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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 149722
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 01.10.2013 - 30.09.2016
Approved amount 968'097.00
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Keywords (6)

synaptic plasticity; extinction; interneurons; amygdala; dis-inhibition; fear conditioning

Lay Summary (German)

Lead
Dieses Projekt hat zum Ziel, die Funktion von neuronalen Netzwerken in der Amygdala und ihre Rolle im Erlernen von Angst und Furchtverhalten zu verstehen.
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.

In den letzten Jahren haben wir damit begonnen, das neuronale Netzwerk der Amygdala (dt.: Mandelkern) zu analysieren, mit dem Ziel, die funtionelle Rolle von spezifischen Nervenzellen und lokalen Netzwerken im Detail zu verstehen. Die Amygdala ist eine zentrale Hirnstruktur, welche der pawlowschen Furchtkonditionierung zu Grunde liegt. In diesem Projekt werden wir die Rolle von Interaktionen zwischen spezifischen inhibitorischen (hemmmenden) Nervenzellen in der Amygdala für das Erlernen und die Kontrolle von konditionierten Furchtantworten untersuchen.

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: 27.01.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.
Bidinosti Michael, Botta Paolo, Krüttner Sebastian, Proenca Catia C, Stoehr Natacha, Bernhard Mario, Fruh Isabelle, Mueller Matthias, Bonenfant Debora, Voshol Hans, Carbone Walter, Neal Sarah J, McTighe Stephanie M, Roma Guglielmo, Dolmetsch Ricardo E, Porter Jeffrey A, Caroni Pico, Bouwmeester Tewis, Lüthi Andreas, Galimberti Ivan (2016), CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency., in Science (New York, N.Y.), 351(6278), 1199-203.
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.
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), 206-12.
Neuroligin 2 deletion alters inhibitory synapse function and anxiety-associated neuronal activation in the amygdala.
Babaev Olga, Botta Paolo, Meyer Elisabeth, Müller Christian, Ehrenreich Hannelore, Brose Nils, Lüthi Andreas, Krueger-Burg Dilja (2016), Neuroligin 2 deletion alters inhibitory synapse function and anxiety-associated neuronal activation in the amygdala., in Neuropharmacology, 100, 56-65.
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), 644-51.
Disinhibition, a Circuit Mechanism for Associative Learning and Memory.
Letzkus Johannes J, Wolff Steffen B E, Lüthi Andreas (2015), Disinhibition, a Circuit Mechanism for Associative Learning and Memory., in Neuron, 88(2), 264-76.
Ensemble coding in amygdala circuits for associative learning.
Gründemann Jan, Lüthi Andreas (2015), Ensemble coding in amygdala circuits for associative learning., in Current opinion in neurobiology, 35, 200-6.
Neuronal circuits for fear and anxiety.
Tovote Philip, Fadok Jonathan Paul, Lüthi Andreas (2015), Neuronal circuits for fear and anxiety., in Nature reviews. Neuroscience, 16(6), 317-31.
Regulating anxiety with extrasynaptic inhibition.
Botta Paolo, Demmou Lynda, Kasugai Yu, Markovic Milica, Xu Chun, Fadok Jonathan P, Lu Tingjia, Poe Michael M, Xu Li, Cook James M, Rudolph Uwe, Sah Pankaj, Ferraguti Francesco, Lüthi Andreas (2015), Regulating anxiety with extrasynaptic inhibition., in Nature neuroscience, 18(10), 1493-500.
Sensory inputs to intercalated cells provide fear-learning modulated inhibition to the basolateral amygdala.
Asede Douglas, Bosch Daniel, Lüthi Andreas, Ferraguti Francesco, Ehrlich Ingrid (2015), Sensory inputs to intercalated cells provide fear-learning modulated inhibition to the basolateral amygdala., in Neuron, 86(2), 541-54.
Amygdala interneuron subtypes control fear learning through disinhibition.
Wolff Steffen B E, Gründemann Jan, Tovote Philip, Krabbe Sabine, Jacobson Gilad A, Müller Christian, Herry Cyril, Ehrlich Ingrid, Friedrich Rainer W, Letzkus Johannes J, Lüthi Andreas (2014), Amygdala interneuron subtypes control fear learning through disinhibition., in Nature, 509(7501), 453-8.
Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling.
Jayachandran Rajesh, Liu Xiaolong, Bosedasgupta Somdeb, Müller Philipp, Zhang Chun-Lei, Moshous Despina, Studer Vera, Schneider Jacques, Genoud Christel, Fossoud Catherine, Gambino Frédéric, Khelfaoui Malik, Müller Christian, Bartholdi Deborah, Rossez Helene, Stiess Michael, Houbaert Xander, Jaussi Rolf, Frey Daniel, Kammerer Richard A, Deupi Xavier, de Villartay Jean-Pierre, Lüthi Andreas, Humeau Yann, Pieters Jean (2014), Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling., in PLoS biology, 12(3), 1001820-1001820.
Ex vivo dissection of optogenetically activated mPFC and hippocampal inputs to neurons in the basolateral amygdala: implications for fear and emotional memory.
Hübner Cora, Bosch Daniel, Gall Andrea, Lüthi Andreas, Ehrlich Ingrid (2014), Ex vivo dissection of optogenetically activated mPFC and hippocampal inputs to neurons in the basolateral amygdala: implications for fear and emotional memory., in Frontiers in behavioral neuroscience, 8, 64-64.
Long-range connectivity defines behavioral specificity of amygdala neurons.
Senn V, Wolff SBE, Herry C, Grenier F, Ehrlich I, Gründemann J, Fadok JP, Müller C, Letzkus JJ, Lüthi A (2014), Long-range connectivity defines behavioral specificity of amygdala neurons., in Neuron, 428.
Pathological circuit function underlying addiction and anxiety disorders.
Lüthi Andreas, Lüscher Christian (2014), Pathological circuit function underlying addiction and anxiety disorders., in Nature neuroscience, 17(12), 1635-43.
Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons.
Pecho-Vrieseling Eline, Rieker Claus, Fuchs Sascha, Bleckmann Dorothee, Esposito Maria Soledad, Botta Paolo, Goldstein Chris, Bernhard Mario, Galimberti Ivan, Müller Matthias, Lüthi Andreas, Arber Silvia, Bouwmeester Tewis, van der Putten Herman, Di Giorgio Francesco Paolo (2014), Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons., in Nature neuroscience, 17(8), 1064-72.
Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway.
Khelfaoui M, Gambino F, Houbaert X, Raggazon B, Müller C, Carta M, Lanore F, Srikumar BN, Gastrein P, Luthi A, Humeaux Y (2013), Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway., in Phil Trans R Soc B, online.

