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Dis-inhibitory amygdala circuits in fear conditioning and extinction

English title Dis-inhibitory amygdala circuits in fear conditioning and extinction
Applicant Lüthi Andreas
Number 170268
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 01.10.2016 - 30.09.2019
Approved amount 1'008'000.00
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Keywords (6)

amygdala; neuronal circuits; mice; interneurons; learning; behavior

Lay Summary (German)

Lead
Die Rolle von inhibitorischen neuronalen Netzwerken in der Amygdala in der klassischen Konditionierung
Lay summary

Das Lernen basiert auf lang anhaltenden funktionellen Veränderungen in neuronalen Netzwerken im Gehirn. Anhand des Modells der klassischen pawlowschen Furchtkonditionierung, einer einfachen Form von assoziativem Lernen, untersuchen wir die neuronalen Grundlagen von Lernen und Gedächtnis. Dazu benutzen wir einen multidisziplinären Ansatz, der auf einer Kombination von molekularen, zellulären und systemischen Methoden basiert.

Dieses Projekt hat zum Ziel,  die Rolle von verschiedenen Subtypen sogenannter inhibitorischer Interneuronen während der Furchtkonditionierung näher zu untersuchen. Im Speziellen, sind wir daran interessiert, wie solche inhibitorischen Netzwerke das Lernen ermöglichen und kontrollieren können. Dies ist nicht nur relevant im Hinblick auf unser Verständnis der grundsätzlichen neuronalen Mechanismen des Lernens, sondern auch aus klinischer Perspektive, da die fehlende Kontrolle oder das Wiederaufflammen von Furcht und Angst ein schwerwiegendes Problem für Patienten mit posttraumatischen Belastungsstörungen oder anderen Angststörungen darstellt.

 

Direct link to Lay Summary Last update: 21.11.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Adaptive disinhibitory gating by VIP interneurons permits associative learning
Krabbe Sabine, Paradiso Enrica, d’Aquin Simon, Bitterman Yael, Courtin Julien, Xu Chun, Yonehara Keisuke, Markovic Milica, Müller Christian, Eichlisberger Tobias, Gründemann Jan, Ferraguti Francesco, Lüthi Andreas (2019), Adaptive disinhibitory gating by VIP interneurons permits associative learning, in Nature Neuroscience, 22(11), 1834-1843.
Structural and Functional Remodeling of Amygdala GABAergic Synapses in Associative Fear Learning
Kasugai Yu, Vogel Elisabeth, Hörtnagl Heide, Schönherr Sabine, Paradiso Enrica, Hauschild Markus, Göbel Georg, Milenkovic Ivan, Peterschmitt Yvan, Tasan Ramon, Sperk Günther, Shigemoto Ryuichi, Sieghart Werner, Singewald Nicolas, Lüthi Andreas, Ferraguti Francesco (2019), Structural and Functional Remodeling of Amygdala GABAergic Synapses in Associative Fear Learning, in Neuron.
Amygdala ensembles encode behavioral states
Gründemann Jan, Bitterman Yael, Lu Tingjia, Krabbe Sabine, Grewe Benjamin F., Schnitzer Mark J., Lüthi Andreas (2019), Amygdala ensembles encode behavioral states, in Science, 364(6437), eaav8736-eaav8736.
Amygdala Inhibitory Circuits Regulate Associative Fear Conditioning
Krabbe Sabine, Gründemann Jan, Lüthi Andreas (2018), Amygdala Inhibitory Circuits Regulate Associative Fear Conditioning, in Biological Psychiatry, 83(10), 800-809.
New perspectives on central amygdala function
Fadok Jonathan P, Markovic Milica, Tovote Philip, Lüthi Andreas (2018), New perspectives on central amygdala function, in Current Opinion in Neurobiology, 49, 141-147.
Neural ensemble dynamics underlying a long-term associative memory
Grewe Benjamin F., Gründemann Jan, Kitch Lacey J., Lecoq Jerome A., Parker Jones G., Marshall Jesse D., Larkin Margaret C., Jercog Pablo E., Grenier Francois, Li Jin Zhong, Lüthi Andreas, Schnitzer Mark J. (2017), Neural ensemble dynamics underlying a long-term associative memory, in Nature, 543(7647), 670-675.
A competitive inhibitory circuit for selection of active and passive fear responses
Fadok Jonathan P., Krabbe Sabine, Markovic Milica, Courtin Julien, Xu Chun, Massi Lema, Botta Paolo, Bylund Kristine, Müller Christian, Kovacevic Aleksandar, Tovote Philip, Lüthi Andreas (2017), A competitive inhibitory circuit for selection of active and passive fear responses, in Nature, 542(7639), 96-100.
Distinct Hippocampal Pathways Mediate Dissociable Roles of Context in Memory Retrieval
Xu Chun, Krabbe Sabine, Gründemann Jan, Botta Paolo, Fadok Jonathan P., Osakada Fumitaka, Saur Dieter, Grewe Benjamin F., Schnitzer Mark J., Callaway Edward M., Lüthi Andreas (2016), Distinct Hippocampal Pathways Mediate Dissociable Roles of Context in Memory Retrieval, in Cell, 167(4), 961-972.e16.
Projection-Specific Dynamic Regulation of Inhibition in Amygdala Micro-Circuits
Vogel Elisabeth, Krabbe Sabine, Gründemann Jan, Wamsteeker Cusulin Jaclyn I., Lüthi Andreas (2016), Projection-Specific Dynamic Regulation of Inhibition in Amygdala Micro-Circuits, in Neuron, 91(3), 644-651.
Midbrain circuits for defensive behaviour
Tovote Philip, Esposito Maria Soledad, Botta Paolo, Chaudun Fabrice, Fadok Jonathan P., Markovic Milica, Wolff Steffen B. E., Ramakrishnan Charu, Fenno Lief, Deisseroth Karl, Herry Cyril, Arber Silvia, Lüthi Andreas (2016), Midbrain circuits for defensive behaviour, in Nature, 534(7606), 206-212.

