ABSTRACT
The periaqueductal gray matter (PAG) is an essential structure involved in the elaboration of defensive responses, such as when facing predators and conspecific aggressors. Using a prey vs predator paradigm, we aimed to evaluate the PAG activation pattern evoked by unconditioned and conditioned fear situations. Adult male guinea pigs were confronted either by a Boa constrictor constrictor wild snake or by the aversive experimental context. After the behavioral test, the rodents were euthanized and the brain prepared for immunohistochemistry for Fos protein identification in different PAG columns. Although Fos-protein-labeled neurons were found in different PAG columns after both unconditioned and conditioned fear situations at the caudal level of the PAG, we found greater activation of the lateral column compared to the ventrolateral and dorsomedial columns after predator exposure. Moreover, the lateral column of the PAG showed higher Fos-labeled cells at the caudal level compared to the same area at the rostral level. The present results suggested that there are different activation patterns of PAG columns during unconditioned and conditioned fear in guinea pigs. It is possible to hypothesize that the recruitment of specific PAG columns depended on the nature of the threatening stimulus.
ABSTRACT
Fear memories are temporarily suppressed after repeated retrieval, a phenomenon known as memory extinction.How to reduce or even eliminate fear memory is the key to the treatment of fear related diseases such as post-traumatic stress disorder(PTSD). A single extinction training based on Pavlov's fear regulation task could only inhibit the expression of conditioned fear memory traces, but it could not eliminate the acquired conditioned fear memory. However, according to the reconsolidation theory based on memory, the retrieval-extinction paradigm has a more lasting effect on the erasure and rewriting of fear memory, and can effectively prevent the return of fear memory. Studies have shown that extraction-regression is closely related to a variety of neurotransmitter receptors such as glutamate receptor(GluR), dopamine receptor(DAR), L-type voltage-gated calcium channels(LVGCs) and cannabinoid. Moreover, its effect is closely related with factors such as retrieval-extinction memory stage. At present, most of the researches on extracted boundary conditions only stay at the level of behavior, with little understanding and exploration on the level of molecular mechanism. From the perspective of molecular neurobiology, with different stages of memory and different types of receptors and molecular mechanisms, this research reviewed the mechanisms of retrieval-extinction in recent years.It provided valuable signaling pathways, molecular targets and research directions for the treatment of fear-related diseases such as PTSD.
ABSTRACT
Objective:To compare the sedative and anti-anxiety effects of levo-tetrahydropalmatine (L-THP) and diazepam on conditioned fear model rats.Methods:According to the random number table method, 32 adult male rats were divided into blank group, model group, diazepam group and L-THP group(with 8 rats in each group). The conditioned fear model was reproduced by the plantar electric shock method. Four days after the modeling, the rats in diazepam group and L-THP group were given diazepam (3.6 mg/kg) and L-THP (25 mg/kg) were respectively gavaged once a day for 10 days, the rats in blank group and model group were given the same volume of saline. After the administration, the elevated plus maze test and the open field test were used to measure the anxiety behavior of the rats, and the sleep energy monitoring system was used to detect changes in sleep and energy-related indicators. SPSS 23.0 and Graphpad Prism 7.0 softwares were used for data analysis, multiple samples between groups were compared by one-way ANOVA, and LSD test was used for pairwise comparison.Results:The results of the elevated plus maze experiment showed that compared with the model group, the percentage of open-arm entry times ((11.27±8.78)%, (30.11±14.59)%, P<0.05) and the percentage of open-arm residence time ((1.94±1.48)%, (17.53±8.21)%, P<0.05) in diazepam group were all significantly increased. Compared with the model group, the open arm residence time, the percentage of open arm residence time and the percentage of open arm entry times in L-THP group showed an upward trend, but there was no statistical significance (all P>0.05). The results of the open field experiment showed that compared with the model group, the time of entering the central grid ((2.99±1.83) s, (6.94±3.52) s, P<0.05) and the time of entering the peripheral field ((297.01±1.83) s, (293.30±3.52) s, P<0.05) in diazepam group both increased. Compared with the model group, there was no significant difference in the changes of various indexes in L-THP group (all P>0.05). The results of locomotor activities showed that the autonomic activity times of model group in nighttime was significantly lower than that of blank group((758.79±375.37)times/h, (1 101.93±525.96)times/h, P<0.05). Compared with the model group, the number of autonomous activities of rats in L-THP group in daytime ((820.57±364.60) times/min, (502.40±228.54)times/min, P<0.05) decreased, and the number of autonomous activities in the nighttime ((758.79±375.37) times/min, (1 146.85±309.69)times/min, P<0.05) increased, but there was no significant change in the number of autonomous activities in the whole day. Correlation analysis of energy metabolism related indexes and sleep time of rats in each group were analyzed. The experimental results showed that the daytime sleep time were negatively correlated with heat value ( r=-0.335, P<0.05), and the night sleep time was positively correlated with daytime heat value ( r=0.352, P<0.05). Conclusion:L-tetrahydropalmatine has no significant anti-anxiety effect in the concentration range used in this study, but its sedative and improving sleep activity rhythm are better than diazepam.
