Dottorato in NEUROSCIENZE DEL COMPORTAMENTO

Titolo della tesi: Synaptic and transcriptomic features of cortical and amygdala pyramidal neurons predict inefficient fear extinction

Fear associative learning increases the chances of survival by allowing individuals to anticipate threatening events and respond pre-emptively. However, the suppression of fear memory when the danger is removed (the so-called extinction process) is crucial to permit other survival functions, and impairment in such a coping mechanism may lead to maladaptive behaviors, as in the case of trauma-related disorders. These highly debilitating conditions have immeasurable social and economic costs and affect more than 4% of the population who have witnessed traumatic events. It is classically considered that traumatized individuals with fear symptomatology show responses that probably activate the neurobiological processes of inadequate fear inhibition (a failure in the extinction process). The ground-breaking hypothesis of this research is that, in susceptible individuals, the fearful event reactivates a footprint already existing before the event itself. Hence, trauma-related disorders might reflect not only post-trauma consequences, but also neural and molecular risk factors present already before the trauma. In this framework, we characterized mouse phenotypes that spontaneously exhibit individual differences in approach and avoidance behaviors toward conflicting emotional stimuli. Their behavioral differences represent robust predictors of vulnerability or resilience to impaired fear extinction. This model enables the identification of specific morphological, electrophysiological, and transcriptomic patterns in amygdala-prefrontal cortex pyramidal neurons predisposing to impaired fear extinction before exposure to fearful experiences. Finally, utilizing an optogenetic approach, we showed the possibility to rescue the inefficient fear extinction activating infralimbic pyramidal neurons and to impair fear extinction by activating prelimbic pyramidal neurons.