fear

Question 1

• components of PTSD

Answer 1

re-experiencing symptoms - PTSD related
avoidance symptoms
hyper-arousal symptoms

Question 2

PTSD and fear memories

Answer 2

re-experiencing: fearful memories went under memory consolidation

Question 3

brain areas in PTSD

Answer 3

mainly amygdala
PFC
hippocampus
fear response

slide 6

Question 4

amygdala

Answer 4

receives input from sensory systems - preprocess

Question 5

behavioral paradigm in rats

Answer 5

tone + footshock

auditory signal combined with somatosensory

Question 6

panic attack

Answer 6

= ‘fear attack’ in fear-related disorders

panic disorder: associate with the context, not the cues
simple phobia is the cue

Question 7

the fear response is a hardwired process involving the amygdala

Answer 7

slide 14

e. x. Retic Pontis Caudalis: increased startle response
e. x. central gray area: freezing, social interaction

Question 8

modeling fear

Answer 8

slide 15/26

Generalization (+): recruitment of non-associated cues
Sensitization (+): increased fear with repeated exposure
Discrimination (-): fear is limited to specific trauma cue
Extinction (-): diminished response to cues over time

pre-existing sensitivity -> learning of fear -> consolidation of fear -> expression of fear

Question 9

genetic studies

Answer 9

HPA axis/ sympathetic axis

Question 10

hypersensitivity of the stress response

Answer 10

enhanced suppression of cortisol following dexamethasone in PTSD patients

Question 11

FKBP5

Answer 11

FKBP5 is a chaperone binding glucocorticoid receptors (GR) - prevent transportation in nucleus, more cortisol releases more FKBP5

Question 12

child trauma + FKBP5

Answer 12

set up amygdala sensitivity

FKBP5 highly correlated to child trauma

Question 13

hippocampal volume reduction in PTSD

Answer 13

hippocampal activation and structural differences in FKBP5 risk allele carriers

polymorphism

Question 14

role of cortisol regulation during development ‘emotional critical period’

Answer 14

amygdala activation is cortisol-dependent;
odor-shock conditioning;
early corticosterone exposure switches amygdala function to aversive;

Question 15

early life stress - HPA axis gene interaction

Answer 15

slide 25

a dynamic amygdala-dependent emotional circuit

Question 16

how we measure fear in animals

Answer 16

fear potentiated startle

freezing

Question 17

NMDA receptor and amygdala-dependent learning

Answer 17

NMDA antagonist (AP5) into amygdala blocks development of extinction ( startle amplitude didn’t decrease after 60 lights without shocks for AP5);

an NMDA agonist (DCS) enhances extinction in rats

Question 18

cellular model of fear learning

Answer 18

slide 29

consolidation
extinction

Question 19

increase extinction in human

Answer 19

D-Cycloserine and virtual reality exposure;
NMDA receptor enhancer improves psychotherapy (extinction) across anxiety disorders;
virtual iraq (slide 34)

Question 20

Treating PTSD/fear disorder: learning not to be afraid

Answer 20

• Molecular mediators of synaptic plasticity (including NMDA-dependent mechanisms) are required for the consolidation and extinction of fear memories
• Enhancement of NMDA function with D-cycloserine enhances extinction in rodents and humans in a variety of paradigms. Other agents affecting CB1 (reuptake inhibitors), CCK (antagonists), or BDNF (future agonists), given in conjunction with exposure therapy may also enhance the reduction of fear which occurs with extinction learning.

Question 21

role of BDNF in fear learning and inhibition

Answer 21

slide 37

genetic inhibition of BDNF receptor inhibits extinction retention

Question 22

TrkB, amygdala and fear

Answer 22

• BDNF mRNA expression and TrkB activation are correlated in the Basolateral amygdala with consolidation of both fear learning and extinction of fear
• Blockade of TrkB receptor function with a lentiviral-mediated dominant negative TrkB prevents consolidation of both conditioned fear and extinction of conditioned fear.
• Thus, TrkB activation, within BLA is required for fear-related synaptic plasticity and learning.

Question 23

the PFC-amygdala-hippocampal circuit

Answer 23

slide 41/53/54

dorsal anterior cingulate cortex increases, SCR increases;
prelimbic neocortex-specific BDNF deletion prevents fear consolidation;
infralimbic BDNF infusion enhances fear extinction;
hippocampal-specific BDNF deletion does not affect fear consolidation;
deletion of hippocampal BDNF impairs extinction of fear;
DCS appears to rescue BDNF val/met extinction deficit

Question 24

summary: BDNF and fear

Answer 24

•
BDNF activation of TrkB is required in Amygdala for synaptic plasticity encoding the consolidation of fear and extinction (Rattiner et al., 2004; Chhatwal et al., 2006)
•
BDNF mRNA expression in Prelimbic Ctx and Amygdala are required for consolidation of learned fear (Choi et al., 2010; Heldt et al., unpublished)
•
BDNF infused into Infralimbic Ctx enhances inhibition and extinction of learned fear (Peters et al., 2010)
•
BDNF mRNA expression is required in Hippocampus – possibly modulating the context-dependency of extinction (Heldt et al., 2007)
•
These data predict that transiently enhancing BDNF functioning during and after extinction would augment the reduction of fear

Question 25

BDNF agonist rescues extinction deficit in stress model

Answer 25

agonist: 7,8 DHF

Question 26

convergent genomics approach: finding genes involved in PTSD and fear neurocircuitry

Answer 26

•
Identify genes in hypothesis neutral fashion that are associated with PTSD (pooled GWAS N~400)
•
Identify genes in hypothesis neutral fashion associated with Fear Conditioning or Extinction Learning (mouse amygdala mRNA array)
•
Prioritize genes that are shared in the above

top convergent candidate: ADCYAP1R1