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Computational and Systems Neuroscience

Project Summary

Our daily life is a complex chain of decisions and actions that shapes our behaviors. Individuals tend to choose the best action possible (‘action-selection’) among different alternatives through “goal-directed” decision-making. To learn and achieve an optimal behavior, individuals must: (i) Predict the potential cost (e.g. risk) and benefit (e.g. reward) that might occur as a consequence of an action (‘outcome’). This ‘action-value’ function is learned from the causal consequences of an action (‘action-outcome’ association), and the subjective value of different outcomes (‘outcome-value’ associations); (ii) Compare ‘action value’ functions and select the action with the greatest value. The probability of selecting one of two choices is called ‘action-selection’ and determined by the difference in their ‘action value’ functions; (iii) Update the ‘action-value’ function according to the difference between the predicted and the obtained reward. Development of neuroeconomics as well as maladaptive decision-making found in many neuropsychiatric disorders highlight the crucial importance of this process.

The prefrontal cortex (PFC) appears to be well suited to organize such action-selection. However, despite the growing interest of ‘action-outcome’ and ‘outcome-value’ associations over the past few years, the neuronal correlates of choices that drive goal-directed ‘action-selection’ as well as the synaptic underpinnings have been largely neglected. By developing new methods and sophisticated strategies in behaving mice, we aim to resolve several outstanding questions:

  • Given that the comparison between choice alternatives should occur in the cortex as a precursor of choice and action, are multiple choices represented in the cortex by specific patterns of cell activation? Are they pre-existing or encoded through learning?
  • Given that the reward values are supposed to be encoded in several cortical structures through the help of subcortical structures, how are these different systems interconnected, and how do they cooperate to implement action values in the cortex and further influence choice? How are components of valuation encoded in the cortex, and to what extent do they modulate action representation?
  • Given that maladaptive decision-making is found in many psychiatric disorders including autism, are the synaptic and cellular underpinnings of decision-making altered in our mouse model of autism? How does the brain integrate previous memory traces to arbitrate between conflicting value information?

This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 677878)

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Team leader: Frédéric Gambino


Frédéric Gambino’s research goal is to understand how neuronal networks of behaving animals modulate the structure of their synaptic connections in response to learning, and how this process regulates the dynamics of representations that drive complex behaviors such as associative fear learning, decision-making, and action selection.

Frédéric Gambino first joined the lab of Pr B. Poulain and Y. Humeau (Strasbourg, France) as a PhD student (2006-2009). He developed patch-clamp and two-photon imaging in vitro strategies to study the properties of long-term synaptic potentiation (LTP), the main synaptic proxy of memories, in several animal models for cognitive disorder (CD). He showed that mice deficient for CD genes Ophn1, Rsk2 and Il1rapl1 exhibit a specific deficit in the non-canonical expression of presynaptic LTP caused by the selective uncoupling of evoked glutamate release from cAMP presynaptic. His PhD work led to 8 publications in high-standard journals (Nature neuro, PNAS,…).

However, because brain’s integrity is critical to fully understand the rules of neuronal plasticity, Frédéric Gambino decided to acquire a unique set of optogenetic, molecular, electrophysiological, and imaging skills in the living animal. First, He was awarded as an independent EMBO fellow and joined the lab of Pr Holtmaat (Geneva, Switzerland, 2009-2012). He single-handedly set up one two-photon microscope for in vivo whole-cell recordings in anesthetized mice, and independently launched his EMBO project. His work revealed new circuit-specific metaplastic rules for LTP upon changes in sensory experience: he showed indeed that disinhibition might be an essential step during cortical plasticity (Gambino and Holtmaat, Neuron 2012). He then got a senior position in the same lab (2012-2014) and implemented in vivo optogenetics and calcium imaging to manipulate thalamocortical sub-circuits in the behaving animal. His work revealed a new form of sensory-evoked, but spiking-independent long-term potentiation, as well as new synapses-specific rules that might be recruited during learning and development plasticity (Gambino et al, Nature 2014; Pouchelon et al, Nature 2014). His work has been awarded by several prestigious prices (e.g. Jansen Award, French National Academy of Medecine, 2015; Swiss Brain League Award, 2016).

This expertise allowed him to develop a fully independent research project that expands on the hypothesis stating that the learning and erasure of fearful events induce cellular plasticity in the dorsal prefrontal cortex (dPFC). This “FEAR-FRA” project has been funded by several international grants (ANR, EU-FP7-CIG, IdEx). He joined the IINS (CNRS, Bordeaux, France) in 2014 as a tenured researcher, and created with the help of local resources the M.I.N.D. platform that brings together multiple in vivo skills (behaviors, 2P imaging, optogenetic, electrophy…). By combining optogenetic, wide-field chronic calcium imaging and whole-cell recording in the behaving animal, he showed that the dPFC plays a key role in the formation of fear memory traces. His team proposes that the dPFC acts as a top-down warning system allowing the animal to detect biologically important events such by learning about signals of their occurrence.

Frédéric Gambino then succeeded in getting an ERC starting grant (2016-2021). His “NEUROGOAL” project is exploring the causal effect of learning during a complex decision task but also, and for the first time, when the mouse learns to perform the task. To achieve this goal, the team of Frédéric Gambino is developing here in Bordeaux unique tools at the cutting edge of technology and innovation. His team is part of a rare imaging infrastructure in vivo in Europe and in the world. This does not only underpin innovative research but also leads its development and creates a highly attractive climate for world-class postdocs and senior researchers.

5 Keys Publications

1. Gambino F, Pagès S, Kehayas V, Baptista D, Tatti R, Carleton A, Holtmaat A. Sensory-evoked long-term synaptic potentiation driven by dendritic plateau potentials in vivo. Nature (2014); 515:116-9

2. Gambino F and Holtmaat A. Spike-timing dependent potentiation of sensory surround in the somatosensory cortex i