Behavioral and molecular effects of sodium butyrate in the prefrontal cortex of mice exposed to a model of post-traumatic stress disorder

Author(s)

Arthur Alves Coelho

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2024-04-12

Examining board members

Sabrina Francesca de Souza Lisboa; Christie Ramos Andrade Leite Panissi; Cristina Aparecida Jark Stern

• Advisor: Sabrina Francesca de Souza Lisboa

Abstract

Exposure to intense stressors can induce neuropsychiatric disorders, notably post-traumatic stress disorder (PTSD). In PTSD, impairment in fear extinction memory is a key factor, and activation of the endocannabinoid system, particularly CB1 receptors, facilitates the extinction of these memories in animal models and humans. There is also evidence that epigenetic mechanisms are involved in PTSD. Stress activates histone deacetylase enzymes (HDACs), and alterations in histone acetylation, resulting from increased activity of these enzymes, can modulate the expression of endocannabinoid system mediators. HDAC enzymes can be pharmacologically modulated, such as by sodium butyrate (NaB). In this study, we investigated whether NaB administered during stress prevents long-term effects on contextual fear conditioning memory, as well as on anxiety-like and social avoidance behaviors. Therefore, different doses of NaB (25, 50, and 100 mg/kg) were systemically administered to mice 30 minutes before each session of the repeated social defeat stress (RSDS) protocol (6 days, 2 hours/day). The animals were then subjected to behavioral tests, including the open field test (OFT) and the social avoidance test (SAT) on the day following the end of RSDS, and the contextual fear conditioning test (CFC), one week later. The results indicated that RSDS induced hypolocomotion in the OFT, and impairment of fear extinction in the CFC. Furthermore, an increase in overall emotionality and a higher proportion of emotionally affected animals were observed in the stress group compared to naïve animals. Additionally, administration of NaB at doses of 25 and 50 mg/kg intensified the hypolocomotion induced by RSDS in the OFT. However, the dose of 50 mg/kg attenuated the impairment in fear extinction in the CFC, and there was a tendency towards reducing overall emotionality, as well as reducing the proportion of emotionally affected animals. In non-stressed animals, NaB at a dose of 50 mg/kg induced an anxiolytic effect without affecting locomotion in the OFT but did not alter behaviors observed in the SAT and CFC. At the molecular level, RSDS increased protein expression of HDAC3 and CB2 in the cytoplasmic fraction of the prefrontal cortex, while NaB reduced the expression of HDAC1 (independent of RSDS) and CB2 (RSDS-dependent). No changes were observed in the expression of HDAC2, HDAC4, CB1, TRPV1, NAPE-PLD, and FAAH in any of the cellular fractions. These findings suggest that the effect of NaB may be through inhibition of cytoplasmic HDACs, possibly through non-epigenetic pathways involving modulation of GPCRs, immune factors, and the microbiota. However, further studies are needed to confirm these conclusions and to better understand the underlying mechanisms of the behavioral response to RSDS and treatment with NaB. (AU)

• FAPESP's process: 21/01656-3 - Evaluation of the involvement of histone acetylation in behavioral changes and in the endocannabinoid system after exposure to trauma in mice
• Grantee: Arthur Alves Coelho
• Support Opportunities: Scholarships in Brazil - Master