Differential fear conditioning generates prefrontal neural ensembles of safety signals

Abstract

Fear discrimination is critical for survival, while fear generalization is effective for avoiding dangerous situations. Overgeneralized fear is a typical symptom of anxiety disorders, including generalized anxiety disorder and posttraumatic stress disorder (PTSD). Previous research demonstrated that fear discrimination learning is mediated by prefrontal mechanisms. While the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) are recognized for their excitatory and inhibitory effects on the fear circuit, respectively, the mechanisms driving fear discrimination are unidentified. To obtain insight into the mechanisms underlying context-specific fear discrimination, we investigated prefrontal neuronal ensembles representing distinct experiences associated with learning to disambiguate between dangerous and similar, but not identical, harmless stimuli. Here, we show distinct quantitative activation differences in response to conditioned and generalized fear experiences, as well as modulation of the neuronal ensembles associated with successful acquisition of context-safety contingencies. These findings suggest that prefrontal neuronal ensembles patterns code functional context-danger and context-safety relationships. The PL subdivision of the mPFC monitors context-danger associations to conditioned fear, whereas differential conditioning sparks additional ensembles associated with the inhibition of generalized fear in both the PL and IL subdivisions of the mPFC. Our data suggest that fear discrimination learning is associated with the modulation of prefrontal subpopulations in a subregion-and experience-specific fashion, and the learning of appropriate responses to conditioned and initially generalized fear experiences is driven by gradual updating and rebalancing of the prefrontal memory representations.

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.…”

“…In this study we determined if sex differences in auditory fear discrimination involve altered mPFC function. 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. 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.…”

Odor Modulates the Temporal Dynamics of Fear Memory Consolidation

“…Fear conditioning has been widely used as a model for PTSD in rodent studies (Rasmusson and Charney, 1997;Morrison and Ressler, 2014;Bali and Jaggi, 2015), and fear memories are encoded as engrams across multiple brain regions (Josselyn et al, 2015) and Grella et al,16 activation of these engrams has been shown to be both necessary and sufficient to drive fear responses. However, while the foundation for cortical traces are laid down early during encoding (Lesburgueres et al, 2011;Wang et al, 2012;Cardenas et al, 2019;Corches et al, 2019;Jacques et al, 2019) there is evidence to suggest that the PFC neurons involved in fear memory retrieval are not the same neurons active during encoding (Giannotti et al, 2019;DeNardo et al, 2019). Within the PFC, we specifically looked at the PL for several reasons.…”

“…In rodent studies, the PL has been implicated in the expression and renewal of fear responses (Corcoran and Quirk, 2007;Sierra-Mercado et al, 2011;Orsini and Maren, 2012;Courtin et al, 2014;Fenton et al, 2014;Corches et al, 2019) and increased activity in this region is associated with extinction deficits (Burgos-Robles et al, 2009) as well as increased input to the basolateral amygdala (BLA) (Likhtik et al, 2005;Maren et al, 2013), an output which promotes freezing behavior and fear (Vidal- Gonzalez et al, 2006).…”