The 5-HT2A, 5-HT5A, and 5-HT6 serotonergic receptors in the medial prefrontal cortex behave differently in extinction learning: Does social support play a role?

Studies on the social modulation of fear have revealed that in social species, individuals in a distressed state show better recovery from aversive experiences when accompanied - referred to as social buffering. However, the underlying mechanisms remain unknown, hindering the understanding of such an approach. Our previous data showed that the presence of a conspecific during the extinction task inhibited the retrieval of fear memory without affecting the extinction memory in the retention test. Here, we investigate the role of serotonergic receptors (5-HTRs), specifically 5-HT2A, 5-HT5A, and 5-HT6 in the medial prefrontal cortex (mPFC), In the retention of extinction after the extinction task, in the absence or presence of social support. Extinction training was conducted on 60-day-old male Wistar rats either alone or with a conspecific (a familiar cagemate, non-fearful). The antagonists for these receptors were administered directly into the mPFC immediately after the extinction training. The results indicate that blocking 5-HT5A (SB-699551-10 µg/side) and 5-HT6 (SB-271046A - 10 µg/side) receptors in the mPFC impairs the consolidation of CFC in the social support group. Interestingly, blocking 5-HT2A receptors (R65777 - 4 µg/side) in the mPFC led to impaired CFC specifically in the group undergoing extinction training alone. These findings contribute to a better understanding of brain mechanisms and neuromodulation associated with social support during an extinction protocol. They are consistent with previously published research, suggesting that the extinction of contextual fear conditioning with social support involves distinct neuromodulatory processes compared to when extinction training is conducted alone.

The Post-conditioning Acute Strength Exercise Facilitates Contextual Fear Memory Consolidation Via Hippocampal N-methyl-D-aspartate-receptors.

The benefits of aerobic exercises for memory are known, but studies of strength training on memory consolidation are still scarce. Exercise stimulates the release of metabolites and myokines that reaching the brain stimulate the activation of NMDA-receptors and associated pathways related to cognition and synaptic plasticity. The aim of the present study was to investigate whether the acute strength exercise could promote the consolidation of a weak memory. We also investigated whether the effects of strength exercise on memory consolidation and on the BDNF and synapsin I levels depends on the activation of NMDA-receptors. Male Wistar rats were submitted to strength exercise session after a weak training in contextual fear conditioning paradigm to investigate the induction of memory consolidation. To investigate the participation of NMDA-receptors animals were submitted to contextual fear training and strength exercise and infused with MK801 or saline immediately after exercise. To investigate the participation of NMDA-receptors in BDNF and synapsin I levels the animals were submitted to acute strength exercise and infused with MK801 or saline immediately after exercise (in absence of behavior experiment). Results showed that exercise induced the consolidation of a weak memory and this effect was dependent on the activation of NMDA-receptors. The hippocampal overexpression of BDNF and Synapsin I through exercise where NMDA-receptors dependent. Our findings showed that strength exercise strengthened fear memory consolidation and modulates the overexpression of BDNF and synapsin I through the activation of NMDA-receptors dependent signaling pathways.

The blockade of the serotoninergic receptors 5-HT5A, 5-HT6 and 5-HT7 in the basolateral amygdala, but not in the hippocampus facilitate the extinction of fear memory.

Extinction is the learned inhibition of retrieval. It is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear-related pathologies such as post-traumatic stress disorder. The serotonin (5-HT) system is positioned to modulate the extinction circuitry via ascending 5-HT projections that innervate certain brain structures including the hippocampus and the basolateral amygdala (BLA). The most recently described serotoninergic receptors 5-HT5A, 5-HT6, 5-HT7 affect different memory processes and so are putative therapeutic targets for disorders related to cognition; however, their role in the extinction of contextual fear conditioning (CFC) has not been studied yet. Here we investigate the role of these receptors in the CA1 region of the hippocampus and the BLA in the extinction of CFC. For this, male rats were implanted with cannulae in the CA1 or in the BLA region through which they received immediately or 3 h after extinction training of CFC infusions of SB699551 (10 µg/side), 5-HT5A antagonist; WAY-208466 (0.04 µg/side), 5-HT6 agonist; SB-271046A (10 µg/side), 5-HT6 antagonist; AS-19 (5 µg/side), 5-HT7 agonist; SB-269970 (5 µg/side), 5-HT7 antagonist. After 24 h, animals were submitted to a 3 min extinction test. Results show that the infusion immediately after extinction training of 5-HT5A, 5-HT6 and 5-HT7 antagonists, and 3 h after extinction training of 5-HT5A and 5-HT7 antagonists in the BLA region, but not in CA1, facilitates the extinction of CFC memory.