The conditional fear model is a process of studying the acquisition, storage, extraction, and regression of fear memory, and the important behavioral model of the central mechanism of these processes. This model procedure is based on typical Baprof conditional reflexes, in which animals are first subjected to a combination of aversive and neutral stimuli (US-CS), where aversive stimuli are unconditioned Stimulus (US, Such as electric shock), Neutral Stimulus (Conditioned Stimulus (CS), such as lighting, sound or training environment), when the animal is exposed to this neutral stimulus again, it will show a conditional fear reaction. However, if the conditional cues are repeatedly presented separately and do not match the aversive stimuli, the conditional fear response of the animal previously acquired to CS will gradually weaken, which is the regression of conditional fear (CS - no US). At present, the clinical application of conditional fear regression is mostly psychotherapy of Post-traumatic Stress Disorder (PTSD), that is, exposure therapy.
Most studies believe that repelling memory does not erase the link between the original CS and US, but instead creates a new conditional reflex between a CS and a US-free security environment. At present, the neurobiological mechanism of the formation of regressive memory is not fully understood. Recent studies have found that norepinephrine (NE) plays an important role in the long-term maintenance of memory regression, and its research progress is reviewed.
1 NE influence on regression memory
The NE cell signaling system plays an important role in the regulation of regressive memory learning. Early studies have found that in the evapotranspiration model, NE can increase the probability of success, while blocking β receptors can attenuate the formation of regressive memory, suggesting that NE increases regression memory learning through the beta receptor signaling system, and NE can enhance the regression by acting on the central nervous system, destroying the NE nerve projection of the blue spot or over-consumption of NE in the blue spot to inhibit its effect on regressive memory. However, inhibition does not work under certain conditions, suggesting that NE does not necessarily play a decisive role in regression memory learning, but only plays an enhanced role in CS-related CS changes, including reward memory. Model and fear memory model.
In recent years, studies have focused more on the regression of fear memory, and the results obtained by administering NE drugs before or after the fear memory subsided are reversed. Systemic injection of the beta blocker propranolol prior to regression training inhibited the subsequent regression of environmental fear memory, but did not work for clue fear memory. In the process of the decline of clue fear memory, propranolol can reduce the fear memory itself without affecting the effect of regression. In addition, yohimbine, an α2 receptor antagonist that promotes NE release, promotes regression in rats in a variety of settings and is dose-dependent, but has no effect on regression in the original environment [7], suggesting yohimbine It can enhance the learning of CS regression in animals. Our research team also recently found that the injection of NE in the dorsal hippocampal CA1 area in the late stage of fear memory consolidation can promote long-term maintenance of regressive memory.
The NE projection of the cerebral cortex is mainly caused by the tiny nuclei of blue nuclei, which are projected to the amygdala, hippocampus and the midbrain leaf cortex. These brain structures participate in the learning and arousal of regressive memory. Among them, the amygdala is involved in the acquisition of regressive memory, and the expression of regressive memory in the hippocampus control CS arouses the condition. The infralimbic Medial Prefrontal Cortex (IL-mPFC) plays an important role in the consolidation process of regressive memory, and then The retreating memory plays a role in evoking again. For example, in the process of regressing memory arousal, IL-mPFC neurons have transient high-frequency electrical activity. In addition, IL-mPFC inhibited the amygdala from projecting outward. Therefore, NE can regulate the learning and arousal of regressive memory through these brain structures.
Studies have shown that IL-mPFC is a key region for NE to regulate fear memory regression. Microinjection of propranolol in IL-mPFC before regression can reduce the regression effect, indicating that NE release around IL-mPFC plays an important role in the formation of regressive memory. In vitro cell assays have demonstrated that NE can increase the excitability of IL-mPFC neurons and act through the beta receptor and cyclic adenosine kinase. Therefore, increased beta activity in the process of regression can enhance fear memory regression. After remission training, the injection of propranolol in IL-mPFC had no effect on regressive memory. This result can be explained by the results of the study on blue plaque, which is the main nucleus of NE nerve projection in the brain. The blue-spotted neurons responded stepwise to the stimulus, and the greater the intensity, the greater the intensity of the stimulus. In fact, the blue-spotted neurons are very sensitive to the contingent changes in the stress intensity of the stimulus. During the process of regression, the stress intensity of the stimulation also changes from incident to failure. The change of the neural response process leads to the behavior of the experimental animals.
