“Enhancement of extinction memory consolidation: The role of the

noradrenergic and GABAergic systems within the basolateral amygdala”

Neurobiology of Learning and Memory

By Daniel J. Berlau and James L. McGaugh

Presented by Muharema MusticOct. 27th 2006

Background Paper-Brioni and colleagues

• 1989 Brioni and colleagues studied the role of amygdala in memory storage modulation

• GABA-main inhibitory neurotransmitter (NT) in the mammalian brain

• Postsynaptic neuron responds to GABA → electrical inhibition-mediated by an increase in Cl¯ channel conductance

Background continued…

• Studies of interest in this paper- memory storage after various GABA agonist and antagonist administration in the amygdala

• Post training systemic injections:GABA(A) -antagonist bicuculline

GABAA agonist muscimol

FIGURE 1- Bicuculline injections

• Foot shock of 0.35mA used

• Rats were injected immediately post-training

• Retention evaluation occurred 48 hrs later

• Significant effect at 0.1nmol dose, others ineffective (0.3,1.0 nmol)

Figure 1-bicuculline in the amygdala

Figure 3 Bicuculline injections

• Evaluation of neuroanatomical specificity of the effect of BMI on retention- amygdala and caudate putamen injections were given to another group and compared

• Significant drug effect: intra-amygdala injections showed increase in retention latency compared to control rats

Figure 3

Figure 1 and Figure 3 conclusion

• Conclusion: giving GABAergic antagonist bicuculline increases rats’ retention of the inhibitory avoidance response

• Bicuculline in caudate putamen-no effect on memory retention

• Conclusion: the amygdala is the critical area

Muscimol effects

• Stronger foot shock (0.45 mA)

• Post training injections of GABAA agonist muscimol decreased 48 hr retention latencies

• Muscimol impaired the retention of the inhibitory avoidance

Figure 4

Take home message-background paper

• This study suggests that the amygdala is critical area in memory retention

• Caudate Putamen injection of bicuculline showed no effect on retention

• Inhibitory avoidance response impaired after muscimol injection

• Short: retention of training tasks ↑ after bicuculline (GABAA antagonist) injection and retention of training ↓ after muscimol (GABAA agonist) injection

Now to my presentation paper

• Since the previous paper suggests memory retention when bicuculline is injected immediately post-training and muscimol decreases memory retention, studies have been preformed to test GABAergic and noradrenergic systems in EXTINCTION MEMORY

• It is suggested that GABA is the inhibitory control in the role of extinction

Drugs used in this paper

GABAergic antagonist Bicuculline (50ng)β-adrenoceptor antagonist propranolol

(500 ng)Bicuculline with propranolol Norepinephrine (NE 0.3,1.0,3.0 µg)GABAergic agonist muscimol NE with muscimol control solution

Materials and Methods

• 267 male Sprague Dawley rats

• Weight 225-250 grams on arrival

• Individually housed at 22˚ C and light/dark cycle [light on at 7 am] controlled vivarium

• Rats received food ad libitum

• Allowed to acclimate to laboratory conditions for one week before surgery

Behavioral Apparatus

• Behavioral Apparatus-trough shaped alley

-divided into two compartments by sliding door

1. light compartment (safe)

2. dark compartment (foot shock)

Procedure

• 1st CFC occurred in the apparatus

- rats placed in the dark compartment

- door to light was closed

- 30 s exploration then foot shock (1mA, 1s)

- 3 additional shocks over next 2 min.

- removed from the apparatus

24 hours later-extinction training

Extinction Training

• Rats were placed into dark compartment facing closed door -allowed to explore it for 120 s• Freezing behavior recorded• Immediately after extinction training-

bilateral, unilateral, or ipsilateral BLA or DH infusion

extinction training and post-training-repeated 24hrs later

Figure 3

GABA and fear learning

• GABA is important for regulating consolidation of fear extinction learning– As well as consolidation of the initial fear

learning– Not important for regulating acquisition

• GABA inhibits consolidation of fear extinction learning

Figure 4

BLA Laterality

• For consolidation of fear learning right and left hemispheres are not equal

• Right BLA is sensitive to GABAergic inhibitory control of consolidation of fear learning– The Left BLA appears to be insensitive

Figure 7-NE infusion into the right BLA

NE in BLA

• Norepinephrine (NE) promotes extinction learning of fear conditioning– Dose specific effect

• NE also promotes the original fear conditioning memory retention

NE

Glu

Figure 6

Propranolol effects

• Propranolol alone on test day-no effect on freezing behavior

• Bicuculline and Propranolol infusion into the right BLA-no sensitivity

• Conclusion: bilateral and right side infusion of bicuculline enhances CFC extinction

Figure 8

GABA – NE interactions in BLA

• NE reverses GABAergic inhibition of fear extinction learning

• NE effect is downstream of GABA regulation– GABA interneuron terminals on NE terminals?

• Does NE promote fear extinction learning?

NE

Glu

GABA

Figure 9 – Dorsal Hippocampus

Dorsal Hippocampus is supposed to be important for contextual learning

Dorsal Hippocampus – BLA

• Dorsal hippocampus does not appear to influence the consolidation of contextual fear conditioning extinction learning

NE

Glu

GABA

BLA

GABADH

+ muscimolGlu

Discussion

• This study suggests that DH is not important in extniction of CFC

• Bad conclusion or bad result?

Conclusion

1. Enhanced extinction if immediate post-training injection of Bicuculline or NE in the BLA

2. Late infusion or no extinction training infusion- freezing behavior occurs

3. Propranolol + Bicuculline injection = blocked enhancement of extinction

4. Inactivate DH with muscimol- did not prevent enhanced CFC extinction induced by NE infused post-training into the BLA (saying that extinction due to NE occurred?)

References

• Berlau, J. Daniel, James L. McGaugh Enhancement of extinction memory consolidation: “The role of the noradrenergic and GABAergic systems within the basolateral amygdala” Neurobiology of Learning and Memory, 2006 pp. 123-132

• Brioni et al. J.D. Brioni, A.H. Nagahara and J. L. McGaugh “Involvement of the amygdala GABAergic system in the modulation of memory storage” Brain Research, 1989 pp.105-112