ABSTRACT
The paraventricular nucleus of the thalamus (PVT), which serves as a hub, receives dense projections from the medial prefrontal cortex (mPFC) and projects to the lateral division of central amygdala (CeL). The infralimbic (IL) cortex plays a crucial role in encoding and recalling fear extinction memory. Here, we found that neurons in the PVT and IL were strongly activated during fear extinction retrieval. Silencing PVT neurons inhibited extinction retrieval at recent time point (24 h after extinction), while activating them promoted extinction retrieval at remote time point (7 d after extinction), suggesting a critical role of the PVT in extinction retrieval. In the mPFC-PVT circuit, projections from IL rather than prelimbic cortex to the PVT were dominant, and disrupting the IL-PVT projection suppressed extinction retrieval. Moreover, the axons of PVT neurons preferentially projected to the CeL. Silencing the PVT-CeL circuit also suppressed extinction retrieval. Together, our findings reveal a new neural circuit for fear extinction retrieval outside the classical IL-amygdala circuit.
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Objective To investigate the effect and mechanism of suberoylanilide hydroxamic acid (SAHA) on the fear extinction in mice with chronic social defeat stress (SD). Methods Fifty-six male C57BL/6J mice aged 7-8 weeks were randomly divided into control group,social defeat group,control-SAHA group and social defeat-SAHA group to investigate the effect of SAHA and social defeat group,social defeat-AAV BDNF group and social defeat-AAV blank group to investigate the effect of BDNF. Fear extinction in mice was evaluated by fear conditioning test (FC). The levels of BDNF and HDAC2 in mice hippocampus were detected by Western blot (WB). The expression of BDNF-overexpressing virus in hippocampus of mice was detected by immunofluorescence assay. Results (1) Compared with control group,fear extinction in the social defeat group was significantly decreased (P<0. 05). Compared with control group, the level of HDAC2(0. 50±0. 02) in the social defeat group was significantly increased (P<0. 001),while the level of BDNF(0. 16 ± 0. 03) was significantly decreased (P<0. 001) in the social defeat group. ( 2) After using SAHA,fear extinction of mice significantly improved (P<0. 05). Compared with control group,the level of HDAC2 (0. 26±0. 02) in the control-SAHA group was significantly decreased(P<0. 001),and the level of BDNF (0. 40±0. 03) was significantly increased (P<0. 001). Compared with social defeat group,the level of HDAC2 (0. 39±0. 03) in the social defeat-SAHA group was significantly decreased (P<0. 001),and the lev-el of BDNF (0. 28±0. 01) was significantly increased (P<0. 001). (3)After injection BDNF-overexpressing virus,fear extinction was significantly improved(P<0. 05). Conclusion SAHA can enhance fear extinction in mice with chronic social defeat stress and its mechanism may be related to the up-regulation of BDNF ex-pression in hippocampus by inhibiting HDAC2 in hippocampal.
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Dept of Physiology, School of Basic Medical Sciences, Bitehou Medical University, Yantai Shandong 264003, China Aim To explore the behavior and CBS/H2S levels in infralimbic (IL) medial prefrontal cortex (mPFC) in conditioned fear rats and study the effect of exogenous H2S on conditioned fear extinction of rats and the related mechanism. Methods The rat conditioned fear model was established with sound pairing with an aversive foot shock. Later the repeated single sound was used for extinction training. CBS/H2S con-tent in IL tissues was measured using Western blot and methylene blue method. In vivo extracellular single u-nit recordings were used to examine the frequency of spontaneous discharges of IL neurons. Results 1. CBS/H2S level in IL tissues of conditioned fear model (control group) decreased (P <0. 01) and the freezing level was aggravated (P < 0. 01) , while after extinction training CBS/H2 S level increased (P < 0.01, P < 0. 05) and the freezing level was alleviated (P < 0.01). 2. Freezing level decreased in NaHS group compared with extinction group (P <0. 01) . 3. L-cys-teine increased the frequency of spontaneous discharges of IL neurons (P < 0. 01). Conclusions Learning and memory ability decreases in PTSD model rats owing to the inhibition of CBS/H2S content in IL tissues. The mechanism of behavior improvement of H2S on PTSD model rats may be related to the excitation of H2S on frequency of spontaneous discharges of IL neurons.