ABSTRACT
Objective To investigate the effect of different extinction training on fear memory,DNA methylation protein and hippocampal newborn neurons in adult rats.Methods Male SD rats were randomly divided into four groups:naive group,conditioned fear group,traditional-extinction group and retrieval-extinction group.Conditioned fear models were established by tone paired foot shock,and retrieval-extinction training or traditional-extinction training were performed in adult rats.Retention test,Western blot and immunnohischemistry were used to detect the no-freezing time percentage,the DNA methylation protein level,the newborn neurons respectively at 1d,4d and 7d after different extinction training.Results The traditional-extinction group((28.06± 11.33) ％) or retrieval-extinction group((30.28± 11.48) ％) had higher percentage of no-freezing time than that of conditioned fear group((21.35±9.45) ％),and lower percentage of no-freezing time than that of naive group ((75.65±8.69)％) (t=2.204,2.517,7.955,7.023,all P＜0.05) at the fourth day after extinction training.At the seventh day after extinotion training,the retrieval-extinction group ((69.72±13.62)％) had higher percentage of no-freezing time than traditional-extinction group((24.27± 11.67)％,t=7.052,P＜0.01) or conditioned fear group((50.64± 12.51)％,t=2.451,P＜0.05),and showed no significant difference compared with naive group((72.03±9.36) ％,t=0.251,P＞0.05).The expressions of Dnmt-1 and MBD-2 in traditional-extinction group or retrieval-extinction group were lower than those in conditioned fear group,and higher than those in naive group (P＜0.05) at 4 d after extinction.training.At 7 d after extinction training,the expressions of Dnmt-1 and MBD-2 in retrieval-extinction group were lower than those in traditional-extinction group or conditioned fear group (P＜0.05),and there was no significant difference between retrieval-extinction group and naive group.The Brdu-positive cells of traditional-extinction group or retrieval-extinction training were higher than conditioned fear group,and less than naive group (P＜0.05) at the fourth day after extinction training.At the seventh day after extinction training,the Brdu-positive cells in retrieval-extinction group were higher than those in traditional-extinction group or conditioned fear group (P＜0.05),and there was no significant difference between retrieval-extinction group and naive group.Conclusion The extinction training can decrease fear memory of rats with conditioned fear memory,and the effect of retrieval-extinction training were better than traditional-extinction training,which may be associated with the increases of hippocampus newborn neurons and the decline of DNA methylation.
ABSTRACT
Post-traumatic stress disorder (PTSD) is a reactive mental disorder that occurs after an individual was exposed to a traumatic event,and the core of the treatment is the extinction of conditioned fear memory caused by stress.Fear memory is an incentive mechanism based on external stimuli that occupy a central position in the defense system.Traditional memory concept convinced that the original memory traces were in an unstable state when the memory was activated.This process is called memory reconsolidation.The research has proved the existence of the fear memory reconsolidation,but the specific mechanism of reconsolidation has not been clarified.The animal studies show that many brain sites and molecular mechanisms are involved in the process of fear memory reconsolidation.Understanding the underlying mechanisms of fear memory reconsolidation is conducive to the treatment of specific phobias and PTSD.This review summarized the brain structure and molecular mechanism of conditioned fear memory reconsolidation,providing a new direction for the in-depth study of conditioned fear memory reconsolidation and PTSD.
