, 14195 Berlin, Germany. Email: bjoern@brembs.net, phone: +49 (0)30 838 55050, fax: +49 (0)30 838 55455

2. Systems BiologyBjörn Brembs, Freie Universität Berlin, http://brembs.net2Lee Hood‘s Automobile Paradigm

3. Gene NetworksEngineeredsystemsentailstablenetworkinteractionsBjörn Brembs, Freie Universität Berlin, http://brembs.net3 M. Costanzo et al., Science 327, 425-431 (2010)

4. ClockworkAre Biological OrganismsEngineered?

5. How Stable Are Gene Interactions?Phenotypeofthetemperature sensitive Syntaxin-1A (Syx1A) mutant:Björn Brembs, Freie Universität Berlin, http://brembs.net5% standingtime39°C25°Cvan Swinderen & Greenspan (2005)

6. Screening forsyxSuppressorsIsolating mutants extending the time standing at 39°C over Syx1ABjörn Brembs, Freie Universität Berlin, Institut für Biologie - Neurobiologie. http://brembs.net6Syx-+% standingSyx-Sup+ +time at 39°Cvan Swinderen & Greenspan (2005)

7. Quantifying Gene InteractionsIn thewildtypebackground…Björn Brembs, Freie Universität Berlin, Institut für Biologie - Neurobiologie. http://brembs.net7expectedobservedSup1Sup2+ +Sup1Sup2+ +…and in theSyx-backgroundSyx-+% standingSyx- +time at 39°Cvan Swinderen & Greenspan (2005)

8. A Gene Interaction Matrix The genematrix in WT background8The genematrix in Syx-backgroundprevious interactionpositive interactionmissing interactionnegative interactionreversed signnew interaction

10. Octopamine and Insect FlightOA isthe relevant amineFlies without OA fly wellFlies withblocked TA receptorsfly wellFlies without OA and TA do notfly wellBjörn Brembs, Freie Universität Berlin, http://brembs.net10Brembs et al. (2007)

11. Robustness by Degeneracy30% ofmurineandupto 50% ofyeastgene knock-outsarewithoutphenotype.redundantdegenerate

12. Neural NetworksDo neuralnetworksbehavelikegenenetworks?

13. General Brain Function

14. Input-OutputI reacttoexternalstimuli, therefore I am?

15. SquidEscapeBehavior

16. Loligogiantaxonswww.mbl.eduElectrode in giantaxon

17. Fish C-start Response

18. TentacleSnakespredictfishresponse

19. Fly Escape Response

20. PaintedRedstartspredictflyresponse

21. PredictabilityBeing predictable is not evolutionary stable

22. DegreesofPredictabilityEvokedFixed stimulus/responseatfixedlatencye.g. reflexMixedComplexstimuli/variable actionsBehavioralsetEndogenousevokedresponsesClosedloopPredictabilitySpontaneousActivityindependentofsensoryinpute.g. explorationStimulus-responsecoupling

23. Degreesof EfficiencyEvokedFixed stimulus/responseatfixedlatencye.g. reflex/ EfficiencyMixedComplexstimuli/variable actionsBehavioralsetEndogenousevokedresponsesClosedloopPredictabilitySpontaneousActivityindependentofsensoryinpute.g. explorationStimulus-responsecoupling

24. Psychological ChallengeResponseAction13.07.2010Björn Brembs, Freie Universität Berlin24

25. Ecological ChallengeExploitationExploration13.07.2010Björn Brembs, Freie Universität Berlin25

26. Evolutionary ChallengeOptimalityFlexibility13.07.2010Björn Brembs, Freie Universität Berlin26

27. Reafferent Feedback13.07.2010Björn Brembs, Freie Universität Berlin27

28. General brainfunctionAction – Outcome Evaluation

29. Drosophila Turning13.07.2010Björn Brembs, Freie Universität Berlin29Behavioralvariability in a constantstimulussituation:Actions, not responses

30. Drosophila Turning13.07.2010Björn Brembs, Freie Universität Berlin30Behavioralvariability in a constantstimulussituation:Actions, not responses

31. Choice or Noise?Decisionsor just noise in complexstimulus-responsesystems?

32. Choice or Noise?13.07.2010Björn Brembs, Freie Universität Berlin32Maye et al. (2007) PLoSOneGeometric Random Inner Products: GRIP

33. Choice or Noise?13.07.2010Björn Brembs, Freie Universität Berlin33correlationnonlinearityMaye et al. (2007) PLoSOneNonlinear (choice)Linear/stochastic (noise)

34. Choice or Noise?Maye et al. (2007) PLoSOne13.07.2010Björn Brembs, Freie Universität Berlin34

35. Choice or Noise?Nonlineardecision-makingsystem underlies spontaneity in flies

36. spontaneityWhatarethefunctionsofspontaneousbehavioralvariability?