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Objective To investigate the effects of nitric oxide synthase inhibitor L-NAME on two tone fear extinction design in rats.Methods In AAA design,the rats received fear conditioning,extinction training and extinction test in the same context.In AAB design,the rats received fear conditioning and extinction training in context A,extinction test in context B.In each task,40 male rats were randomly divided into 4 groups (n =10 per group),and L-NAME(10,20 and 40 mg/kg) or saline was injected intraperitoneally (i.p) 30 min prior to extinction training.Percent freezing was used as an index for fear memory during extinction test phases.Further experiments were used to test state-dependency effects or nonspecific changes of locomotor activity that followed L-NAME injection.Results In AAA design,percent freezing was (27.42 ± 6.52) ％ in saline group,and (30.83 ±7.15) ％,(32.49 ± 8.55) ％,(38.94 ± 11.48) ％ in 10,20,40 mg/kg L-NAME group respectively.There was no significant difference in the level of percent freezing among the four groups (P＞0.05).In AAB design,percent freezing was (30.32 ± 6.15) ％ in saline group,and (32.83 ± 6.64) ％,(39.49 ± 8.74) ％,(49.94 ± 10.83) ％in 10,20,40 mg/kg L-NAME group respectively.Compared with saline,only rats with L-NAME 40 mg/kg showed more levels of freezing (P ＜0.01).In state-dependency effects test,compared with Sal-Sal group ((26.73 ±5.62) ％) which received both saline injections 30 min before extinction training and extinction test,respectively,both NAME-Sal group((48.44 ± 10.46) ％) and NAME-NAME group((61.25 ± 13.24) ％) showed more levels of freezing (P＜0.01,respectively).Conclusion These results show that L-NAME produces a task-dependent impairment of fear extinction,and implies that nitric oxide signaling is involved in memory process of certain extinction tasks.
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ObjectiveTo study the effect of music exposure in juvenile stage on anxiety-like behavior and fear extinction in adult rats.Methods4 broods of two-week-old healthy Sprague-Dawleyda rats were separated into two groups randomly.The music groups were exposed to music from 20:00 to 22:00 for 21 consecutive days.When the rats were 5 weeks old,they were caged by sex,with 8 male rats and 6 female rats in each group.When the rats were 8 weeks old,the two groups were assessed in the elevated-plus maze test,the open-field test,trained and assessed by the conditional fear training and fear extinction training.ResultsIn the elevated-plus maze test:Prior to the foot shock,the percent of time spent in the open arms in the music group (female(7.07 ± 1.14)％,male (5.12 ± 1.95 ) ％ ) exhibited no significant difference (P＞ 0.05 ) comparing with the rats in the control group (female (4.65 ± 0.86 ) ％,male ( 4.86 ± 1.95 ) ％ ).After the foot shock,the percent of time spent in the open arms in the music group ( female ( 8.63 ± 3.35 ) ％,male ( 7.79 ± 2.49 ) ％ ) increased comparing to the control group (female(1.48 ±0.11)％,male(4.29 ± 1.68)％) (P＜0.01). In the open-field test:prior to the foot shock,the percent of time spent in the center zone of the music group ( female (6.16 ± 2.17 ) ％,male (6.25 ±3.47) ％ ) exhibited no significant difference (P＞ 0.05) comparing with the rats in control group (female(5.27 ±1.95 )％,male (6.22 ± 3.13 )％ ).After the foot shock,the percent of time spent in the center zone in the music group (female(8.52 ± 1.93) ％,male (6.95 ± 2.46 ) ％ ) was larger than the control group ( female ( 3.47 ±0.93 ) ％,male (4.36 ± 2.22 ) ％ ) (P ＜ 0.05 ).The fear extinction training showed that the percent of freezing time exhibited no significant difference between the male and female rats of the music group and control group in the first block of the first extinction training day and the percentage of freezing time of female rats in music group was significantly lower than that of female rats in control group on the third extinction training day.The percentage of freezing time of male rats in the music group was significantly lower than that of male rats in control group on the second and third training day.ConclusionMusic exposure in juvenile stage decreases the anxiety level after foot shock,and promotes the long-term fear extinction,while has no effect on the level of fear memory.
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Objective To investigate the change of cyclin-dependent kinase 5(CDK5)during 1 week after conditioned fear extinction.Methods Forty-two male adult SD rats were randomly divided into native group,extinction control group and 24h extinction group.Extinction retention test and immunohistochemistry of CDK5 of hippocampus were done at 1st,3rd,7th day after fear extinction.The numbers of CDK5 positive cell in hippocam-pus CAI was measured by computer analytic system.Results (1)Extinction retention scores were increasedgradually in extinction group compared with native group(75.60±2.51)%,the scores of extinction control group was decreased at 1st day(15.62±10.28)% and 3th day(20.58±7.79)% after extinction(P＜0.01);24h extinction group(71.04±11.65)% were better than extinction control group(35.48±12.37)at 7th day after extinction(P＜0.01).(2)The number of CDK5 positive cell was increased significantly in 24h extinction group (24.94±5.20;32.25±6.14;33.28±6.56)compared with native group(75.60±2.51;P＜0.01).In 24h extinction group the number was increased significantly at 3rd day(P＜0.01)and 7th day(P＜0.05)compared with extinction control group(25.09±4.83;26.70±4.57),and decreased at 1st day compared to 3rd day(P＜0.05)and 7th day(P＜0.01).Conclusion From 1st to 7th day after extinction,CDK5 may contribute to the retention of fear extinction in hippocampal CA1.