Repetitive transcranial magnetic stimulation ameliorates anxiety-like behavior and impaired sensorimotor gating in a rat model of post-traumatic stress disorder

Abstract

Background: Repetitive transcranial magnetic stimulation (rTMS) has been employed for decades as a non-pharmacologic treatment for post-traumatic stress disorder (PTSD). Although a link has been suggested between PTSD and impaired sensorimotor gating (SG), studies assessing the effects of rTMS against PTSD or PTSD with impaired SG are scarce.

Aim: To assess the benefit of rTMS in a rat model of PTSD.

Methods: Using a modified single prolonged stress (SPS&S) rat model of PTSD, behavioral parameters were acquired using open field test (OFT), elevated plus maze test (EPMT), and prepulse inhibition trial (PPI), with or without 7 days of high frequency (10Hz) rTMS treatment of SPS&S rats.

Results: Anxiety-like behavior, impaired SG and increased plasma level of cortisol were observed in SPS&S animals after stress for a prolonged time. Interestingly, rTMS administered immediately after stress prevented those impairment.

Conclusion: Stress-induced anxiety-like behavior, increased plasma level of cortisol and impaired PPI occur after stress and high-frequency rTMS has the potential to ameliorate this behavior, suggesting that high frequency rTMS should be further evaluated for its use as a method for preventing PTSD.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Study design.

(A) The animals (no SPS&S) were submitted to a behavioral test 1 day after stress induction in other groups, together with the SPS&S 1 d group. Behavioral test were carried out with SPS&S 7 d and SPS&S 14 d, 7 and 14 days after SPS&S stress induction; (B) After SPS&S and control administered, the rats treated with rTMS for 7 days, then the behavioral tests were given and part of rats were sacrificed for the plasma CORT test and Western blot; The remaining rats were submitted to the behavioral tests and then sacrificed for the plasma CORT test and Western blot 7 days later.

Fig 2. Spontaneous locomotor activity in a rat model of PTSD.

Total distance of movement (A), time of central movement (B), distance and time of central movement relative to overall levels (%) values (C, D). Data are expressed as mean ± standard error of the mean (SEM) (n = 12 per group). *P < 0.05 vs. control.

Fig 3. Behavior of approach-avoidance conflict in a rat model of PTSD.

Time spent in open arms (A), number of entries into open arms (B) and their relative to overall levels (%) values (C, D) tested in the elevated plus maze. Data are expressed as mean ± SEM (n = 12 per group). *P < 0.05 vs. control.

Fig 4. Sensorimotor gating in a rat model of PTSD.

%PPI (Prepulse inhibition (%)) among four groups (n = 12 per group). Mean ± SEM of %PPI by prepulses with different intensities (72, 76, and 82 dB) and calculated all over the three prepulse intensities in each group (Av.PPI is average of total 70–82 dB %PPI in each group).*P < 0.05.

Fig 5. Effect of rTMS on spontaneous locomotor activity in a rat model of PTSD.

Distance of central movement and Time of central movement in absolute after SPS&S treatment for 7 day (A, B) or 14 day (E, F) and relative to overall levels (%) values after SPS&S treatment for 7 day (C, D) or 14 day (G, H) tested in open field. Data are expressed as mean ± SEM (n = 10 per group). *P< 0.05 vs. control or SPS&S + rTMS group.

Fig 6. Effect of rTMS on behavior of approach-avoidance conflict in a rat model of PTSD.

Time spent in open arms and number of entries into open arms in absolute after SPS&S treatment for 7 day (A, B) or 14 day (E, F) and relative to overall levels (%) values after SPS&S treatment for 7 day (C, D) or 14 day (G, H) tested in the elevated plus maze. Data are expressed as mean ± SEM (n = 10 per group). *P< 0.05 vs. control or SPS&S + rTMS group.

Fig 7. Effect of rTMS on sensorimotor gating in a rat model of PTSD.

%PPI among four groups after SPS&S treatment for 7 day (A) or 14 day (B). Mean ± SEM of %PPI by prepulses with different intensities (72, 76, and 82 dB) and calculated over all three prepulse intensities in each group (Av. PPI is the average of total 70–82dB %PPI in each group). *P < 0.05.

Fig 8. Effect of rTMS on the expression of c-fos and glucocorticoid receptor (GR) in the mPFC and the plasma level of cortisol.

Representative bands (A) and the densitometric analysis (B, C) for the protein expression of c-fos and GR and the plasma level of CORT (D) at SPS&S 7 d and SPS&S 14 d. **P < 0.01, *P < 0.05, #P < 0.01 vs. control or rTMS group, ▲P < 0.05 vs. control.