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 systemsneurobiology Björn Brembs http://brembs.net Freie Universität Berlin, Institut für Biologie – Neurobiologie Königin-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 Biology Björn Brembs, Freie Universität Berlin, http://brembs.net 2 Lee Hood‘s Automobile Paradigm

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

4. Clockwork Are Biological OrganismsEngineered?

5. How Stable Are Gene Interactions? Phenotypeofthetemperature sensitive Syntaxin-1A (Syx1A) mutant: Björn Brembs, Freie Universität Berlin, http://brembs.net 5 % standing time 39°C 25°C van Swinderen & Greenspan (2005)

6. Screening forsyxSuppressors Isolating mutants extending the time standing at 39°C over Syx1A Björn Brembs, Freie Universität Berlin, Institut für Biologie - Neurobiologie. http://brembs.net 6 Syx- + % standing Syx-Sup + + time at 39°C van Swinderen & Greenspan (2005)

7. Quantifying Gene Interactions In thewildtypebackground… Björn Brembs, Freie Universität Berlin, Institut für Biologie - Neurobiologie. http://brembs.net 7 expected observed Sup1Sup2 + + Sup1Sup2 + + …and in theSyx-background Syx- + % standing Syx- + time at 39°C van Swinderen & Greenspan (2005)

8. A Gene Interaction Matrix The genematrix in WT background 8 The genematrix in Syx-background previous interaction positive interaction missing interaction negative interaction reversed sign new interaction

10. Octopamine and Insect Flight OA isthe relevant amine Flies without OA fly well Flies withblocked TA receptorsfly well Flies without OA and TA do notfly well Björn Brembs, Freie Universität Berlin, http://brembs.net 10 Brembs et al. (2007)

11. Robustness by Degeneracy 30% ofmurineandupto 50% ofyeastgene knock-outsarewithoutphenotype. redundant degenerate

12. Neural Networks Do neuralnetworksbehavelikegenenetworks?

13. General Brain Function

14. Input-Output I reacttoexternalstimuli, therefore I am?

15. SquidEscapeBehavior

16. Loligogiantaxons www.mbl.edu Electrode in giantaxon

17. Fish C-start Response

18. TentacleSnakespredictfishresponse

19. Fly Escape Response

20. PaintedRedstartspredictflyresponse

21. Predictability Being predictable is not evolutionary stable

22. DegreesofPredictability Evoked Fixed stimulus/responseatfixedlatency e.g. reflex Mixed Complexstimuli/variable actions Behavioralset Endogenousevokedresponses Closedloop Predictability Spontaneous Activityindependentofsensoryinput e.g. exploration Stimulus-responsecoupling

23. Degreesof Efficiency Evoked Fixed stimulus/responseatfixedlatency e.g. reflex / Efficiency Mixed Complexstimuli/variable actions Behavioralset Endogenousevokedresponses Closedloop Predictability Spontaneous Activityindependentofsensoryinput e.g. exploration Stimulus-responsecoupling

24. Psychological Challenge Response Action 13.07.2010 Björn Brembs, Freie Universität Berlin 24

25. Ecological Challenge Exploitation Exploration 13.07.2010 Björn Brembs, Freie Universität Berlin 25

26. Evolutionary Challenge Optimality Flexibility 13.07.2010 Björn Brembs, Freie Universität Berlin 26

27. Reafferent Feedback 13.07.2010 Björn Brembs, Freie Universität Berlin 27

28. General brainfunction Action – Outcome Evaluation

29. Drosophila Turning 13.07.2010 Björn Brembs, Freie Universität Berlin 29 Behavioralvariability in a constantstimulussituation: Actions, not responses

30. Drosophila Turning 13.07.2010 Björn Brembs, Freie Universität Berlin 30 Behavioralvariability in a constantstimulussituation: Actions, not responses

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

32. Choice or Noise? 13.07.2010 Björn Brembs, Freie Universität Berlin 32 Maye et al. (2007) PLoSOne Geometric Random Inner Products: GRIP

33. Choice or Noise? 13.07.2010 Björn Brembs, Freie Universität Berlin 33 correlation nonlinearity Maye et al. (2007) PLoSOne Nonlinear (choice) Linear/stochastic (noise)

34. Choice or Noise? Maye et al. (2007) PLoSOne 13.07.2010 Björn Brembs, Freie Universität Berlin 34

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

36. spontaneity Whatarethefunctionsofspontaneousbehavioralvariability?

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 Feedback 13.07.2010 Björn Brembs, Freie Universität Berlin 40

41. BehavioralVariability 13.07.2010 Björn Brembs, Freie Universität Berlin 41

42. BehavioralOutcomes operant self classical world 13.07.2010 Björn Brembs, Freie Universität Berlin 42

43. Operant conditioning 13.07.2010 Björn Brembs, Freie Universität Berlin 43

44. Action - Outcome Evaluation Brembs & Plendl (2008) CurrentBiology rut-AC dependentSynapticPlasticity Protein Kinase C world self 13.07.2010 Björn Brembs, Freie Universität Berlin 44

45. Conservation PKC but not rut-AC involved in Aplysiaself-learning Aplysiacalifornica F. Lorenzetti, D. Baxter, J. Byrne (2008): Neuron 59, 815-828

46. Action – Outcome Evaluation FoxP2 Language learning

47. 13.07.2010 Björn Brembs, Freie Universität Berlin 47 FoxPisNecessaryforSelf-Learning

48. PKC/FoxPrequiredforSelf-Learning FoxP PKC Not required Not required Required Required 13.07.2010 Björn Brembs, Freie Universität Berlin 48

49. Two Components 13.07.2010 Björn Brembs, Freie Universität Berlin 49

50. Multiple Memories Whyhavemorethanonelearningsystem?

51. Evolutionary Dilemma Exploitation Exploration 13.07.2010 Björn Brembs, Freie Universität Berlin 51

52. Multiple Learning Systems 13.07.2010 Björn Brembs, Freie Universität Berlin 52

53. From Exploration toExploitation Brembs (2009)

54. Reciprocal, Hierarchical Interactions Facilitation: Learning-by-doing Inhibition: Regulateshabitformation/generalization : Exploitation Exploration 13.07.2010 Björn Brembs, Freie Universität Berlin 54

55. General FLY brainfunction Action – Outcome Evaluation

56. Gáspár Jékely Ancestral: Stimulus-Response? Max Planck Institute for Developmental Biology Phototaxis Polychaete: Platynereisdumerilii

57. Ancestral: Stimulus-Response? Phototaxis Stimulus – Response Sensoryneurons – Ciliatedcells Polychaete: Platynereisdumerilii

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

59. Ancestral State Ongoingactivitymodulatedbyexternalstimuli

60. The Default Mode Network The limitingfactor in theevolutionofbrainsize was energysupply 60

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

62. Human State Ongoingactivitymodulatedbyexternalstimuli

63. The Engineering Approach toBiology Can beseenasanalogoustoNewtonianMechanics in physics

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 Lorenzetti Riccardo Mozzachiodi VuHyun Elizabeth Wilkinson Fredy Reyes Jack Byrne Aplysiaimaging: Quentin Gaudry William Kristan Fly spontaneity: Alexander Maye ZacHsieh George Sugihara Fly aggression: Britta Wittek Andrea Baier Ed Kravitz Fly attention: Bruno van Swinderen