Encoding of conditioned fear in central amygdala inhibitory circuits
description
Transcript of Encoding of conditioned fear in central amygdala inhibitory circuits
![Page 1: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/1.jpg)
1
Encoding of conditioned fear in central
amygdala inhibitory circuits
Stephane Ciocchi1*, Cyril Herry1*{, François Grenier1, Steffen B. E.Wolff1, Johannes J. Letzkus1, Ioannis Vlachos2, Ingrid Ehrlich1{,
Rolf Sprengel3, Karl Deisseroth4, Michael B. Stadler1, Christian Mu¨ller1 & Andreas Lu¨thi1
Nature Volume:468, Pages:277–282Date published: (11 November 2010)
![Page 2: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/2.jpg)
2
BACKGROUND
• The central amygdala (CEA)has been considered to be primarily involved in the behavioural expression of conditioned fear responses
• CEAoutput neurons(CEm) project to downstream targets in the brainstem and in the hypothalamus where they orchestrate conditioned autonomic and motor responses
• CEm output neurons are under tight inhibitory control from the lateral and capsular subdivisions (together referred to as CEl)
![Page 3: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/3.jpg)
3
How the acquisition and expression of conditioned fear are encoded within CEA inhibitory circuits ?
![Page 4: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/4.jpg)
4
WHAT WE WILL KNOW IN THIS ARTICLE
• Neuronal activity in the lateral subdivision of the central amygdala (CEl) is required for fear acquisition.
• Conditioned fear responses are driven by output neurons in the medial subdivision (CEm).
• Inhibitory CEA microcircuits are highly organized
• Cell-type-specific plasticity of phasic and tonic activity in the CEl to CEm pathway may gate fear expression and regulate fear generalization.
![Page 5: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/5.jpg)
5
TECHNOLOGY
![Page 6: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/6.jpg)
6
TECHNOLOGY
Opto genetics
![Page 7: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/7.jpg)
7
TECHNOLOGY
For more information, go to www.stanford.edu/group/dlab/optogenetics/
![Page 8: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/8.jpg)
8
TECHNOLOGY
Microiontophoresis is the techniquewhereby ions and charged moleculescan be ejected in very small amounts from solutions contained in micropipettes
OFTEN USED FOR:(1) deposition of dyes and neural transport tracers for histologicalexamination (2) for administration of neuroactive compounds (e.g. transmitters, modulators, drugs or hormones) by microiontophoresis to examine their effects on firing parameters of single neurons in vivo.
For more information, go to www.kationscientific.com/basics.html
![Page 9: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/9.jpg)
9
RESULTS
Differential role of CEl and CEm
1.The impact of neuronal activity in CEm on freezing behavior
OPTOGENETICS (Activation)Virus expressing ChR2 in neurons
![Page 10: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/10.jpg)
10
RESULTS
• Bilateral activation of CEm induced strong and reversible freezing responses
![Page 11: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/11.jpg)
11
RESULTSMICROIONTOPHORESIS (Inhibition)Fluorescently labelled GABAA receptor agonist (muscimol-bodipy (BPY))
Bilateral inactivation of CEm, or of the entire CEA (CEm and CEl), did not elicit freezing behaviour.
Inactivation of CEl alone induced unconditioned freezing.
![Page 12: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/12.jpg)
12
RESULTS
2. The contribution of distinct CEA subnuclei to the acquisition of conditioned freezing
![Page 13: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/13.jpg)
13
RESULTS3. The role of CEl and CEm for memory retrieval or expression
Local application of muscimol-BPY 24 h after conditioning
Inactivation of the entire CEA or CEm resulted in a retrieval/ expression deficit. Inactivation of CEl did not reduce conditioned freezing levels
![Page 14: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/14.jpg)
14
CONCLUSION 1
Conditioned and unconditioned freezing behaviouris driven by CEm output neurons which are under tonic inhibitory control originating in CEl.
CEl as an essential component of the neuronal circuitryunderlying the acquisition of conditioned fear.
![Page 15: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/15.jpg)
15
RESULTS
Organization of CEA inhibitory networks
1. Fear conditioning-induced changes in CS evoked neuronal firing in the CEl
30% of units acquired an excitatory response (CElon neurons) (Fig.a)
25% of CEl neurons displayed a strong inhibitory response to the CS1 after fear conditioning(CEloff neurons) (Fig.b)
![Page 16: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/16.jpg)
16
RESULTS
![Page 17: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/17.jpg)
17
RESULTS
The inverse direction of fear-conditioning-induced plasticity in CEIon and CEIoff neurons indicated that ...
![Page 18: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/18.jpg)
18
RESULTS
CElon to CEloff, 9 of 35 pairs; CEloff to CElon, 3 of 35 pairs;
![Page 19: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/19.jpg)
19
RESULTS
2.Anatomical and functional connectivity between CEl and CEm.
Injections into CEm resulted in intense retrograde labelling of neurons in CEl
CEm remained largely devoid of GFP after injections into CEl
![Page 20: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/20.jpg)
20
RESULTS
2.1 Whether identified CElon or CEloff neurons project to CEm
• The axons of both subtypes arborize locally within CEl, and send collaterals to CEm
![Page 21: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/21.jpg)
21
RESULTS
2.2Whether CElon and CEloff neurons functionally inhibit CEm neurons
Two distinct subclasses of CEl neurons inhibit CEm neurons in vivo
![Page 22: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/22.jpg)
22
3.Considering that CElon and CEloff neurons exhibited opposite changes in CS-evoked firing during fear conditioning, this raises the question of whether at the level of CEm output neurons fear conditioning results in CS-evoke
d inhibition or disinhibition.
![Page 23: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/23.jpg)
23
RESULTS
![Page 24: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/24.jpg)
24
RESULTS
Conditioned CS responses of CEm output neurons reflect the integration of both excitatory and disinhibitory inputs.
![Page 25: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/25.jpg)
25
CONCLUSION 2
CEl contains two functionally distinct subpopulationsof neurons forming highly organized local inhibitory circuits which inhibit CEm output neurons.
Conditioned fear responses are driven by CS-evokeddisinhibition of CEm output neurons
![Page 26: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/26.jpg)
26
RESULTS
Tonic inhibition and fear generalization
1.Whether spontaneous activity in CEl and CEm is subject to regulation ?
2.How plasticity of spontaneous activity might contribute to the encoding of conditioned fear responses ?
![Page 27: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/27.jpg)
27
RESULTS
•Spontaneous activity of CEm output neurons was markedly decreased after fear conditioning.
•CEloff neurons exhibited increased spontaneous activity after fear conditioning
•On average CElon neurons showed a slight decrease
![Page 28: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/28.jpg)
28
RESULTS
![Page 29: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/29.jpg)
29
RESULTS
3.What might be the behavioural relevance of plasticity of tonicactivity in CEA inhibitory circuits?
After fear conditioning, absolute and z-scored levels of tonic activity were only poorly correlated with freezing
![Page 30: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/30.jpg)
30
RESULTS
Fear-conditioning induced changes in tonic activity were not limited to periods of CS+ exposure, but were also manifest during CS- stimulation
![Page 31: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/31.jpg)
31
RESULTS
A decrease in tonic activity of CEm output neurons was associated with generalization, CEloff neuronsand CElon neurons exhibited the inverse correlation.
![Page 32: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/32.jpg)
32
SUMMARY
SECTION 3SECTION 1、 2
![Page 33: Encoding of conditioned fear in central amygdala inhibitory circuits](https://reader036.fdocuments.in/reader036/viewer/2022062323/568157bc550346895dc53fbe/html5/thumbnails/33.jpg)
33
Thank you !