Neuronal epigenetic traces of reward – EPITRACES

Brain reward system plays a crucial role to maximize fitness by adapting behavior to environment contingencies (e.g. to optimize food consumption). Deciphering the cellular and molecular mechanisms by which activation of reward circuits leads to long-lasting behavioral adaptations is a major challenge for neuroscience. This information is highly relevant for medicine and society at large since addiction and eating disorders, two major health problems of modern societies, involve dysfunction of reward systems.
Dopamine neurons play a central role in the reward system, by reporting several aspects of reward prediction and value and controlling the function and plasticity of target neurons. However, very little is known about the cellular populations that are actually modified when an animal learns a rewarding task and the possible existence and nature of persistent molecular modifications in these cells. In this project we propose to address this issue by using a simple incentive learning protocol based on food reward and focusing our analyses on striatal projection neurons that are a major target of dopamine. Our general aim is to identify persistent transcriptional/epigenetic traces of operant learning in functionally relevant ensembles of striatal neurons.
We will use a combination of powerful mouse models to identify changes in mRNA and DNA modifications following operant conditioning for regular or highly palatable food. We will determine the persistence of these modifications and we will identify in which neuronal populations they take place. We will use an inducible tagging strategy to identify neuronal ensembles specifically activated during conditioning and will characterize the morphological and physiological changes occurring in these activated neurons. We will test their functional role in behavior by blocking their activity with a chemogenetic approach. We will then try and establish a causal relationship between mRNA and epigenetic modifications in these neurons and cellular or behavioral adaptations by specific targeting of candidates genes.
This project will shed light on molecular and cellular mechanisms of incentive learning and and memory. It will provide useful information and potential targets in the context of obesity-related eating disorders.