Coherent Activity between the Prelimbic and Auditory Cortex in the Slow-Gamma Band Underlies Fear Discrimination

Abstract

The medial prefrontal cortex and the basolateral amygdala (BLA) are essential for discriminating between harmful and safe stimuli. The primary auditory cortex (Te1) sends projections to both sites, but whether and how it interacts with these areas during fear discrimination are poorly understood. Here we show that in male rats that can differentiate between a new tone and a threatening one, the selective optogenetic inhibition of Te1 axon terminals into the prelimbic (PL) cortex shifted discrimination to fear generalization. Meanwhile, no effects were detected when Te1 terminals were inhibited in the BLA. Using a combination of local field potential and multiunit recordings, we show that in animals that discriminate successfully between a new tone and a harmful one, the activity of the Te1 and the PL cortex becomes immediately and tightly synchronized in the slow-gamma range (40-70 Hz) at the onset of the new tone. This enhanced synchronization was not present in other frequency ranges, such as the theta range. Critically, the level of gamma synchrony predicted the behavioral choice (i.e., no freezing or freezing) of the animals. Moreover, in the same rats, gamma synchrony was absent before the fear-learning trial and when animals should discriminate between an olfactory stimulus and the auditory harmful one. Thus, our findings reveal that the Te1 and the PL cortex dynamically establish a functional connection during auditory fear-discrimination processes, and that this corticocortical oscillatory mechanism drives the behavioral choice of the animals. Identifying neural networks that infer safety versus danger is of great interest in the scientific field. Fear generalization reduces the chances of an animal's survival and leads to psychiatric diseases, such as post-traumatic stress disorders and phobias in humans. Here we demonstrate that animals able to differentiate a new tone from a previous threating tone showed synchronization between the prefrontal and primary auditory cortices. Critically, this connectivity precedes and predicts the behavioral outcome of the animal. Optogenetic inhibition of this functional connectivity leads to fear generalization. To the best of our knowledge, this study is the first to demonstrate that a corticocortical dialogue occurring between sensory and prefrontal areas is a key node for fear-discrimination processes.

Sex differences in auditory fear discrimination are associated with altered medial prefrontal cortex function

“…Our finding of fear discrimination in males accompanied by differences in oscillatory activity in mPFC during CS+ vs CS− presentation at retrieval adds to growing evidence of the involvement of this region in fear discrimination [27][28][29][30][31][32][33][34][35][36] . Although we found quantitative differences in theta and gamma power between CS+ and CS− presentation when activity was averaged over the entire frequency band and cue duration (see below), no qualitative differences were apparent when activity was examined throughout each frequency band or cue www.nature.com/scientificreports www.nature.com/scientificreports/ duration.…”

“…We found IL gamma activation in response to the CS+ during retrieval, in keeping with other evidence indicating that this area is involved in fear discrimination 29,36 . Gamma oscillations mediate the functional connectivity between mPFC and primary auditory cortex that underpins successful auditory fear discrimination 35 , highlighting their importance for mediating communication within the neural circuitry underlying fear discrimination. Interestingly, we found that fear generalization in females was associated with a lack of gamma activation in IL at retrieval.…”

“…As with fear extinction, mPFC plays a key role in fear discrimination [27][28][29][30][31][32][33] . Moreover, theta and gamma oscillations in mPFC are also implicated in fear discrimination 34,35 . After extended auditory fear discrimination training, we recorded local field potentials (LFPs) in mPFC during retrieval testing to determine if discrimination and generalization in males and females, respectively, are characterized by sex differences in mPFC function.…”

“…After extended auditory fear discrimination training, we recorded local field potentials (LFPs) in mPFC during retrieval testing to determine if discrimination and generalization in males and females, respectively, are characterized by sex differences in mPFC function. The prelimbic (PL) and infralimbic (IL) subregions of mPFC play opposing roles in the expression and extinction of learned fear 4 and we have previously shown sex differences in theta (4-12 Hz) and low gamma (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) oscillations in these areas during learned fear expression and extinction 14,15 . As there is also evidence for distinct contributions of PL and IL to fear discrimination 29,36 , we recorded LFPs from both of these mPFC subregions at retrieval.…”

New insights from 22-kHz ultrasonic vocalizations to characterize fear responses: relationship with respiration and brain oscillatory dynamics

“…Finally, the increase in gamma power observed during escape might reflect an increased emotional level compared to freezing. Indeed, previous studies both in humans and animals have shown that gamma oscillations are enhanced during emotional situations (reviewed in Headley and Paré, 2013;Stujenske et al, 2014;Concina et al, 2018).…”