TY - JOUR T1 - Hippocampal inputs in the prelimbic cortex curb fear after extinction JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.0764-20.2021 SP - JN-RM-0764-20 AU - Weronika Szadzinska AU - Konrad Danielewski AU - Kacper Kondrakiewicz AU - Karolina Andraka AU - Evgeni Nikolaev AU - Marta Mikosz AU - Ewelina Knapska Y1 - 2021/09/13 UR - http://www.jneurosci.org/content/early/2021/09/10/JNEUROSCI.0764-20.2021.abstract N2 - In contrast to easily formed fear memories, fear extinction requires prolonged training. The prelimbic cortex (PL), which integrates signals from brain structures involved in fear conditioning and extinction such as the ventral hippocampus (vHIP) and the basolateral amygdala (BL), is necessary for fear memory retrieval. Little is known, however, about how the vHIP and BL inputs to the PL regulate the display of fear after fear extinction. Using functional anatomy tracing in male rats, we found two distinct subpopulations of neurons in the PL activated by either the successful extinction or the relapse of fear. During the retrieval of fear extinction memory, the dominant input to active neurons in the PL was from the vHIP, whereas the retrieval of fear memory, irrespective of the age of a memory and testing context, was associated with greater BL input. Optogenetic stimulation of the vHIP-PL pathway after one session of fear extinction increased conditioned fear, while stimulation of the vHIP inputs after several sessions of extinction decreased the conditioned fear response. This latter effect was, however, transient, as stimulation of this pathway 28 days after extinction increased conditioned fear response again. The results show that repeated fear extinction training gradually changes vHIP-PL connectivity making fear suppression possible, whereas in the absence of fear suppression from the vHIP, signals from the BL can play a dominant role, resulting in high levels of fear.STATEMENT OF SIGNIFICANCEBehavioral therapies of fear are based on extinction learning. As extinction memories fade over time, such therapies produce only temporary suppression of fear, which constitutes a clinical and societal challenge. In our study, we provide a framework for understating the underlying mechanism by which extinction of fear memories fade, by demonstrating the existence of two subpopulations of neurons in the prelimbic cortex, associated with low and high levels of fear. Insufficient extinction and exposure to the context in which fear memory was formed promoted “high fear” neuronal activity in the prelimbic cortex, leading to fear retrieval. Extensive extinction training, on the other hand, boosted “low fear” neuronal activity and, as a result, extinction memory retrieval. This effect was, however, transient and disappeared with time. ER -