Final Report Summary - NEUROFEAR (Neuronal circuits controlling fear behavior)
The goal of the NEUROFEAR project, which started in November 2011, was to identify the medial prefrontal cortex (mPFC) circuits involved in the control of fear behavior in three aims. The first aim was to identify the activation/connectivity of mPFC circuits during fear behavior using extracellular electrophysiology. The second was to determine the causal role of mPFC circuits in the control of fear behavior using optogenetic manipulations. The last one was to determine the plasticity and anatomical properties of mPFC circuits involved in the control of fear behavior. Using single unit recordings and optogenetic manipulations of specific neuronal elements in behaving mice, we first demonstrated that the medial prefrontal cortex contain a disinhibitory microcircuit required for the expression of conditioned fear memory. Parvalbumin-expressing interneurons constitute the central element of the circuit and are phasically inhibited during presentations of conditioned tones. We next demonstrated that this inhibition induced the disinhibition of cortical pyramidal neurons by releasing the ongoing perisomatic inhibition mediated by parvalbumin-expressing interneurons onto pyramidal neurons. We next demonstrated that expression of fear behavior is causally related to the phasic inhibition of prefrontal parvalbumin-expressing interneurons. Inhibition of parvalbumin-expressing interneuron activity disinhibits prefrontal pyramidal neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. In addition, we identify a physiological signature of fear memory in the development of 4 Hz oscillations in the mPFC-BLA pathway, which synchronizes the firing activity of neurons during fear behavior. Using unprecedented closed-looped optogenetic manipulation we further demonstrated that the collective and synchronize firing activity of subpopulation of mPFC neurons in the ascending phase of 4 Hz oscillations constraint the dynamics of fear behavior. These results identify complementary neuronal mechanisms both dependent on prefrontal circuits that precisely coordinate and enhance the neuronal efficiency of prefrontal pyramidal neurons to drive fear expression.