amygdala; neuronal circuits; mice; interneurons; learning; behavior
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.
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
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.
Krabbe Sabine, Gründemann Jan, Lüthi Andreas (2018), Amygdala Inhibitory Circuits Regulate Associative Fear Conditioning, in Biological Psychiatry
, 83(10), 800-809.
Fadok Jonathan P, Markovic Milica, Tovote Philip, Lüthi Andreas (2018), New perspectives on central amygdala function, in Current Opinion in Neurobiology
, 49, 141-147.
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.
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.
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.
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.
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.
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.