21 February 2022

Fares SAYEGH – PhD defense

"Triggering hippocampal LTP and learning by dopamine : a teaching signal"

PhD defense in english

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Supervisor : Lionel DAHAN, REMEMBeR team

Comitee members :

  • M. Lionel DAHAN, Directeur de thèse, Université Toulouse III – Paul Sabatier
  • M. Antoine ADAMANTIDIS, Rapporteur, University of Bern
  • Mme Stéphanie DAUMAS, Rapporteure, Sorbonne Université
  • M. Vivien  CHEVALEYRE, Rapporteur, Institute Psychiatry And Neuroscience De Paris
  • Mme Stéphanie TROUCHE, Examinatrice, University of Montpellier
  • Mme Elisa BOUTET-ROBINET, Examinatrice, Université Toulouse III – Paul Sabatier

Abstract :

The hippocampus is the main brain structure involved in episodic memory formation. The role of the hippocampus in learning, memory and their underlying mechanisms has been studied extensively in rodents, in particular by using contextual learning.

Long-Term Potentiation (LTP) is an increase in synaptic transmission of glutamatergic afferents that lasts for hours, days or months and is thought to underlie hippocampal memory formation. It can be triggered in the hippocampus by an artificial High frequency Stimulation (HFS). This mechanism helped in deciphering memory mechanisms, showing that both memory and LTP rely firstly on phosphorylation and later on de novo protein synthesis. The link between memory and LTP was confirmed by showing that blocking LTP mechanisms hinders memory formation, and that contextual learning induces LTP in the CA1 of the hippocampus. Since LTP, just like memory, can be saturated, the nervous system cannot store every sensory input that the animal encounters. Moreover, HFS is not compatible with neuronal activity. Hence, there must be a teaching signal that would be the natural molecular trigger of LTP during learning, acting as a filter choosing the pertinent inputs to store. Dopamine is a neuromodulator that has historically been thought of as a value signal, for dopamine gets released during rewarding events. However, dopamine has later been shown to be released whenever a salient unrewarding, or even punishing, event occurs. Dopamine receptors can trigger both phosphorylation and de novo protein formation in most brain structures showing plasticity, and D1/5 Dopaminergic receptors are necessary for LTP maintenance and long-term memory. Moreover, dopaminergic stimulation in vitro can modulate synaptic transmission in CA1. Thus, we hypothesized that dopamine could act as a teaching signal.

In this work, we use behavior and electrophysiology coupled with optogenetic manipulations of midbrain dopamine afferents and pharmacology inhibition of D1/5 dopaminergic receptors in order to study the role of dopamine as a teaching signal triggering LTP so that pertinent sensory inputs get stored. Using electrophysiology, we show that coupling optogenetic stimulations of midbrain dopamine with glutamatergic inputs in CA1 induces a progressive LTP that reaches its plateau 90 minutes after the pairing. This LTP endures at least 5 hours, is dependent on D1/5 receptors and partially occludes HFS-triggered LTP. Then, using contextual fear conditioning coupled with auditory cue conditioning we show that intraperitoneal injection of D1/5 receptor inhibitor, SHC23390, hinders both contextual and cue fear memories. Alternatively, intra-hippocampal infusion of SCH23390 blocks contextual memory but preserves cue fear memory intact. These results allowed us to conclude that hippocampal D1/5 receptors are necessary for contextual fear memories and in another brain structure for associative fear memories. Finally, we use a variation of contextual fear conditioning called contextual pre-exposure facilitation effect, which separates contextual learning from fear conditioning since the animal in this task learns each of them on two consecutive days. This allows studying dopamine as a teaching signal without the interference of any value inputs. We show that mice require between 2-8 minutes to encode contextual information. Furthermore, we show that D1/5 receptors are necessary for contextual and fear learning. Finally, we show that optogenetic stimulation of dopaminergic axons in the hippocampus promotes contextual learning and, conversely, their inhibition hinders contextual learning.

This work allows us to conclude that the dopaminergic pathway from the midbrain to the hippocampus has all the characteristics of a teaching signal, namely, triggering LTP on co-activated sensory inputs promoting the storage of contextual information in the hippocampus without the need for any value information.

21 February 2022, 14h0017h00
4R4-RDC | Salle Conférence CBI