ABSTRACT
Post-traumatic stress disorder (PTSD) is a reactive mental disorder that occurs after an individual was exposed to a traumatic event,and the core of the treatment is the extinction of conditioned fear memory caused by stress.Fear memory is an incentive mechanism based on external stimuli that occupy a central position in the defense system.Traditional memory concept convinced that the original memory traces were in an unstable state when the memory was activated.This process is called memory reconsolidation.The research has proved the existence of the fear memory reconsolidation,but the specific mechanism of reconsolidation has not been clarified.The animal studies show that many brain sites and molecular mechanisms are involved in the process of fear memory reconsolidation.Understanding the underlying mechanisms of fear memory reconsolidation is conducive to the treatment of specific phobias and PTSD.This review summarized the brain structure and molecular mechanism of conditioned fear memory reconsolidation,providing a new direction for the in-depth study of conditioned fear memory reconsolidation and PTSD.
ABSTRACT
ObjectiveTo investigate the expression and activity of p38 mitogen-activated protein kinase (p38 MAPK)in hippocampus CA1 and CA3 area of rats with conditioned fear.Methods 24 h after rat model of conditioned fear was established,rats were sacrificed,then expression of p38 MAPK and phosphorylated p38 MAPK (Thr180/Tyr182) in hippocampus CA1 and CA3 area of rats were detected by western blot.ResultsCompared with control group ( ratios of value of gray scale were 1.0 ± 0.1 and 1.0 ± 0.2,respectively),expression of p38 MAPK and phosphorylated p38 MAPK (Thr180/Tyr182) in hippocarpus CA1 area of rats with conditioned fear (9.4 ± 2.6 and 7.8 ± 2.1,respectively) were significantly increased ( n =9,P ＜ 0.05 ).Compared with control group ( 2.1 ± 0.5 and 1.4 ± 0.5,respectively),expression of p38 MAPK and phosphorylated p38 MAPK (Thr180/Tyr182 ) in hippocampus CA3 area of rats with conditioned fear (6.2 ± 3.3 and 2.6 ± 0.6,respectively)were also significantly increased ( n =9,P ＜ 0.05 ).Conclusionp38 MAPK may play important role in the formation of long term memory of conditioned fear.
ABSTRACT
El Condicionamiento Pavloviano de Miedo es uno de los modelos preclínicos más comunes en el estudio del Trastorno de Estrés Post-traumático. El objetivo de la presente investigación consistió en utilizarlo como biomodelo para el estudio de las diferencias sexuales que caracterizan este síndrome, así como elaborar una descripción preliminar de las diferencias a lo largo de la trayectoria ontogenética. Se utilizaron 45 sujetos, de tres camadas diferentes de ratas ingenuas de ascendencia Wistar, 18 machos y 27 hembras, dos aproximadamente por camada para cada uno de los dos grupos experimentales: animales adolescentes y adultos. Los resultados señalan diferencias significativas en la segunda medición del estímulo condicionado en la interacción entre sexo y edad y al comparar las tres mediciones del estímulo condicionado. Se discuten los resultados en torno a las discrepancias en la literatura respecto al efecto de las variables evaluadas en la adquisición de miedo condicionado.
Pavlovian fear conditioning is one of the most popular preclinical models in the study of Post-Traumatic Stress Disorder (PTSD). The aim of the present research was explore the sex differences that characterize PTSD by means of this experimental paradigm, as well as to offer a preliminary description of how these sex differences behave throughout development. Forty five native rats, of Wistar descent were used as subjects, with 18 males and 27 females approximately balanced by litter across the two experimental groups: adolescents and adults. The results show significant differences in the second measurement of the conditioned stimulus in the interaction between sex and age and to compare the tree measurements of the conditioned stimulus. Results are discussed regarding the discrepancies in the literature regarding the effect of the variables evaluated in the acquisition of Conditioned fear.
ABSTRACT
Objective To investigate neurogenesis in the dentate gyrus of adult rat following conditioned fear stimulus.Methods 24 adult male rats were randomly divided into conditioned fear stimulus group and control group,and all rats were intraperitoneally injected bromodeoxyuridine(BrdU)3 days before conditioned fear stimuli.Animals in conditioned fear stimulus group were given monotone matching foot shock and made conditioned fear stimulus model,animals in control group only give monotone.Freezing time was detected before stimuli and 7th,14th days after stimuli,then rats were sacrificed 7th or 14th day after fear conditioned stimulus,and immunohistochemistry for Brdu was detected.Results Behavioral assessment showed that the percents of freezing time in conditioned fear stimulus group 7th,14th days after conditioned fear stimulus were significantly high(88.68%,91.33%)than those in control group(11.18%,14.23%,P<0.01)and before stimulus(24.11%,16.11%,P<0.01).Compared to control group(1567±28,580±5),Brdu positive cells in dentate gyrus of rat in conditioned fear stimulus group(1364±21,296±22)were decreased,and it reached to a statistical significance on 14th day (P<0.05).Conclusion The decreased neurogenesis in the dentate gyrus of adult rat following conditioned fear stimuli may have relation to fear and other emotion memory.
