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Flashcards in fear Deck (26)
1

* components of PTSD

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

2

PTSD and fear memories

re-experiencing: fearful memories went under memory consolidation

3

brain areas in PTSD

mainly amygdala
PFC
hippocampus
fear response

slide 6

4

amygdala

receives input from sensory systems - preprocess

5

behavioral paradigm in rats

tone + footshock

auditory signal combined with somatosensory

6

panic attack

= 'fear attack' in fear-related disorders

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

7

the fear response is a hardwired process involving the amygdala

slide 14
e.x. Retic Pontis Caudalis: increased startle response
e.x. central gray area: freezing, social interaction

8

modeling fear

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

9

genetic studies

HPA axis/ sympathetic axis

10

hypersensitivity of the stress response

enhanced suppression of cortisol following dexamethasone in PTSD patients

11

FKBP5

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

12

child trauma + FKBP5

set up amygdala sensitivity
FKBP5 highly correlated to child trauma

13

hippocampal volume reduction in PTSD

hippocampal activation and structural differences in FKBP5 risk allele carriers

polymorphism

14

role of cortisol regulation during development 'emotional critical period'

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

15

early life stress - HPA axis gene interaction

slide 25
a dynamic amygdala-dependent emotional circuit

16

how we measure fear in animals

fear potentiated startle
freezing

17

NMDA receptor and amygdala-dependent learning

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

18

cellular model of fear learning

slide 29

consolidation
extinction

19

increase extinction in human

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

20

Treating PTSD/fear disorder: learning not to be afraid

• 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.

21

role of BDNF in fear learning and inhibition

slide 37

genetic inhibition of BDNF receptor inhibits extinction retention

22

TrkB, amygdala and fear

• 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.

23

the PFC-amygdala-hippocampal circuit

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

24

summary: BDNF and fear


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

25

BDNF agonist rescues extinction deficit in stress model

agonist: 7,8 DHF

26

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


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