Excitation of prefrontal cortical neurons during conditioning enhances fear memory formation

Abstract

Animals can remember a situation associated with an aversive event. contextual fear memory is initially encoded and consolidated in the hippocampus and gradually consolidated in multiple brain regions over time, including the medial prefrontal cortex (PFC). However, it is not fully understood how PFC neurons contribute to contextual fear memory formation during learning. In the present study, neuronal activity was increased in PFC neurons utilizing the pharmacogenetic hM3Dq-system in male mice. We show that fear expression and memory formation are enhanced by increasing neuronal activity in pfc during conditioning phase. Previous studies showed that the activation of hM3Dq receptor in a subset of amygdala neurons enhanced fear memory formation and biased which neurons are allocated to a memory trace, in which immediate early gene c-fos was preferentially expressed following memory retrieval in these pre-activated neurons. In this study, hM3Dq activation in PFC could not change the probability of c-fos expression in pre-activated neurons flowing memory retrieval. Instead, the number c-fos positive neurons following memory retrieval was significantly increased in the basolateral amygdala. our results suggest that neuronal activity in pfc at the time of learning modulates fear memory formation and downstream cellular activity at an early phase. Memories of fearful events can be retained for extended periods of time, which allows animals to predict danger; thus, this process is important for their survival. In humans, the formation of strong fear memory can drive the development of neuropsychiatric disorders, such as posttraumatic stress disorder (PTSD). Both the hippocampus and amygdala are critical structures for contextual fear memory formation 1,2. The contribution of the hippocampus to contextual fear memory retrieval decreases over time 1,3,4. Alternatively, some cortical areas such as the PFC and the anterior cingulate cortex gradually become more impactful on memory retrieval 5-8. It is reported that PFC activity is associated with inappropriate fear in PTSD patients 9. The dorsal and ventral subdivisions of PFC regulate the expression and extinction of fear in rodents, respectively 10. Inactivation of the dorsal PFC interferes with the expression of fear in cued and contextual fear conditioning (CFC) 11-15. In the PFC, expression of conditioned fear is temporally controlled by oscillation of functional assemblies 16 , and stimulation of the BLA to PFC projection increases cue-associated freezing behavior 17. In contrast, inactivation of PFC and stimulating PFC to BLA projection during conditioning has a small influence on memory consolidation at an early phase 11,18. Nonetheless, it has been shown that micro-stimulation of the PFC during tone representation increases conditioned fear expression under low foot shock conditions 19. However, the contribution of PFC to consolidation in CFC at an early phase of learning is not fully understood. Recent works show that a subset of PFC neurons is rapidly tagged duri...

Prefrontal neural ensembles develop selective code for stimulus associations within minutes of novel experiences

“…In fact, one hour after training in contextual fear conditioning, the transcription of multiple plasticity-related genes is upregulated in the mPFC, leading to immediate changes in synaptic structure and physiology (Bero et al, 2014). Parallel studies also showed that by enhancing the activity of mPFC neurons during training, it is possible to facilitate the acquisition of hippocampusdependent memories (Benn et al, 2016;Volle et al, 2016;Jarovi et al, 2018;Shibano et al, 2020). These observations, along with earlier findings of impaired hippocampus-dependent memories with disrupted mPFC (Hannesson et al, 2004;Takehara-Nishiuchi et al, 2005;Zhao et al, 2005;Barker and Warburton, 2008;Gilmartin and Helmstetter, 2010;Devito and Eichenbaum, 2011;Gilmartin et al, 2013;Bero et al, 2014), led us to hypothesize that the mPFC may work with, but not follows, the hippocampus to form new memories (Takehara-Nishiuchi, 2020b).…”

Prefrontal Neural Ensembles Develop Selective Code for Stimulus Associations within Minutes of Novel Experiences

“…The copyright holder for this preprint this version posted August 27, 2020. ; https://doi.org/10.1101/2020.08.26.269035 doi: bioRxiv preprint mPFC neurons during training, it is possible to facilitate the acquisition of hippocampusdependent memories (Benn et al, 2016;Volle et al, 2016;Jarovi et al, 2018;Shibano et al, 2020). These observations, along with earlier findings of impaired hippocampus-dependent memories with disrupted mPFC (Hannesson et al, 2004;Takehara-Nishiuchi et al, 2005;Zhao et al, 2005;Barker and Warburton, 2008;Gilmartin and Helmstetter, 2010;Devito and Eichenbaum, 2011;Gilmartin et al, 2013;Bero et al, 2014), led us to hypothesize that the mPFC may work with, but not follows, the hippocampus to form new memories (Takehara-Nishiuchi, 2020b).…”

Prefrontal GABAergic Interneurons Gate Long-Range Afferents to Regulate Prefrontal Cortex-Associated Complex Behaviors

“…Temporal inhibition or permanent lesion of the mPFC significantly reduces the freezing behaviors in the fear-conditioned group in rats ( Frysztak and Neafsey, 1991 , 1994 ; Resstel et al, 2006 ). In contrast, elevating the neural activity of mPFC enhances fear expression and memory formation following the conditioning stimulus (CS) ( Shibano et al, 2020 ). Etkin et al (2011) elaborate on the recruitment of ACC and mPFC, two subdivisions of the PFC in emotion regulation and found that the activation of mPFC was seen in the fear expression, retention, and extinction, suggesting that mPFC conveys both safety and danger information.…”