1. I Fórum em Neurobiologia do Estresse Neural circuitry of fear and pain and their possible relationships with anxiety and panic Jesús Landeira-Fernandez PUC-Rio & UNESA

2. Two functions of the nervous system Functions of the Nervous System Regulation of the internal environment through homeostasis Visceral Nervous System Interact with external environment through behavior Somatic Nervous System

3. Organization of the Nervous System BEHAVIOR Defense Feeding Reproduction STIMULUS

4. Organization of the Defense System Dangerous Stimulus Nervous System Defensive Response

5. Organization of the Defense System Dangerous Stimulus Cause some threat to the life to the individual Learned Innate

6. Organization of the Defense System

7. Defensive Response Escape Freezing Fight Danger Stimulus Behavioral Inhibition Behavioral Activation ACTIVITY BURST

8. Organization of the Defense System Theoretical Constructs

9. Organization of the Fear Motivational System Somatic Nervous System Visceral Nervous System

10. Somatic Nervous System Visceral Nervous System Organization of the Pain Motivational System

11. Interaction between the Pain and the Fear Motivational System Pain Motivational System Fear Motivational System Neutral Stimuli Contextual Fear Conditioning Pain motivational system activates fear motivational system through classical conditioning

12. Interaction between the Fear and Pain Motivational System Pain Motivational System Fear Motivational System Analgesia Fear motivational system inhibits pain motivational system through analgesia

13. Interaction between the Fear and the Pain Motivational System Analgesia Classical Conditioning

14. Contextual Fear Conditioning Paradigm 0:003:003:203:404:00 Dia 1 Treinamento 0:003:00 First Day: Training Session Second Day: Testing Session A few rapid and not very intense footshocks A few minutes of habituation

15. Typical Contextual fear Conditioning Result Freezing depends on the intensity of the shock

16. Activation of the Pain Motivational System in the Vacuum: The Immediate Shock Deficit

17. Activation of the fear Motivational System in the Vacuum: The Immediate Shock Deficit

18. Delayed but not Immediate Shock Induces Analgesia

19. Immediate Shock does not Induce Analgesia

20. Opioid Analgesia

22. Non-Opioid Analgesia

23. Fear and Pain Motivational Systems Fear Pain Dangerous Stimuli Distal Innate Proximal Motivational Systems Defense Responses Learned Innate Freezing Activity Burst Analgesia Classical Conditioning

24. Fear Pain Motivational Systems Defense Responses Freezing Activity Burst Analgesia Classical Conditioning Motivational Systems Dysfunctions Anxiety Panic Attack Fear and Pain x Anxiety and Panic

25. Deakin-Graeff Model Dysfunctions Anxiety Panic Attack Inhibits Activates

26. Freud and the anxiety disorders _______________

27. Function x Dysfunction Functions Fear Pain Dysfunctions Anxiety Panic Attack Inhibits Activates Analgesia Classical Conditioning Deakin-Graeff ModelFanselow Model

28. Animal Models to Investigate Anxiety and Panic Attack dPAG Electrical Stimulation (Model of Panic Attack) Contextual fear conditioning (Model of Generalized Anxiety Disorder)

29. Animal Model of Panic Attack dPAG electrical stimulation

30. Increasing the intensity of the dPAG electrical stimulation there is first a freezing response followed by vigorous running and jump reactions. dPAG electrical stimulation

31. The Periaqueductal Gray Matter Cerebral Aqueduct Periaqueductal Gray (PAG) Stimulation Site in the Dorsal Portion of the PAG Electrode Tract

32. Does Anxiety (contextual fear conditioning) Inhibits Panic Attacks (dPAG electrical stimulation)? dPAG Electrical Stimulation (Model of Panic Attack) Contextual fear conditioning (Model of Generalized Anxiety Disorder)

33. Does Anxiety (contextual fear conditioning) Inhibits Panic Attacks (dPAG electrical stimulation)?

34. Does Anxiety (contextual fear conditioning) Inhibits Panic Attacks (dPAG stimulation- NMDA 15.0µg/µl)?

35. Does Anxiety (PTZ - 15.0 mg/kg i.p ) Inhibits Panic Attacks (dPAG stimulation- NMDA 15.0µg/µl)?

36. Two Types of Freezing: the context shift test Contextual fear conditioning

37. Two Types of Freezing: the context shift test

38. dPAG electrical stimulation Two Types of Freezing: the context shift test

39. dPAG electrical stimulation Two Types of Freezing: the context shift test

40. dPAG electrical stimulation Contextual fear conditioning Two Types of Freezing: the context shift test: sumary

41. Two Types of Freezing Amygdala Freezing Induced by Contextual Fear Conditining vPAGFreezing Freezing Induced by dPAG Electrical Stimulation ?dPAG?

42. Comparison between dlPAG and vlPAG electrical stimulation

43. Freezing after dPAG electrical stimulation

44. Effect of vPAG Lesions on Conditioned and Unconditioned Freezing

45. Histology of vPAG Lesion and dPAG Electrical Stimulation vPAG LesionsdPAG Electrical Stimulation

46. Effect of vPAG Lesions on Conditioned and Unconditioned Freezing Contextual fear conditioning dPAG electrical stimulation

47. Effect of Amydgala Lesions on Conditioned and Unconditioned Freezing

48. Amygdala Lesions Histology of Amygdala Lesion and dPAG Electrical Stimulation dPAG Stimulation

49. Effect of Amygdala Lesions on Conditioned and Unconditioned Freezing Contextual fear conditioning dPAG electrical stimulation

50. So far, these are the results … vPAG

51. Fear Motivational System Responsibe for General Anxiety Disorder Pain Motivational System Responsibe for Panic Attack AmygdalavPAGFreezing?dPAG? …and this is the circuitry

52. Fear and pain X anxiety and panic

56. Fear and Pain

57. Future perspectives Where are we going ? We go to Rio !

58. The Carioca High - and Low - Conditioned Freezing Rats Future directions: heading to Rio

59. Carioca High-Freezing (CHF) and Carioca Low-Freezing (CLF)

60. The CHF rats in the Elevated Plus Maze

61. The CHF rats in the Social Interaction Test

62. The CHF rats in the Forced Swimming Test

63. The CHF rats in the Object Recognition Test

64. The Dorsal Hippocampus Cells in CHF Rats

65. The effect of amygdaloid lesions in the CHF and CLF rats

66. Collaborators Frederico G. Graeff – USP-RP Marcus Brandão – USP-RP A.Pedro de Mello Cruz - UnB Regina Nogueira -UNESA Valeska Mageriek - UNIFESP Cecília De Luca – USP-RP Luciana Oliveira – USP-RP Daniel M Vianna – USP-RP Vitor C. Gomes – PUC-Rio Bruno Galvão – PUC-Rio

67. Contact Núcleo de Neuropsicologia Clínica e Experimental www.nnce.org landeira@puc-rio.br