Collaboration

Group / person Country
Types of collaboration
Karl Deisseroth, Stanford United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Josh Huang, Cold Spring Harbor Laboratories United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
See attached list Talk given at a conference See attached list 01.12.2016 See attached list, Switzerland Krabbe Sabine; Meyer Elisabeth; Tovote Philip; D'Aquin Simon; Xu Chun; Tsai Alejandro; Lüthi Andreas; Lavi Karen;


Awards

Title Year
Cloetta Prize 2016 2016

Associated projects

Number Title Start Funding scheme
133137 Controlling fear: function and plasticity of inhibitory circuits in the amygdala 01.10.2010 Project funding (Div. I-III)
170268 Dis-inhibitory amygdala circuits in fear conditioning and extinction 01.10.2016 Project funding (Div. I-III)
130080 Emotional Memory in Health and Disease 01.10.2010 Sinergia

Abstract

BACKGROUNDIn 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. 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 started to dissect 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 amygdala and 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; Ehrlich et al., 2009). In the present grant proposal, we describe a multidisciplinary approach involving in vitro and in vivo physiological recordings together with anatomical, behavioral and optogenetic techniques, to investigate the mechanisms underlying dis-inhibition of distinct subpopulations of basolateral amygdala interneurons and to address how dis-inhibition contributes to specific aspects of fear and extinction behavior at the level of defined neuronal circuits.HYPOTHESESIn particular, based on our preliminary findings, we hypothesize that:1) The acquisition of conditioned fear responses is gated by compartment-specific dis-inhibition of amygdala principal neurons mediated by interactions between parvalbumin (PV)- and somatostatin (SOM)-expressing interneurons.2) Activity-dependent dis-inhibition of cholecystokinin (CCK)-expressing inter-neurons sets the balance of activity between distinct basal amygdala output pathways involved in fear extinction.EXPECTED VALUEMuch evidence suggests that dysregulation of amygdala function is at the core of human anxiety disorders and that altered GABAergic inhibition may be an important mechanism contributing to amygdala-related psychiatric conditions. Therefore, understanding the neural mechanisms controlling and gating amygdala activity and amygdala-dependent learning is of clinical relevance and should eventually lead to novel therapeutic strategies for psychiatric disorders involving excessive fear responses such as post-traumatic stress disorder and other anxiety disorders. Besides clinically relevant aspects, the proposed experiments will address basic questions in systems and circuit neuroscience. The amygdala is one of the most powerful systems to address questions regarding the causal relationships between circuit function and behavior. Thus, the expected results will further our understanding of the cellular basis of learning processes in general.
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