Hippocampal CCR5/RANTES Elevations in a Rodent Model of Post-Traumatic Stress Disorder: Maraviroc (a CCR5 Antagonist) Increases Corticosterone Levels and Enhances Fear Memory Consolidation

Abstract

Background: Contextual fear conditioning (CFC) is a rodent model that induces a high and long-lasting level of conditioning associated with traumatic memory formation; this behavioral paradigm resembles many characteristics of posttraumatic stress disorder (PSTD). Chemokines (chemotactic cytokines) play a known role in neuronal migration and neurodegeneration but their role in cognition is not totally elucidated. Aim: We ascertain whether CCR5/RANTES beta chemokines (hippocampus/prefrontal cortex) could play a role in fear memory consolidation (CFC paradigm). We also evaluated whether chronic stress restraint (21 days of restraint, 6-h/day) could regulate levels of these beta chemokines in CFC-trained rats; fear memory retention was determined taking the level of freezing (context and tone) by the animals as an index of fear memory consolidation 24 h after CFC training session; these chemokines (CCR5/RANTES) and IL-6 levels were measured in the hippocampus and prefrontal cortex of chronically stressed rats, 24 h after CFC post-training, and compared with undisturbed CFC-trained rats (Experiment 1). In Experiment 2, rats received 1 mA of footshock during the CFC training session and fear memory consolidation was evaluated at 12 and 24 h after CFC training sessions. We evaluated whether RANTES levels could be differentially regulated at 12 and 24 h after CFC training; in Experiment 3, maraviroc was administered to rats (i.m: 100 mg/Kg, a CCR5 antagonist) before CFC training. These rats were not subjected to chronic stress restraint. We evaluated whether CCR5 blockade before CFC training could increase corticosterone, RANTES, or IL-6 levels and affects fear memory consolidation in the rats 24-h post-testing compared with vehicle CFC-trained rats. Results: Elevations of CCR5/RANTES chemokine levels in the hippocampus could have contributed to fear memory consolidation (24 h post-training) and chronic stress restraint did not affect these chemokines in the hippocampus; there were no significant differences in CCR5/RANTES levels between stressed and control rats in the prefrontal cortex (Experiment 1). In Experiment 2, hippocampal CCR5/RANTES levels increased and enhanced fear memory consolidation was observed 12 and 24 h after CFC training sessions with 1 mA of footshock. Increased corticosterone and CCR5/RANTES levels, as well as a higher freezing percentage to the context, were found at 24 h CFC post-testing in maraviroc-treated rats as compared to vehicle-treated animals (experiment-3). Conversely, IL-6 is not affected by maraviroc treatment in CFC training. Conclusion. Our findings suggest a role for a hippocampal CCR5/RANTES axis in contextual fear memory consolidation; in fact, RANTES levels increased at 12 and 24 h after CFC training. When CCR5 was blocked by maraviroc before CFC training, RANTES (hippocampus), corticosterone levels, and fear memory consolidation were greater than in vehicle CFC-trained rats 24 h after the CFC session.

Effects of Septin-14 Gene Deletion on Adult Cognitive/Emotional Behavior

“…Interestingly, male and female SEPT14 KO mice, in fact, had lower observational learning trial-stimulated CORT secretion as compared to their same-sex WT mice. These findings imply that SEPT14 KO may impede observational fear conditioning magnitude by attenuating animals' CORT secretion-related attention to demonstrators' experiences and/or CORT secretion-related memory consolidation ( Lesuis et al, 2018;de Tommaso et al, 2019;Merino et al, 2020). Accordingly, the causative relationship between Septin-14 intactness and attention-coordinating prefrontal cortex (Wulaer et al, 2020) and memory consolidation-related hippocampus (Keller et al, 2015) throughout development deserves further study.…”

Targeting C–C Chemokine Receptor 5: Key to Opening the Neurorehabilitation Window After Ischemic Stroke

“…As a strong inhibitor of hippocampal and cortical plasticity, CCR5 affects the MAPK/CREB signaling pathway to influence learning and memory. During learning, MAPK and CREB levels are enhanced after CCR5 antagonist use, region-specific viral knockdown, or CCR5 knockout, whereas transgenic mice that overexpress CCR5 in excitatory neurons display learning and memory deficits ( Zhou et al, 2016 ; Merino et al, 2020 ). The transcription factor CREB in neurons promotes long-term potentiation and enhances synaptic plasticity.…”

Cellular, synaptic, and network effects of chemokines in the central nervous system and their implications to behavior

“…Increasing evidence has indicated the role of another chemokine receptor, CCR5, in cognitive functions (Table 3 ). While the activation or overexpression of CCR5 was reported to impair the hippocampal and cortical neuronal plasticity, leading to deficits in learning and memory [ 162 ], both genetic depletion and pharmacological inhibition of CCR5 was shown to enhance memory in rats [ 165 ], as measured by both fear-conditioning (contextual learning) and Morris water maze (spatial learning, see Table 3 ).…”