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Controlling fear: function and plasticity of inhibitory circuits in the amygdala

English title Controlling fear: function and plasticity of inhibitory circuits in the amygdala
Applicant Lüthi Andreas
Number 133137
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2010 - 30.09.2013
Approved amount 600'000.00
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Keywords (10)

amygdala; fear conditioning; extinction; receptive fields; inhibition; synaptic plasticity; Learning; memory; fear; circuits

Lay Summary (English)

Lead
Lay summary
Learning is mediated by long-term functional modifications in brain circuits. We are taking a multidisciplinary approach to investigate the neuronal substrates underlying Pavlovian fear conditioning, a simple form of associative learning which can easily be studied in rodents. Using a combination of cellular and systems electrophysiological and imaging techniques, together with molecular and behavioral manipulations, we aim to understand how function and plasticity of neuronal circuits relates to learning at the behavioral level.The inability to control or inhibit inappropriate fear responses is a hallmark of human anxiety disorders. We are investigating the cellular mechanisms underlying fear extinction, an associative learning process mediating inhibitory control of inappropriate fear behavior. This aspect of our research not only addresses fundamental mechanisms underlying memory processes in the brain, but is also clinically highly relevant, because the relapse of pathological fear and anxiety is a major problem in patients suffering from post-traumatic stress disorder and other anxiety disorders.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Controlling the elements: an optogenetic approach to understanding the neural circuits of fear
Johanssen J et al. (2012), Controlling the elements: an optogenetic approach to understanding the neural circuits of fear, in Biol Psychiatry, 1053.
Genetic strain differences in fear are associated with converging alterations at the neuroendocrine, autonomic and amygdala dendritic morphology level
Camp M et al. (2012), Genetic strain differences in fear are associated with converging alterations at the neuroendocrine, autonomic and amygdala dendritic morphology level, in PNAS, 1534.
A disinhibitory microcircuit for associative fear learning in auditory cortex
Letzkus JJ et al. (2011), A disinhibitory microcircuit for associative fear learning in auditory cortex, in Nature, 331.
Context-dependent encoding of fear and extinction memories in a large scale network model of the basal amygdala
Vlachos I et al. (2010), Context-dependent encoding of fear and extinction memories in a large scale network model of the basal amygdala, in PLoS Computational Biology, e1001104.
Encoding of conditioned fear in central amygdala inhibitory circuits
Ciocchi S Herry C Grenier F Wolff SBE Letzkus JJ Vlachos J Ehrlich I Sprengel R et al. (2010), Encoding of conditioned fear in central amygdala inhibitory circuits, in Nature, 468, 277-282.
Impaired fear extinction in mice lacking protease nexin 1
Meins M et al. (2010), Impaired fear extinction in mice lacking protease nexin 1, in Eur J Neurosci, 2033.
Inhibitory gating of learned fear by a microcircuit in the central amygdala
Haubensak W et al. (2010), Inhibitory gating of learned fear by a microcircuit in the central amygdala, in Nature, 270.
Neuronal circuits of fear extinction
Herry C et al. (2010), Neuronal circuits of fear extinction, in Eur J Neurosci, 599.
Long-range connectivity defines behavioral specificity of amygdala neurons
Senn V et al., Long-range connectivity defines behavioral specificity of amygdala neurons, in Neuron.

Collaboration

Group / person Country
Types of collaboration
Maz Hasan, Rolf Sprengel, MPI for Medical Resarch, Heidelberg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Josh Huang, CSHL United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Karl Deisseroth, Stanford United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
GRC "Amygdala in health and disease" Talk given at a conference 01.08.2013 Boston, United States of America Lüthi Andreas;
RIKEN Summer School Talk given at a conference 01.07.2013 Tokyo, Japan Lüthi Andreas;
GRC "Inhibition" Talk given at a conference 01.05.2013 Les Diablerets, Switzerland Lüthi Andreas;
ESF Conference on emotions Talk given at a conference 01.10.2012 Stresa, Italy Lüthi Andreas;
FENS Talk given at a conference 01.07.2012 Barcelona, Spain Lüthi Andreas;
CSHL Neuronal Circuits Meeting Talk given at a conference 01.03.2012 New York, United States of America Lüthi Andreas;
Annual Meeting of the Society for Neuroscience, Plenary Lecture Talk given at a conference 13.11.2011 Washington, United States of America Lüthi Andreas;
European Science Meeting Talk given at a conference 01.11.2011 Budapest, Hungary Lüthi Andreas;
BCCN Annual Meeting 2011, Plenary Lecture Talk given at a conference 01.10.2011 Freiburg, Germany Lüthi Andreas;
GRC "Amygdala in health and disease" Talk given at a conference 01.08.2011 Colby, United States of America Lüthi Andreas;
IBRO World Congress, Plenary Lecture Talk given at a conference 01.07.2011 Florence, Italy Lüthi Andreas;
French Neuroscience Meeting, Plenary Lecture Talk given at a conference 05.05.2011 Marseille, France Lüthi Andreas;
Talk, MIT Individual talk 01.05.2011 Cambridge, United States of America Lüthi Andreas;
Winter Neuroscience Conference, Sölden Talk given at a conference 15.03.2011 Sölden, Austria Lüthi Andreas;
German Neuroscience Meeting, Göttingen Talk given at a conference 10.03.2011 Göttingen, Germany Lüthi Andreas;
Talk, NYU Individual talk 02.03.2011 New York, United States of America Lüthi Andreas;
Talk, Columbia University Individual talk 01.03.2011 New York, United States of America Lüthi Andreas;
Talk, NCBS, Bangalore Individual talk 20.10.2010 Bangalore, India Lüthi Andreas;
Talk, Univ Basel Individual talk 10.10.2010 Basel, Switzerland Lüthi Andreas;
Talk, Univ Helsinki Individual talk 05.10.2010 Helsinki, Finland Lüthi Andreas;
SFB Symposium Talk given at a conference 01.10.2010 Mannheim, Germany Lüthi Andreas;


Associated projects

Number Title Start Funding scheme
149722 Dis-inhibitory amygdala circuits in fear conditioning and extinction 01.10.2013 Project funding (Div. I-III)
130080 Emotional Memory in Health and Disease 01.10.2010 Sinergia
117935 Controlling fear: function and plasticity of inhibitory circuits in the amygdala 01.10.2007 Project funding (Div. I-III)

Abstract

Experience-dependent changes in behavior are mediated by long-term functional modifications in brain circuits. We are interested to understand the underlying mechanisms at the molecular, cellular and circuit level. As a model system we are using classical (Pavlovian) fear conditioning, a simple form of associative learning that depends on the amygdala, a brain area in the temporal lobe. While tremendous progress has been made in identifying the basic mechanisms underlying fear learning, much less is known about the mechanisms preventing inappropriate fear reactions and pathological anxiety. Recent evidence suggests that GABAergic inhibition mediated by local amygdala interneurons may play a key role in controlling amygdala plasticity and inhibition of inappropriate fear reactions.Using a multidisciplinary and integrated experimental approach in mice, we are combining in vitro and in vivo electrophysiological with genetic and behavioral techniques to address the functional properties of identified amygdala inhibitory circuits and their relevance to behavioral learning. The expected results will further our understanding of the cellular basis of learning processes in general. Moreover, elucidating the neural mechanisms constraining or inhibiting amygdala activity should also lead to novel therapeutic strategies for psychiatric disorders involving excessive fear responses such as post-traumatic stress disorder and other anxiety disorders.
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