Variety. Therefore, the blue spot neurons respond strongly to CS at the beginning of the regression training. Studies have shown that the excitation of blue-spotted neurons in untrained animals exhibits an explosive response in the first few minutes of training, but when CS does not cause a US response, the excitability of neurons decreases. In the early stages of regression training, CS-induced release of blue spot NE is critical for the subsequent formation of regressive memory. However, in the later stages of regressive memory, NE release no longer stimulates the cell's NE signaling system and increases neuronal cell excitability and cell membrane plasticity.
2 Molecular mechanism of the noradrenergic system in regressive memory
The mechanism by which NE acts on regressive memory is to increase the excitability of neuronal cells and the synaptic plasticity of cells, and to increase the neuronal excitability of amygdala, hippocampus, and IL-mPFC through beta receptor and PKA pathways [20] . NE increases the excitability of cells and can affect receptor plasticity.
NE can activate beta receptors alone, but not enough to activate long-term potentiation (LTP) in hippocampus, but it can produce LTP under subthreshold stimulation. In addition, beta receptors can mediate AMCA receptor GluR1 phosphorylation, increase AMPA receptor insertion and LTP formation, and reduce the threshold for memory formation. In the amygdala, emotional memory can produce long-term neuronal excitability, which is the result of activation of the NE signaling system. Therefore, the reason for the enhancement of NE formation by NE is to increase the plasticity of related brain structure neuronal cells. CS can evoke the release of NE when the training is faded. NE can further activate the downstream cAMP cycle by activating the beta receptor, which activates the PKA pathway to regulate receptor plasticity. PKA promotes AMPA receptor opening through receptor phosphorylation and activation of ion channels, thereby activating transcription factor CREB, indirectly activated
MAPK channel that regulates gene transcription and translation. In IL-mPFC, transcription and translation of related genes affect the consolidation of regressive memory. In addition, this signal activation can promote synaptic regulation and the maintenance of regressive memory. Although there is clear evidence that NE activation of beta receptors increases the formation of regressive memory, there is also evidence that systemic injection of propranolol to block beta receptors does not impair regression. This is because the NE signaling system can increase neuronal cell excitability, but injection of propranolol alone does not alter neuronal excitability. In addition, the use of beta blockers alone has no effect on LTP production. Therefore, beta blockers can not interfere with the formation of memory, but early injection of NE can enhance memory.
3 Clinical research and application
Regression training is the most common means of treating pathological hyperresponsiveness in clinical practice. In the field of reward memory, conditional overreaction can lead to addiction. In the field of aversive memory, excessive reaction of conditional fear can lead to anxiety disorder. Regression training as cognitive behavioral therapy has been applied to human addiction treatment. However, in both human and animal trials, regressive memory did not achieve the desired effect in reducing recurrence. In addition, regression theory is the main treatment for many anxiety disorders, including phobia, panic disorder, social anxiety, obsessive-compulsive disorder, and post-traumatic stress disorder. Many drugs can affect the effect of regression training, and now summarize its clinical application research according to drug classification.
3.1 Adrenergic beta receptor antagonists Propranolol and atenolol are common beta receptor antagonists used to treat anxiety disorders. Many trials have shown that beta blockers are used to acutely treat anxiety caused by anxiety disorders and drug withdrawal. There is also some prima facie evidence that propranolol and prazosin are effective in the treatment of PTSD, but the symptoms are rapidly repeated after stopping taking the drug. Based on the aforementioned clinical studies, propranolol can be used in combination with regression training to treat chronic stress disorder and increase the effectiveness of regression training. Exposure to stress levels, high levels of NE release can cause excessive re-consolidation of traumatic memory, leading to PTSD. Therefore, studies have suggested that the use of Pulrol immediately after exposure to a traumatic environment can impede the consolidation of traumatic memory and thus prevent the production of PTSD. A randomized, double-blind, controlled study by Pitman et al found that the traumatic memory of the propranolol group was significantly reduced 1 month after trauma. At 3 months after trauma, the placebo group had significantly more memory of traumatic memory than that of propranolol. Group. Vaiva et al. studied the difference in trauma recalls after propranolol administration within 20 h after trauma in the emergency department. The prevalence of PTSD was significantly higher in the propranolol group (n = 11) than in the placebo group (8). Example) Low. Stein et al [compared with traumatic memory of propranolol (17 patients), gabapentin (14 patients) and placebo group (n = 17) within 48 hours after trauma, evaluated after 1, 4, and 8 months, and found no Any differences. Stein's trial did not find evidence that propranolol was effective, probably because of the limitations of the trial itself. Of the 569 patients, only 8% were willing to participate in the trial, and this high rejection rate led to trial bias. There have been trials investigating the fear response of patients with chronic stress disorder who were given propranolol immediately after exposure to a fearful environment. Bruâ€net et al found that in 9 patients with PTSD, pre-administering propranolol before arousing fear memory can significantly reduce the flashback of trauma-related fear memory after 1 week. Morton et al. studied four patients with social anxiety disorder, and four patients received propranolol, benzodiazepine, placebo, and a blank control. Compared with baseline, 4 patients had a decrease in related anxiety symptoms on the first day after treatment. However, on the second day, the differences between the different groups disappeared. The study concluded that propranolol can increase the learning of regressive memory, but it can not increase or inhibit the subsequent regressive memory arousal.
