Exploration Of An Animal Model For Fear Memory Generalization And The Regulatory Role Of Dopamine D3 Receptor

Being able to correctly identify sensory stimuli related to safety and threats is crucial for individuals to make appropriate behavioral decisions.If the learned fear is extended to clues unrelated to or similar to harmful stimuli,or the fear response to stimuli cannot be avoided under safe conditions,it will not only seriously affect social functions and daily life,but also damage physical and mental health,and even lead to anxiety related disorders with fear generalization as the core feature,such as generalized anxiety disorder,obsessive-compulsive disorder,post-traumatic stress disorder,etc.At present,the relationship between dopamine D3 receptor and addiction and anxiety symptoms has been studied,because fear generalization is the core symptom of anxiety diseases,and has a long-term nature.Therefore,it is very important to explore the regulatory role of dopamine D3 receptor on fear discrimination learning,long-term fear memory generalization and anxiety-like symptoms,and to find the predictive indicators and intervention methods for the degree of fear generalization in the later stage.METHODS:In this study,the stress model of plantar electric shock was first used to establish a conditioned animal model of discriminative fear.One auditory stimulus(CS+)is matched with one aversive stimulus(US),and the other acoustic stimulus(CS-)is presented as a safety signal.Through randomized presentation,the mice were trained to discriminate fear.The rigidity behavior of rodents was measured to evaluate the level of conditional fear response.The study used low intensity shock 0.3m A and high intensity shock 1.0m A for training to explore the impact of shock intensity on fear discrimination learning.Using the randomized clue presentation method,the study conducted 5 times of shock and CS+ matching training,10 times of CS-no match training with shock.On the basis of the establishment of the discriminative fear conditioning model,a long-term retention mouse model of fear memory generalization was further established to explore the level of fear generalization and the retention of fear memory of different sound frequencies in mice of different treatment groups at different test times.In the test of fear memory generalization,five pure tone stimuli with different frequencies,including CS+ and CS-,were randomly presented,with frequencies of 9k/6.2k/4.2k/2.9k/2k Hz,respectively,to quantify the animal’s defense response by testing the level of stiffness response.Results:The continuous presentation of safety signals seems to be regarded as a reward,and there is a certain phenomenon of fear regression.Compared with the control group,the level of fear reaction to CS-in1.0m A*YQA14 group increased.The level of fear response to CS+ in almost all groups was higher than that of the adjacent fear response to CS-,indicating that under the experimental procedure set up in this time,mice learned to distinguish between safety signals and fear clues.The effects of stress intensity,dopamine D3 receptor,sound frequency and test time on the generalization of fear memory were studied by analyzing the percentage of rigidity response of mice to each sound frequency.The results showed that YQA14 had a significant effect on the percentage of freedom of 4.2k Hz sound frequency in Day1 mice,and the fear response of YQA14 mice was stronger than that of normal saline mice.However,YQA14 has no significant effect on the fear generalization test of Day14 and 28 on mice in different treatment groups.Different stress intensities have significant differences in the fear response of Day1,14,and 28 mice to various sound frequencies.The percentage of free zing response of 1.0m A shock group mice is higher than that of 0.3m A shock group mice.There is a significant interaction between the shock intensity and the generalized test time.With the extension of the interval between training and test,the rigidity response of the 0.3m A shock group mice is limited to the sound cues(CS+)directly related to the threat information,while the 1.0m A shock group mice have a generalized fear generalization phenomenon.The interaction between generalization test time and sound frequency is significant.With the extension of the time between stress and test,the generalization gradient developed from gentle to steep.In addition,there is a significant correlation between the percentage of freedom at 2.9k Hz in the Day1 fear generalization test and the fear response of mice to sounds at various frequencies in the Day14 and 28 generalization test.Therefore,it is the best early identification sign.Conclusion:This study explored the animal model of fear generalization and established a mouse model of fear conditioned discrimination learning and long-term maintenance of fear generalization.Among them,strong electric shocks can trigger higher fear responses,and are more likely to lead to fear memory generalization and anxiety like symptoms.The interval between training and testing,as well as the physical similarity of stimuli,can have a significant impact on fear generalization.Dopamine D3 receptor antagonists may play a role in discriminative learning,but their effect is not significant in the long-term maintenance of fear generalization.In addition,the level of stiffness response to 2.9k Hz within 24 hours after stress can serve as an early identification indicator for generalization.