Prof. Anagnostaras, Lecture 7: Fear

1. Prof. Anagnostaras, Lecture 7: Fear

2. Historical views that “thought” and “emotion” were processed separately in the brain So far, fear is the best understood

3. Fear What is fear? • Dictionary: A feeling of agitation and anxiety caused by the presence or imminence of danger My definition: an adaptive emotional state which motivates and organizes defensive responses necessary for survival. Fear is inferred by the presence of defensive responses. It is indexed by the level of those responses.

4. Issues in Fear What is innate or unlearned fear? - Inherited (instinctive) fear e.g., loud noise, painful stimuli - Stimuli that produce innate fear are called unconditional stimuli (USs) What is conditioned fear? Acquired fear enhances the adaptive value of innate fear. • Most fear is acquired. • Conditional stimuli (CSs) acquire fear by being paired with USs

5. Species that exhibit learned fear have a distinct adaptive advantage • All animals rapidly acquire learned fear

6. Two kinds of learning (Fear & Avoidance) CONDITIONED FEARClassical (Pavlovian) fear conditioning CS is paired with US (red stove-heat) Fear generalizes to CS Environment controls subject AVOIDANCEInstrumental (Operant) conditioning Response is paired with US (touch-pain) Avoid response because of expected US Subject controls environment Always occur together, but dissociable

7. Fear memories are robust and long-lasting Pavlovian: Sight of plane elicits fear. Instrumental: Avoid flying.

8. Fear memories are robust and long-lasting Conditioned fear is very rapid (1 trial) and very long-lasting (forever)

9. Pavlovian fear conditioning is reducible to discrete mnemonic processes Tone – Shock Pairing Procedure: Conditional Stimulus, CS Unconditional Stimulus, US Unconditional Response, UR (Fear)

10. Pavlovian fear conditioning is reducible to discrete mnemonic processes Tone – Shock Pairing Procedure: Memory Process: Association Tone Representation Shock Representation

11. Pavlovian fear conditioning is reducible to discrete mnemonic processes Tone – Shock Pairing Procedure: Memory Process: Association Tone Representation Shock Representation Conditioned Response, CR: Tone Repr. Shock Repr. Tone

12. Pavlovian fear conditioning is reducible to discrete mnemonic processes Tone – Shock Pairing Procedure: Memory Process: Association Tone Representation Shock Representation Conditioned Response, CR: Fear Responses Freezing Potentiated Startle Blood Pressure Flight ... Fear State Tone Repr. Shock Repr. Tone

13. Pavlovian fear conditioning protocol TRAINING Training Context • Bright White Lighting • Grumbling Noise • Ammonia Odor • Flat Shock Grids

14. Pavlovian fear conditioning protocol TRAINING CONTEXT TEST Freezing response measured CR = Freezing Testing Context • Bright White Lighting • Grumbling Noise • Ammonia Odor • Flat Shock Grids

15. Pavlovian fear conditioning protocol TRAINING CONTEXT TEST TONE TEST CR = Freezing Alternate Context • Baseline Period • Dark Red Lighting • Triangular Insert • White Noise • Vinegar Odor • Staggered Shock Grids

17. Fear-potentiated startle McNish, Gewirtz, & Davis, Beh Neurosci, 2000

18. Unconditioned Fear Circuit: Central Nucleus of the Amygdala and its Outputs AMYGDALA = "ALMOND"

19. Lee Walker & Davis (1997) Amygdala has temporally-stable role in fear memory. Forever?

20. Within-subjects design REMOTE TRAINING RECENT TRAINING 480 d later Sham or Basolateral Amygdala Lesion REMOTE CONTEXT RECENT TONE REMOTE TONE RECENT CONTEXT

21. The basolateral amygdala is involved in lifelong retention of fear memories Remote and Recent training separated by sixteen months Doesn't matter how old the fear memory is or what kind of fear memory. Amygdala lesions DO NOT affect many other forms of learning, however (e.g. maze learning or word lists).

22. Dorsal hippocampus lesions produce a highly selective deficit in recent contextual fear memory Content could be: • Context-shock association • Just memory of the context

23. Unconditioned Fear Circuit: Central Nucleus of the Amygdala and its Outputs

24. Circuit for fear-potentiated startle identified by M. Davis & colleagues

25. Basic model that has emerged for Pavlovian fear conditioning Innate fear Learned fear thalamus Central nucleus = output of fear/unlearned fear Basolateral/lateral nucleus = learned fear

26. Unconditioned Fear Circuit: Central Nucleus of the Amygdala and its Outputs Central nucleus outputs coordinate all of the defensive responses (learned and innate).

27. Circuit for conditioned freezing identified by Fanselow, LeDoux & colleagues context Periaqueductal grey (freezing)

28. Basic model that has emerged for Pavlovian fear conditioning Footshock Fear Tone Most research focused on what the synaptic changes are at the point of convergence in the lateral/ basolateral amygdala

29. Storage and "Stamping in" roles of the Amygdala CS-US associations (Pavlovian fear) in the basolateral amygdala. Fear can also "stamp" in emotional memories elsewhere (video next class). Amygdala sends upstream connections to signal danger and reinforce "cognitive" memories elsewhere (cortex).

30. Modulatory model proposed by McGaugh et al. amygdala can store memory or stamp in memory elsewhere

31. AVOIDANCE fear conditioning Passive avoidance (Jim McGaugh) - shock on one side of the box - avoids that side - Neurobiology not clearly understood, only partially overlaps with conditioned fear • - Probably mediated by "cognitive" representations in the cortex

32. Pavlovian fear, Phobias, and Anxiety Conditioning model of phobias 2. Problem is not everyone develops phobia, and in anxiety disorders there is the problem of overgeneralized threat 3. Likely reflects genetic predisposition -- more likely to interpet threat -- but most studies done in normal lab rats 4. Combine with traumatic event to produce characteristic disorder

33. Genetically modified mice (xx) • several hyper-anxious mutant mice Most candidates are changes in GABA or serotonin receptors, or in stress hormone receptors (CRH) Drugs used to treat abnormal fear: • Anxiolytics (benzodiazepines) enhance GABA-A • Serotonin-specific reuptake inhibitor (SSRIs) (Paxil) enhance serotonin

34. Elevated plus maze - unlearned fear test

35. Open Field

36. Crhr2knockouttotal deletion of gene for corticotropin releasing factor receptor type 2 Spiess et al. Nat Gen

37. GABA-A receptor subunits Can be made from 18 different genes

38. GABA-A g2 heterozygous deletion produces Hyper-anxiety (innate fear) Crestani et al. Nat Neurosci

39. Hypersensitivity to diazepam

40. Hypersensitivity to learned fear

41. Altered sensitivity to fear conditioning • Complex genetically-produced syndromes more reminiscent of anxiety disorders • Small alternations in various anxiety-related genes may lead to anxiety disorders, I.e., increased threat appraisal • Traumatic events bring out various disorders Especially irrational phobias • -Some events sufficient to produce phobia or anxiety disorder in anyone?