Final Report Summary - FEAR-FRA (Neural coding of fear memories formation and extinction in frontal association network) The ability of an organism to predict forthcoming events is crucial for self-preservation, and depends on accurate internal representations to discriminate among similar sensory inputs. The dorsal prefrontal cortex (dPFC) of humans and rodents has emerged as a key structure of fear discriminative learning, and its dysfunctions may well be involved in many anxiety-related psychiatric diseases. However, the circuit and synaptic mechanisms by which the brain learns to detect and disambiguate cues predicting threat from safety noise remain largely ignored . With FEAR-DPFC we developed and implemented unique tools at the cutting edge of technology and innovation to understand how computations are performed in prefrontal neuronal microcircuit during discriminative learning. 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. We demonstrated that discrimination of safe and fear-conditioned stimuli is an active learning process that depends on full activity of the frontal association cortex, and is associated with the formation of cue-specific neuronal assemblies therein. During learning, prefrontal pyramidal neurons were potentiated through specific sensory-driven non-linearities supported by the activation of long-range inputs from the basolateral amygdala (BLA). Taken together, our data provide evidence for a new active dendritic mechanism that associates during learning features of perceived experience with BLA-mediated emotional state into prefrontal memory assemblies. Our “learning under the microscope” strategy tackled several outstanding issues that have never been addressed in the past most likely because of technical limitations. It gave special insight into the higher-cognitive functions performed by the prefrontal cortex, including the cellular and synaptic mechanisms underlying associative 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 FEAR-FRA will certainly help to advance the design of new diagnosis framework and strategies towards behavioral enhancement in a wide range of neuropsychiatric diseases.
