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Encoding of Associative Fear Memory in Identified Neuronal Circuits of Auditory Cortex

English title Encoding of Associative Fear Memory in Identified Neuronal Circuits of Auditory Cortex
Applicant Letzkus Johannes Jakob
Number 131802
Funding scheme Ambizione
Research institution Max Planck Gesellschaft zur Förderung der Wissenschaften MPI für Hirnforschung
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Neurophysiology and Brain Research
Start/End 01.12.2010 - 31.08.2014
Approved amount 645'412.00
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Keywords (6)

auditory cortex; optogenetics; memory formation; classical conditioning; neuronal identity; 2-photon imaging

Lay Summary (English)

Lead
Lay summary
One of the central goals in Neuroscience is to understand the mechanisms mediating the enormous information storage capacity of the brain. Associative learning is the process by which we form connections between environmental stimuli, thoughts and feelings. A large body of research has characterized plastic changes in the strength of connections between single nerve cells, termed synaptic plasticity, which are thought to underlie learning. However, neuronal networks are composed of many different types of nerve cells with specific functions, which interact during information processing. Therefore, our focus is to understand how the various circuit elements are modified by learning, and how the sum of these changes translates to altered network function. We have established a set of advanced physiological techniques utilizing 2-photon imaging combined with viral and transgenic tools to simultaneously measure activity in many, identified neurons in auditory cortex of the intact mouse. These approaches are applied to study classical (Pavlovian) fear conditioning, a simple form of associative learning. In addition to recording activity patterns, we are also able to manipulate the activity of identified neuronal populations in behaving animals during learning using optogenetic approaches. This allows us to directly test the effect of activity in specific neuronal populations on memory formation. Our results will define the roles of specific neuronal sub-populations in neocortex in the acquisition and expression phase of associative learning. In addition, fear learning in mice shares major hallmarks with human anxiety disorders, and we expect to gain insights into the cortical mechanisms determining whether learning leads to the formation a specific (appropriate) memory, as opposed to a generalized (pathological) memory.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A disinhibitory microcircuit for associative fear learning in the auditory cortex
Letzkus Johannes, Wolff Steffen, Meyer Elisabeth, Tovote Philip, Courtin Julien, Herry Cyril, Luthi Andreas (2011), A disinhibitory microcircuit for associative fear learning in the auditory cortex, in Nature, 480(7377), 331-335.
Circuit Mechanisms of Memory Formation
Kampa Bjoern, Gundlfinger Anja, Letzkus Johannes, Leibold Christian (2011), Circuit Mechanisms of Memory Formation, in Neural Plasticity, 2011, 1-2.
Long-range connectivity defines behavioral specificity of amygdala neurons
Senn Verena, Wolff Steffen, Herry Cyril, Grenier Francois, Ehrlich Ingrid, Gründemann Jan, Fadok Jonathan, Müller Christian, Letzkus Johannes, Luthi Andreas, Long-range connectivity defines behavioral specificity of amygdala neurons, in Neuron.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Optogenetics: From cells to circuits and behaviour Talk given at a conference 14.07.2013 Weizmann Institute, Rehovot, Israel Letzkus Johannes Jakob;
Cellular and Molecular Neurobiology of Mental Disease Talk given at a conference 30.05.2013 Giessbach, Switzerland Letzkus Johannes Jakob;
MPG leadnet meeting Talk given at a conference 06.05.2013 Mainz, Germany Letzkus Johannes Jakob;
Society for Neuroscience Annual Meeting Poster 13.10.2012 New Orleans, USA, United States of America Letzkus Johannes Jakob;
Congress of the Swiss Society of Psychiatry and Psychology Talk given at a conference 12.09.2012 Interlaken, Switzerland, Switzerland Letzkus Johannes Jakob;
FENS Forum 2012 Poster 14.07.2012 Barcelona, Spain, Spain Letzkus Johannes Jakob;
Inhibition in the CNS, Gordon Research Conference and Research Seminar Talk given at a conference 24.07.2011 Colby College, ME, USA, United States of America Letzkus Johannes Jakob;
Neuronus IBRO Young Neuroscience Forum Talk given at a conference 15.04.2011 Krakow, Poland, Poland Letzkus Johannes Jakob;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Ohne Faszination geht es nicht OTX world German-speaking Switzerland 2013
New media (web, blogs, podcasts, news feeds etc.) Circuit Training Nature Neuropod International 2011

