synaptic plasticity; extinction; interneurons; amygdala; dis-inhibition; fear conditioning
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.
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.
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.
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.
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.
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.
Gründemann Jan, Lüthi Andreas (2015), Ensemble coding in amygdala circuits for associative learning., in Current opinion in neurobiology
, 35, 200-6.
Tovote Philip, Fadok Jonathan Paul, Lüthi Andreas (2015), Neuronal circuits for fear and anxiety., in Nature reviews. Neuroscience
, 16(6), 317-31.
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.
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.
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.
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.
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.
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
Lüthi Andreas, Lüscher Christian (2014), Pathological circuit function underlying addiction and anxiety disorders., in Nature neuroscience
, 17(12), 1635-43.
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.
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
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.