Associated projects

Number Title Start Funding scheme
189123 Neuronal plasticity for associative learning and memory 01.10.2019 Project funding (Div. I-III)
189123 Neuronal plasticity for associative learning and memory 01.10.2019 Project funding (Div. I-III)
149722 Dis-inhibitory amygdala circuits in fear conditioning and extinction 01.10.2013 Project funding (Div. I-III)
125759 NCCR SYNAPSY: The synaptic bases of mental diseases (phase I) 01.10.2010 National Centres of Competence in Research (NCCRs)

Abstract

In contrast to the well-understood contribution of different brain areas and synaptic plasticity to learning, the most pressing unresolved issues today relate to the events in neuronal circuits during learning and memory. At this mesoscopic level, associative learning manifests as a change in information processing. How these changes are induced, and how memory formation in turn alters the function of the neuronal circuits is only beginning to emerge. A key feature of neuronal circuits is that they are composed of a multitude of excitatory and inhibitory neuron types. While the lion’s share of insights into the mechanisms and consequences of learning have been obtained from excitatory projection neurons in cortical structures, this project focuses on the role of inhibition in associative learning.As a model system, we use Pavlovian fear conditioning, a very robust form of associative learning which allows addressing fundamental questions about the underlying neuronal circuit mechanisms (Tovote et al., 2015). Studies in humans and animals have identified the amygdala as a key brain structure necessary for the acquisition and extinction of conditioned fear responses. Over the past few years, we have dissected amygdala circuitry with the overall aim to understand its functional organization, the computations that are performed by its elements during learning, and how these elements communicate with other brain structures. In particular, we found inhibition of inhibitory neurons (i.e. dis-inhibition) in various sub-nuclei of the amygdala and in cortex to be an important mechanism gating the acquisition and expression of conditioned fear responses (Ciocchi et al., 2010; Haubensak et al., 2010; Letzkus et al., 2011; Wolff et al., 2014; Tovote et al., 2016). The present grant proposal encompasses a multidisciplinary approach involving in vitro and in vivo electrophysiological recordings and imaging approaches together with anatomical, behavioral and optogenetic techniques, to investigate the mechanisms underlying disinhibition of distinct subpopulations of basolateral and central amygdala inhibitory neurons and to address how disinhibition contributes to specific aspects of fear and extinction behavior at the level of defined neuronal circuits.In particular, based on our previous findings, we will address the following hypothesis:1) Given that both PV+ and SOM+ BLA interneurons are inhibited during US (footshock) exposure (Wolff et al., 2014), we hypothesize that VIP+ interneurons are causally involved in conditioned fear learning by opening a disinhibitory learning gate for BLA principal neurons via inhibition of PV+ and SOM+ interneurons during aversive US presentation.2) Our present results indicate that disinhibition of defined central amygdala output pathways underlies the expression of conditioned defensive behaviors (Ciocchi et al., 2010; Tovote et al., 2016). In the next three years, we plan to investigate the mechanisms underlying disinhibitory gating and selection of defensive behaviors in CEA and midbrain circuits.
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