Awards

Title Year
Pfizer Forschungspreis 2013
University Prize of the Adrian and Simone Frutiger Foundation 2012

Associated projects

Number Title Start Funding scheme
117935 Controlling fear: function and plasticity of inhibitory circuits in the amygdala 01.10.2007 Project funding (Div. I-III)

Abstract

One of the central goals in Neuroscience is to understand the mechanisms mediating the enormous information storage capacity of the brain. A complete and detailed understanding of memory formation would be a quantum leap for fields as diverse as basic science, medicine (to develop therapeutic approaches for conditions that impair memory, such as Alzheimer’s and dementia) and computer sciences (to implement the storage rules into neural network software). Associative learning is the process by which we form connections between environmental stimuli, thoughts and feelings. While its underlying physiological mechanisms have been studied extensively using in vitro preparations, much less is known about how memories are stored at the level of local neuronal circuits in the intact animal. This is an essential question since the dynamic interaction of neurons in their network is absolutely critical to any form of higher brain function. Here we outline a strategy to analyze associative learning in identified neuronal circuits in the intact animal.In laboratory research on mice, a simple associative learning paradigm is classical fear conditioning. It is performed by pairing an emotionally neutral stimulus (e.g. a tone) with an aversive one (e.g. a mild foot-shock), so that over time the tone acquires aversive significance for the animal. Research on the neuronal mechanisms underlying this straightforward and robust form of learning has been enormously successful, identifying the amygdala as a key brain area for association of the two stimuli (LeDoux, 2000; Maren, 2001). In recent years, however, it has become increasingly clear that the amygdala performs this function as a hub in a large-scale network of several brain areas (McGaugh, 2004; Phelps and LeDoux, 2005). In particular, neocortex is engaged during fear conditioning (Romanski and LeDoux, 1992), and indispensable when complex, more natural stimuli are employed (Lindquist et al., 2004; Yaniv et al., 2004). Previous research in primary auditory cortex indicates that auditory fear conditioning induces an increase in neuronal responses to the conditioned tone, along with an expansion of the representation of this tone in the tonotopic map (Weinberger, 2007). Together with several other lines of evidence, these results indicate that auditory cortex actively participates in forming fear memories. However, we know next to nothing about the role of different types of neurons in this phenomenon. This is a crucial question since the properties of neuronal networks are dominantly determined by interaction of the different circuit elements (different types of projection neurons and interneurons). We have established a set of advanced physiological techniques utilizing 2-photon imaging combined with viral and transgenic tools to simultaneously measure activity in many (up to 100) identified neurons in the intact mouse brain. Importantly, we are also able to manipulate the activity of identified neuronal populations in behaving animals using optogenetic approaches (Zhang et al., 2007). We have begun experimental analysis of two stages of fear learning:1. Circuit mechanisms of fear memory acquisitionAuditory fear learning occurs due to pairing of a tone with an electric shock. When we apply this protocol in anesthetized mice (c.f. Rosenkranz and Grace, 2002) while monitoring the activity of ensembles of neurons in auditory cortex, we find a significant enhancement of responses during pairing compared to presentation of the tone alone. Our data indicate that this could be due to activation of layer 1 interneurons by the foot-shock. These neurons preferentially inhibit other interneurons (Christophe et al., 2002), so that their activation will likely cause a disinhibition of the excitatory network. Here we propose a thorough test of this hypothesis, including experiments into the necessity and sufficiency of L1 interneuron firing for network disinhibition and formation of a behavioral memory.2. Circuit mechanisms of fear memory storage / retrievalAfter acquisition, memories undergo consolidation to form a stable memory trace. We will investigate which circuit elements contain the memory trace in animals with a consolidated, behavioral memory and how this affects the stimulus representation in the network. Our results suggest that circuit activity in auditory cortex correlates with the level of fear associated with a tone. Importantly, discrimination between fearful and neutral stimuli appears to be mainly performed by a small population of neurons. We aim to identify these neurons based on their axonal projection targets, the current working hypothesis being that they project to the amygdala. In addition, we will assess whether fear learning also elicits plastic changes in defined interneuron sub-populations.
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