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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    486—Neural Mechanisms Mediating Fear and Anxiety

    Monday, November 11, 2013, 1:00 pm - 5:00 pm

    486.13: Prefrontal parvalbumin-expressing interneurons control fear expression

    Location: Halls B-H

    Neurocentre Magendie Inserm U862, Bordeaux, France

    Abstract Body: Accumulating evidence indicate that the medial prefrontal cortex is necessary for conditioned fear expression. Indeed, whereas inactivation of the prelimbic area prevents fear expression, its electrical stimulation facilitates conditioned fear responses. It is likely that neuronal activity occurring during fear expression depends on specific interactions between prefrontal excitatory neurons and inhibitory interneurons. However the precise role played by prefrontal excitatory and inhibitory circuits in mediating fear expression is still largely unknown. To address this question, we used single unit and field potential recordings combined with optogenetics in behaving mice submitted to auditory fear conditioning. Our results indicate that tone-evoked inhibition in a subpopulation of prefrontal PV-expressing interneurons inversely correlates with fear behavior and coincides with an increase of neuronal excitability in prefrontal principal neurons. Furthermore, targeted optogenetic inhibition or excitation of prefrontal PV-expressing interneurons during conditioned tone presentations respectively enhanced or decreased fear expression. Interestingly, inhibition of PV-expressing interneurons was associated with theta phase resetting of prefrontal field potentials that synchronizes neuronal activity in prefrontal projection neurons during fear expression. Our results identify two neuronal mechanisms mediated by prefrontal PV-expressing interneurons, enhancing the excitability and neuronal synchronization of prefrontal principal neurons to gate fear expression.

    Lay Language Summary: In the cortex, neurons receive, organize, store, and transmit a variety of information to ultimately modify behavior. However, the cortex contains several distinct subtypes and populations of neurons whose functions are unknown. Investigating the function of neuronal subtypes and how they give rise to distinct neural circuits will be fundamental in understanding the cellular basis of behavioral control, and will allow for the development of new therapeutic strategies for psychiatric disorders.
    Our research indicates that a specific population of interneurons in the prefrontal cortex is required to efficiently drive fear behavior. Under pathological fear conditions, the precise regulation of these interneurons could provide novel therapeutic approaches. It has been estimated that 14% of the adult population in the United States exhibit anxiety or post-traumatic stress disorders. These disorders are characterized by maladaptive fear behavior to stimuli that were associated with a traumatic event. These psychiatric disorders are associated with dysfunction of the dorsal anterior cingulate cortex, which is homologous to the prefrontal cortex in rodents. Despite the enormous social and economic impact of these disorders, effective treatments are still lacking.
    In the laboratory, fear is often studied using auditory fear conditioning, a robust learning paradigm in which rodents learn to associate an initially neutral stimulus, such as tone, with a coincident aversive footshock. Re-exposure to the tone induces the expression of a broad range of conditioned fear behaviors. To understand the neural correlates of fear, we recorded neural activity in the prefrontal cortex during fear expression. From these recordings we found that a population of interneurons that contain the protein parvalbumin, are controlling fear expression. Using innovative methodology of optogenetics, we activated and inhibited these parvalbumin-expressing interneurons during fear behavior and found that fear expression is high when activity of prefrontal parvalbumin interneurons is low. Furthermore, we showed that these inhibitory interneurons control fear behavior by synchronizing the activity of prefrontal neurons that project to downstream neuronal structures responsible for the expression of fear memories.
    Our findings suggest that organization and expression of fear behavior, which is at the core of several psychiatric conditions, might be finely regulated by the activity of prefrontal parvalbumin interneurons.