37. Pursuit-evasioncontests& competition (courtship, predator-prey, territoriality, chess, sports etc.)

38. Exploration (find thathiddenresourceyouwouldotherwisenever find.)

39. Detectionofre-afferent signals in thesensorystream (trytotickleyourself!) -> operant behavior/learning

40. Reafferent Feedback13.07.2010Björn Brembs, Freie Universität Berlin40

41. BehavioralVariability13.07.2010Björn Brembs, Freie Universität Berlin41

42. BehavioralOutcomesoperantselfclassicalworld13.07.2010Björn Brembs, Freie Universität Berlin42

43. Operant conditioning13.07.2010Björn Brembs, Freie Universität Berlin43

44. Action - Outcome EvaluationBrembs & Plendl (2008) CurrentBiologyrut-AC dependentSynapticPlasticityProtein Kinase Cworldself13.07.2010Björn Brembs, Freie Universität Berlin44

45. ConservationPKC but not rut-AC involved in Aplysiaself-learningAplysiacalifornicaF. Lorenzetti, D. Baxter, J. Byrne (2008): Neuron 59, 815-828

46. Action – Outcome EvaluationFoxP2Language learning

47. 13.07.2010Björn Brembs, Freie Universität Berlin47FoxPisNecessaryforSelf-Learning

48. PKC/FoxPrequiredforSelf-LearningFoxPPKCNot requiredNot requiredRequiredRequired13.07.2010Björn Brembs, Freie Universität Berlin48

49. Two Components13.07.2010Björn Brembs, Freie Universität Berlin49

50. Multiple MemoriesWhyhavemorethanonelearningsystem?

51. Evolutionary DilemmaExploitationExploration13.07.2010Björn Brembs, Freie Universität Berlin51

52. Multiple Learning Systems13.07.2010Björn Brembs, Freie Universität Berlin52

53. From Exploration toExploitationBrembs (2009)

54. Reciprocal, Hierarchical InteractionsFacilitation:Learning-by-doingInhibition:Regulateshabitformation/generalization :ExploitationExploration13.07.2010Björn Brembs, Freie Universität Berlin54

55. General FLY brainfunctionAction – Outcome Evaluation

56. Gáspár JékelyAncestral: Stimulus-Response?Max Planck Institute for Developmental BiologyPhototaxisPolychaete: Platynereisdumerilii

57. Ancestral: Stimulus-Response?PhototaxisStimulus – ResponseSensoryneurons – CiliatedcellsPolychaete: Platynereisdumerilii

58. Phototaxis: Stimulus-Response?Behavior (action)Stimuli inhibitormodulateactionResult: PhototaxisG Jékelyet al.Nature456, 395-399 (2008) doi:10.1038/nature07590

59. Ancestral StateOngoingactivitymodulatedbyexternalstimuli

60. The Default Mode NetworkThe limitingfactor in theevolutionofbrainsize was energysupply60

61. The Default Mode NetworkThe limitingfactor in theevolutionofbrainsize was energysupply61The additional energyburdenassociatedwith […] theenvironmentmaybeaslittleas .5-1.0% ofthe total energybudget.Marcus Raichle (2006): Science314, p1249

62. Human StateOngoingactivitymodulatedbyexternalstimuli

63. The Engineering Approach toBiologyCan beseenasanalogoustoNewtonianMechanics in physics

64. Standing on the shoulder of giants…Teachers & CollaboratorsFlight performance:Carsten DuchFrauke ChristiansenJochen PflügerFly learning:Wolfgang PlendlJan WienerNatalie Hempel de IbarraTroy ZarsReinhard WolfMartin HeisenbergTeachers:Martin Heisenberg

65. Jack Byrne

66. Randolf Menzel

67. Bernard Balleine

68. Ralph Greenspan

69. George Sugihara

70. Bill Kristan

71. David Glanzman

72. Eric Kandel

73. Jochen Pflüger

74. Ed Kravitz

75. Richard Morris

76. Hans-Peter Lipp

77. David Wolfer

78. Barry Keverne

79. KlaudeWeiss

80. Cathy RankinAplysiaconditioning:Fred LorenzettiRiccardo MozzachiodiVuHyunElizabeth WilkinsonFredy ReyesJack ByrneAplysiaimaging:Quentin GaudryWilliam KristanFly spontaneity:Alexander MayeZacHsiehGeorge SugiharaFly aggression:Britta WittekAndrea BaierEd KravitzFly attention:Bruno van Swinderen