ABSTRACT
Objective To investigate the effects of 860MHz microwave on the formation and extinction of context conditioned fear in mice. Methods The mice were exposed to 860MHz continuous microwave ( power density were 380 μW/cm2 or 550 μW/cm2, respectively) for 30 min or 2 h, which then were divided in to 5 groups.Each group consisted of 15 animals. Footshocks were used to induce context conditioned fear by 75 voltages. The frequency and time of freezing after irradiation were investigated. Results When 24 h after foot shocking, the values of freezing time: control group was 2.31 ±4. 17 , two groups of the microwave irradiation 2 h were 3.93 ±6.99 and 2.47 ± 3.34, the Nemenyi test results (P = 0.004): control group was 32.63333, while two groups of the microwave irradiation 2 h were 52.46667 and 39.76667; and the values of freezing frequency: control group was 0.73 ± 1.16 , two groups of the microwave irradiation 2 h were 0.86 ± 1.41 and 1.07 ± 1.16, the Nemenyi test results of (P=0. 014): control group was 33. 26667, while two groups of the microwave irradiation 2 h were 50. 76667 and 40.90000. Conclusion The mice receiving relatively longer period of microwave irradiation showed more stable memory of the context conditioned fear.
ABSTRACT
Corticotropin-releasing factor(CRF) and neuropeptide Y(NPY) are known to play important roles in mediating stress responses and stress-related behavior. To elucidate the role of neuropeptides in response to the condition that had paired with traumatic event, we observed the changes of CRF and NPY by immunohistochemistry using a conditioned footshock paradigm. Male Sprague-Dawley rats were placed in a shuttle box and exposed to 20 pairings of a tone(< 70dB, 5sec) followed by a footshock(FS, 0.8mA, 1sec) over 60min. A second group was exposed to the tone-footshock pairings, returned to the homecage for 2days, and then reexposed to the test chamber and 20tones alone for 60min, prior to sacrifice. Control groups were : a) sacrificed without exposure to FS ; b) exposed to the tone-footshock pairings and then sacrificed two days later ; or c) exposed to the chamber and tones alone, returned to the homecage for 2days and then reexposed to the chamber and 20tones over 60min prior to sacrifice. CRF was increased in animals exposed to FS or the aversive condition(context and tone) that had paired to FS in bed nucleus of the stria terminalis (BNST) compared to the control. NPY was increased by FS in amygdala and PVN, but the condition previously associated with FS results in slight increase only in amygdala area. These results suggest that the BNST appears to be the mostly involved neural circuit in response to explicit cues previously paired with footshock. Moreover, this study raise the possibility that increased CRF peptide in the BNST in response to re-exposure to the aversive condition may underlie, in part, the experience of conditioned fear-related anxiety behavior.
Subject(s)
Animals , Humans , Male , Rats , Amygdala , Anxiety , Cues , Immunohistochemistry , Negotiating , Neuropeptides , Rats, Sprague-DawleyABSTRACT
σ receptors are particularly abundant in the CNS. σ receptors have been shown to exhibit such a wide variety of actions as modulating glutaminergic, dopaminergic and cholinergic neurotransmission. They also play an important role in maintaining cell growth and proliferation, learning and memory. Recent evidence suggests the possible involvement of σ receptors in the pathogenesis of schizophrenia. More researches are expected to supply new targets for treatment and diagnosis.
ABSTRACT
?receptors are particularly abundant in the CNS. ? receptors have been shown to exhibit such a wide variety of actions as modulating glutaminergic, dopaminergic and cholinergic neurotransmission. They also play an important role in maintaining cell growth and proliferation, learning and memory. Recent evidence suggests the possible involvement of ? receptors in the pathogenesis of schizophrenia. More researches are expected to supply new targets for treatment and diagnosis.