1 Prof. Anagnostaras, Lecture 7: Fear

Historical views that “thought” and “emotion” were processed separately in the brain

So far, fear is the Prof. Anagnostaras, Lecture 7: best understood Fear

Fear Issues in Fear

What is fear? What is innate or unlearned fear? - Inherited (instinctive) fear Dictionary: A feeling of agitation and anxiety e.g., loud noise, painful stimuli caused by the presence or imminence of danger - Stimuli that produce innate fear are called unconditional stimuli (USs) My definition: an adaptive emotional state which motivates and organizes defensive What is conditioned fear? responses necessary for survival. Acquired fear enhances the adaptive value of innate fear. Fear is inferred by the presence of defensive • Most fear is acquired. responses. It is indexed by the level of those • Conditional stimuli (CSs) acquire fear by responses. being paired with USs

Species that exhibit learned fear have a Two kinds of learning (Fear & Avoidance) distinct adaptive advantage CONDITIONED FEAR Classical (Pavlovian) fear conditioning CS is paired with US (red stove-heat) Fear generalizes to CS Environment controls subject

AVOIDANCE Instrumental (Operant) conditioning Response is paired with US (touch-pain) Avoid response because of expected US Subject controls environment • All animals rapidly acquire learned fear Always occur together, but dissociable

1 Fear memories are robust and long-lasting Fear memories are robust and long-lasting

Pavlovian: Sight of plane elicits fear. Conditioned fear is very rapid (1 trial) and Instrumental: Avoid flying. very long-lasting (forever)

Pavlovian fear conditioning is reducible to Pavlovian fear conditioning is reducible to discrete mnemonic processes discrete mnemonic processes Tone – Shock Pairing Tone – Shock Pairing Procedure: Procedure:

Conditional Stimulus, CS Unconditional Stimulus, US Unconditional Response, UR (Fear) Memory Association Process:

Tone Shock Representation Representation

Memory Association Memory Association Process: Process:

Tone Shock Tone Shock Representation Representation Representation Representation

Conditioned Response, CR: Conditioned Response, CR: Fear Responses Freezing Potentiated Startle Blood Pressure Tone Shock Tone Shock Fear Flight Tone Tone ... Repr. Repr. Repr. Repr. State

2 Pavlovian fear conditioning protocol Pavlovian fear conditioning protocol

TRAINING TRAINING CONTEXT TEST

Freezing response measured

CR = Freezing

Training Context Testing Context

• Bright White Lighting • Bright White Lighting • Grumbling Noise • Grumbling Noise Shock US • Ammonia Odor • Ammonia Odor • Flat Shock Grids • Flat Shock Grids

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

Unconditioned Fear Circuit: Central Fear- Nucleus of the Amygdala and its Outputs potentiated startle

McNish, Gewirtz, & Davis, Beh Neurosci, 2000 AMYGDALA = "ALMOND"

3 Within-subjects design

Lee Walker & Davis (1997) REMOTE RECENT TRAINING TRAINING

480 d later Sham or Basolateral Amygdala Lesion

RECENT REMOTE REMOTE RECENT TONE TONE CONTEXT CONTEXT

Amygdala has temporally-stable role in fear memory. Forever?

The basolateral amygdala is involved in Dorsal hippocampus lesions produce a highly lifelong retention of fear memories selective deficit in recent contextual fear memory Remote and Recent training separated by sixteen months Content could be: • Context-shock association • Just memory of the context

100 Context Summary 100 Tone Summary

75 75

Sham 50 50 DH

Doesn't matter how old the fear memory is 25 25 or what kind of fear memory. Amygdala 0 0 lesions DO NOT affect many other forms of Remote Recent Remote Recent learning, however (e.g. maze learning or (first six min) (six min) word lists).

Unconditioned Fear Circuit: Central Circuit for fear-potentiated startle Nucleus of the Amygdala and its Outputs identified by M. Davis & colleagues

4 Basic model that has emerged for Unconditioned Fear Circuit: Central Pavlovian fear conditioning Nucleus of the Amygdala and its Outputs

Central nucleus outputs coordinate all of the Innate fear defensive responses (learned and innate). Learned fear thalamus

Central nucleus = output of fear/unlearned fear Basolateral/lateral nucleus = learned fear

Circuit for conditioned freezing identified Basic model that has emerged for by Fanselow, LeDoux & colleagues Pavlovian fear conditioning

context Footshock

Fear Tone

Most research focused on what the synaptic Periaqueductal grey changes are at the point of convergence in the (freezing) lateral/ basolateral amygdala

Storage and "Stamping in" roles of the Modulatory model proposed by McGaugh et al. 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).

amygdala can store memory or stamp in memory elsewhere

5 AVOIDANCE fear conditioning Pavlovian fear, Phobias, and Anxiety

Passive avoidance (Jim McGaugh) 1. Conditioning model of phobias - shock on one side of the box - avoids that side 2. Problem is not everyone develops phobia, and in anxiety disorders there is - Neurobiology not clearly understood, only the problem of overgeneralized threat partially overlaps with conditioned fear 3. Likely reflects genetic predisposition -- - Probably mediated by "cognitive" more likely to interpet threat -- but most representations in the cortex studies done in normal lab rats

4. Combine with traumatic event to produce characteristic disorder

Elevated plus maze - unlearned fear test 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

Open Field Crhr2 knockout

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

6 GABA-A receptor subunits GABA-A γ2 heterozygous deletion produces Can be made from 18 different genes Hyper-anxiety (innate fear) Crestani et al. Nat Neurosci

Hypersensitivity to diazepam Hypersensitivity to learned fear

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?