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Neuronal plasticity for associative learning and memory

English title Neuronal plasticity for associative learning and memory
Applicant Lüthi Andreas
Number 189123
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 01.10.2019 - 30.09.2023
Approved amount 1'478'087.00
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Keywords (7)

learning and memory; neuromodulation; plasticity; neuronal circuits; interneurons; amygdala; fear conditioning

Lay Summary (German)

Lead
Neuronale Mechanismen der klassischen Furchtkonditionierung: Implikationen für das Veständnis von Lernvorgängen und Angststörungen
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 zugrunde liegenden zellulären Mechanismen und ihre Auzwirkungen auf die Aktivität des sogenannten Mandelkerns, eines wichtigen Schaltzentrums für emotionales Lernen, zu studieren. Uns interessieren die Rollen sogenannter neuromodulatorischen Systeme und verschiedener Subtypen von inhibitorischen Interneuronen während der Furchtkonditionierung. Im Speziellen sind wir daran interessiert, wie solche inhibitorischen Netzwerke das Lernen ermöglichen und kontrollieren können. Zudem möchten wir untersuchen, welche Zellen des Mandelkerns für das "Speichern" des Furchtgedächttnis' verantwortlich sind. 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: 25.10.2019

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
170268 Dis-inhibitory amygdala circuits in fear conditioning and extinction 01.10.2016 Project funding (Div. I-III)
170268 Dis-inhibitory amygdala circuits in fear conditioning and extinction 01.10.2016 Project funding (Div. I-III)

Abstract

Background: Associations are fundamental building blocks of memory. Neuroscientists have studied associative memory for >100 years, from both experimental (e.g. Pavlov) and theoretical (e.g. Hebb) perspectives. To date, the vast majority of all research on the biological substrates of associative memory has focused on molecular, synaptic and cellular level substrates. Surprisingly little is known how associative memories are formed and stored at the level of neural ensembles and, in particular, how interactions between distinct types of neurons within local circuits contribute to the process of 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 animals and humans have identified the amygdala as a key brain structure necessary for the acquisition and extinction of conditioned fear responses. The present grant application is based on recent results from our lab demonstrating that fear conditioning and extinction result in transformations of sensory representations at the level of large ensembles of neurons in the basolateral amygdala (BLA)(Grewe et al., 2017; Gründemann et al., 2019). Overall, these results provide first insights into the neuronal population algorithms underlying associative learning and memory, yet the mechanistic implementation and its relation to neuronal memory engrams defined activity-dependent genetic markers remains unknown.Hypotheses:1. We hypothesize that large-scale transformations of sensory representations upon associative learning involve distinct forms of synaptic and cellular plasticity that are gated and controlled by local micro-circuits and neuromodulatory inputs.2. We propose that such transformations result in the formation of neuronal ensembles partially that partially overlap with memory engrams defined by activity-dependent genetic markers (IEGs).To test these hypotheses we propose the following specific aims:Aim 1: Investigate cellular and subcellular mechanisms of associative plasticity using two-photon Ca2+ imaging of BLA principal neurons in behaving animals.Aim 2: Address circuit level mechanisms with a focus on the role of defined inhibitory micro-circuits and neuromodulatory inputs using a combination of behavioral, imaging, optogenetic and transcriptomic approaches.Aim 3: Clarify the relation between memory engram ensembles and functional plasticity based on Ca2+ imaging data using a combination different imaging techniques with optogenetic and anatomic approaches.Expected Value: One of the greatest challenges in neuroscience is to understand the neural basis of learning and memory. Learning is one of the most important aspects of brain function in health and in disease. By integrating across different levels of analysis, we expect to gain fundamental mechanistic insight into the neuronal basis of associative learning and memory. Given that the amygdala is a key node in a brain-wide network necessary for predicting threatening (or rewarding) consequences of sensory experiences and actions, we will gain insight into the physiology of brain networks central for mental health. Such mechanistic insight is crucial for future developments of novel therapeutic strategies for psychiatric disorders including anxiety and mood disorders.
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