Behavioral Neuroscience, lecture on fear conditioning
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Behavioral Neuroscience
Summers
Fear
Afferent Path for Fear
Amygdala
Fear Conditioning
Afferent Shock (US) Pathway
Efferent Output
Neuromuscular Production of Fear Potentiated Startle
Integration of Fear Conditioning
ACh
BDNF
Gephyrin
Enkephalin
Substance P
Fear figures
Fear Conditioning Circuitry
end     Acronyms/Abbreviations
Fear Conditioning
V. Conditioning of Fear Responses 			back to  Amygdala 

	A. Acquisition
	
		1. visual stimulus (CS) for acoustic startle fear conditioning
		
			a. visual information: visual thalamus (LGN & lpostn) to
			   temporal cortex  perirhinal cortex then to  LA
			
				i. not direct route from visual thalamus to amygdala
						
			b. input from LA to the BLA is Glu
			
			c. olfactory and auditory stimuli (CSs) can also
			    provoke fearful CRs to acoustic startle  
	
			
		2. Glu binding to NMDA Receptors in BLA
		    is required for acquisition of fear conditioning
				
			a. NR2B subunit of NMDA receptor necessary for acquisition
			
				i. acquisition blocked by AP5 (general NMDA antagonist)
				    or infenprodil (NR2B antagonist)
	
				
			b. NMDA necessary for acquisition of conditioning
			    with visual, olfactory or auditory CS
			
				i. may activate MAPK
				
				ii. ERK/MAPK in BLA necessary for acquisition
				     of fear conditioning memory formation
				
					(1) blocked by the MEK inhibitor UO126
			
			c. necessary for the ability to process the CS
			
				i. into a CR
				
				ii. not for startle itself
	
				
		2. CS-shock pairing = conditioning upregulates BDNF 
		    (brain derived neurotrophic factor) in BLA
		
			a. visual or olfactory CS
			
				i. not light or olfactory or shock alone
					
			b. not in MeA, vPosteromedial Thalamic N, or dorsal Hippocampus
					
			c. BDNF in BLA necessary for acquisition of fear conditioning
			
				i. BDNF binds to TrKB receptors
				
				ii. acquisition blocked by TrKB inhibitors
				    K252a (general) and TrKB.T1 (specific) into BLA
				
				iii. TrKB powerfully regulates PI3K
				
				iv. BDNF/TrKB mediate translocation of MAPK to nucleus
				
			d. BDNF/TrKB increase NMDA function
			
				i. increase the duration of NMDA channel opening
				
		3. increased PKA and PKC in BLA (freezing)
		
		4. CREB promotes a dramatic pairing specific increase
		    in fear potentiated startle
		
			a. CREB also promotes conditioned social defeat
	
	
	B. Consolidation
	
		1. a period of increased excitability in the amygdala
		
			a. several hours
		
		2.  GABAA in BLA
		
			a. GABAA activity in BLA  decreases initial consolidation
	
		3. Gephyrin is down-regulated in BLA
		    during consolidation of fear conditioning
		
			a. gephyrin is a clustering protein
			
				i. increases transmitter action by localizing receptors
				
				ii. including GABA and Gly receptors
				
			b. regulated by GABA or Gly receptors
			
			c.  gephyrin   GABAA
	
		4.  GABAA allows LTP in the amygdala
		
			a. important for consolidation of long term memory
			
		5. NE promotes consolidation of fear conditioning for memory retention
		
			a. norepinephrine (NE) reverses GABAA inhibition of consolidation 
		
		6. BDNF/TrKB also necessary for consolidation
		
		
	C. Expression of Fear potentiated Acoustic Startle  
	
		1. AMPA receptors necessary in BLA, MeA and CeA
				
			a. not required for startle alone
			
			b. visual, auditory and olfactory CS 
			
			c. NMDA in BLA were thought to be not required but
			
		2. NR2A subunits of NMDA receptors
			
			a. enhance expression
		
			
		3. Rapid response conditioning, via CeA output
		
			a. mediates short term responses to specifically threatening cues
			
			b. i.e. fear 
	
		
		4. CRF markedly increases the amplitude of acoustic startle
		
			a. effective in BNST
			
			b. blocked by CRF antagonist 
			    α-helical-CRF in BNST
			
				i. or lesion of BNST
				
				ii. not blocked by lesion of BLA or CeA
				
			c. but α-helical-CRF in or 
			   lesion of BNST do not block fear conditioned startle
			
				i. BNST lesions do block context conditioned fear (freezing)
			
		5. BNST mediates fear responses to unpredictable stimuli with longer cues
			
			a. conditioning similar to 9/11
				
			b. PTSD
				
			c. i.e. anxiety
		
	
	D. Extinction
	
		1. extinction is not an erasure of original fear memory
		
		2. extinction actively inhibits memory
		
			a. valium reduces fear enhanced component of startle
			    and not the original level of startle reflex
				
				i. valium is a benzodiazepine: binds to GABAA
				
					(1) increases duration channel opening
		
			b. Inactivation of amygdala (CeA or BLA) also 
			    removes fear potentiation without changing the original startle
		
		3. extinction is context specific
		
		4. extinction of fear may be disrupted by stress
		
		5. increased regulation of gephyrin in BLA during extinction
		
			a. \ increased GABA binding
			
		6. NMDA-R in Amygdala are necessary for acquistion of extinction learning
		
			a. but NMDA-R are only functional with contextual cues
			
				i. MAPK in BLA necessary for extinction
			
			b. extinction blocked by AP5 in BLA
			
			c. D-cycloserine into BLA enhances extinction
			
				i. enhances function of NMDA receptors
				
				ii. NR2C sensitive to D-cycloserine
			
					(1) NR2C may be important for extinction
					
					(2) NR2A, NR2B & NR2C may all
					     be necessary for fear learning
					
		7. Extinction consolidation
		
			a. AP5 in BLA after extiction training
			    blocks expression of extinction
			
			b. NMDA receptors are necessary
			    for consolidation of extinction	
			
			
	E. Reinstatement
			
		1. Like addiction stress can reinstate conditioned fear responses
					
		2. stimulating NMDA-R with D-cycloserine blocks
		    stress induced reinstatement of fear potentiation
		
			a. D-cycloserine is used as an adjunct to therapy
			    to improve learning during extinction
	
			b. does not facilitate fear memories themselves
		

V.V. BDNF

VI. Afferent Pathways for Fear; US: Shock