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Periodic Report Summary 1 - FEAR-FRA (Neural coding of fear memories formation and extinction in frontal association network)

The dorsal prefrontal cortex (dPFC) of humans and rodents has emerged as a key structure of fear learning, and its dysfunctions may well be involved in many anxiety-related psychiatric diseases. The goal of FEAR-FRA is therefore to understand how the formation, consolidation and extinction of associative fear memories traces are implemented by the dPFC. By using challenging new imaging methods and sophisticated strategies in the behaving animals, we aim to:
1) Test whether fear learning learning alter synapses dynamics in the dPFC. We will image dendritic spines of dPFC Layer (L) 2-pyramidal neurons that express fluorescent synaptic marker through high-resolution 2-photon laser scanning microscopy (2PLSM)-based time lapse imaging. This will be done over long time frames in living mice through a cranial window chronically implanted over the dPFC.
2) Test whether predictive learning and goal-directed behaviors alter the computations performed by dmPFC microcircuit. We will combine chronic 2PLSM-based calcium probing of large-scale neuronal activity with in vivo patch-clamp recordings in the awake behaving mouse.
3) Identify the synaptic properties as well as the neuromodulatory effects of the long-range connections between dPFC and subcortical structrures by using in vivo whole-cell recordings, calcium imaging and optogenetic tools.

Our project combine a wide range and unique set of optical, electrophysiological, genetic, and optogenetic tools in vivo in the behaving animal to understand how computations are performed in prefrontal neuronal microcircuit during fear lerning. We developped and implemented unique tools at the cutting edge of technology and innovation. Longitudinal in-vivo two-photon imaging and whole-cell recordings in the behaving animal are indeed at the forefront of the modern neuroscience techniques. When combined with the high temporal precision of optogenetics, calcium dynamics makes it possible to decipher the causal role of the interaction between different interconnected brain structures during behaviors.
Here, we first show that fear learning, a widely used form of predictive learning, is strongly affected by optogenetic inactivation of the dorsal prefrontal cortex (dPFC). Then, by combining in vivo two-photon large-scale neuronal calcium imaging and whole-cell recordings in behaving mice, we observe that layer II dPFC pyramidal neurons are activated upon sound presentation. This low and frequency-independent activation may act as an alert system with rapid habituation upon sound re-presentation. Interestingly, when the same sound is associated in time to an aversive stimulus (e.g. a foot-shock), the subsequent activation of dPFC neuronal network is strongly reinforced and synchronized upon sound presentation with increased spiking reliability across sessions and days suggesting that behavioraly-relevant pattern of activity have been stabilized following fear learning. Altogether our data show that the dPFC plays key role in the formation and expression of fear memory traces. In addition we hypothesize that the dPFC acts as a top-down warning structure allowing the animal to detect biologically important events such as downstream fear association by learning about signals of their occurrence.

Our “learning under the microscope” strategy tackles several outstanding issues that have never been addressed in the past most likely because of technical limitations. It will indeed give special insight into the higher-cognitive functions performed by the prefrontal cortex, including the cellular and synaptic mechanisms underlying fear memories formation, as well as the integration of cortical and subcortical valuation systems that may participate in fear learning. Studying such interactions is of crucial importance as many maladaptive behaviors in our daily life (e.g. impulsivity; anxiety, high-risk gambling...) may arise from their dysfunctional use. As a consequence it will certainly help to advance the design of new diagnosis framework and strategies towards behavioral enhancement in a wide range of neuropsychiatric diseases.

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Life Sciences
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