3.2 Glucocorticoids Glucocorticoids can also enhance memory consolidation. Beta blockers inhibit the memory enhancement of glucocorticoids, and glucocorticoids act through the beta receptor and PKA signaling pathways. Glucocorticoids act on noradrenergic neurotransmitters that project on the basolateral amygdala nucleus to increase noradrenergic neurotransmitters. In addition, glucocorticoids increase the sensitivity of the NE signaling system by activating intracellular cAMP-PKA signaling. Studies have shown that glucocorticoids have the same effects as propranolol. In social phobia patients, glucocorticoids can be administered before exposure to fear cues to reduce fear response. Intravenous administration of cortisol during stress can reduce subsequent PTSD symptoms. Corticosterone or placebo was given to spider phobia before exposure to spider images, and the fear response in the corticosterone group was found to be significantly lower in the follow-up test than in the placebo group. Therefore, corticosterone can reduce anxiety and increase the maintenance of regressive memory in exposure therapy.
3.3 Adrenergic drugs Previous studies have shown that yohimbine is an anxiety symptom that can cause anxiety disorders. For example, yohimbine can cause pain symptoms in patients with PTSD and pain disorders. Cain et al found that Yohimbe can delay the decline of fear memory. The Power team studied the role of yohimbine in claustrophobia. Yohimbine (12 patients) and placebo (12 patients) were given 1 h before remission training. In the remission training, both groups had lower anxiety symptoms. In subsequent tests, the yohimbine group had a more pronounced reduction in claustrophobia and anxiety symptoms than the placebo group.
4 Summary
The aforementioned clinical studies and basic research have shown that NE's theory of regulating regressive memory has two methods for clinical treatment of anxiety disorders. The first system, through the systemic injection of the beta blocker propranolol, reduces the activity of the NE signaling pathway and reduces anxiety symptoms when exposed to fear-related environments. Administration of propranolol immediately after a traumatic event can promote rapid recovery of symptoms and reduce the incidence of PTSD. Administration of propranolol immediately after activation of traumatic memory in patients with chronic PTSD reduces anxiety from traumatic memory. Administration of propranolol prior to regression training reduces anxiety symptoms in regressive training and reduces anxiety symptoms in the absence of medication. Acute high doses of glucocorticoids can reduce the anxiety caused by the fear environment, hinder the development of PTSD, and increase the success rate of regression training. The second way is to increase NE levels by systemic injection of yohimbine to regulate NE system activity. Yohimbine can increase anxiety levels, especially in patients with pain disorders and PTSD, often leading to pain and flashback. Therefore, combined yohimbine and regression training can increase the therapeutic effect. Giving yohimbine before remission training can increase fear memory regression, and it is also effective to give NE immediately after remission training, suggesting that NE can enhance the consolidation of regressive memory. At present, although yohimbine may have its clinical application as a drug method, its clinical trials have not been carried out in large numbers. Because clinical regression training can not be carried out as planned, and the level of anxiety may be higher than expected, resulting in patients requiring repeated continuous treatment, or patients with repeated anxiety reduction, the failure to successfully resolve. The limitation of clinical research is that it is impossible to ensure the success of regression in the regression training, and thus it is impossible to confirm whether the drug is effective.
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