Molecular mechanisms of fear learning and memory

Pavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias.     

杏仁复合体β受体参与条件性恐惧记忆

杏仁复合体是条件性恐惧记忆形成和储存的关键脑区。杏仁复合体β受体参与条件性恐惧记忆的巩固。β受体激活易化杏仁复合体内突触传递的长时程增强,增强条件性恐惧记忆的巩固;而阻断β受体则抑制杏仁复合体内突触传递的长时程增强,损害条件性恐惧记忆的巩固。     

Mice lacking synapsin III show abnormalities in explicit memory and conditioned fear

Synapsin III is a neuron‐specific phosphoprotein that plays an important role in synaptic transmission and neural development. While synapsin III is abundant in embryonic brain, expression of the protein in adults is reduced and limited primarily to the hippocampus, olfactory bulb and cerebral cortex. Given the specificity of synapsin III to these brain areas and because it plays a role in neurogenesis in the dentate gyrus, we investigated whether it may affect learning and memory processes in mice. To address this point, synapsin III knockout mice were examined in a general behavioral screen, several tests to assess learning and memory function, and conditioned fear. Mutant animals displayed no anomalies in sensory and motor function or in anxiety‐ and depressive‐like behaviors. Although mutants showed minor alterations in the Morris water maze, they were deficient in object recognition 24 h and 10 days after training and in social transmission of food preference at 20 min and 24 h. In addition, mutants displayed abnormal responses in contextual and cued fear conditioning when tested 1 or 24 h after conditioning. The synapsin III knockout mice also showed aberrant responses in fear‐potentiated startle. As synapsin III protein is decreased in schizophrenic brain and because the mutant mice do not harbor obvious anatomical deficits or neurological disorders, these mutants may represent a unique neurodevelopmental model for dissecting the molecular pathways that are related to certain aspects of schizophrenia and related disorders.     

利用正交试验优化建立大鼠条件恐惧记忆模型

目的 利用正交试验,优化建立大鼠条件恐惧记忆模型的最佳实验参数,寻找最佳试验条件。方法利用巴普洛夫条件恐惧原理,建立大鼠条件恐惧记忆模型;采用3因素3水平的正交试验设计,以模型建立24h后大鼠木僵反应时间为指标,观察不同参数条件下恐惧记忆的表达情况,确定最佳试验条件。以优选的实验条件建立条件恐惧记忆模型,并于24h、1周、2周、4周和8周后进行恐惧记忆保持检测。结果 直观分析结果表明,各因素影响能力依次为声音强度=循环次数>电击强度;方差分析结果表明,循环次数对实验结果有显著影响(P<0.05),声音强度和电击强度影响不显著(P>0.05)。确定最优实验条件为:声音75dB,电击0.8mA,循环15次。在模型建立24h和1周时,大鼠恐惧记忆保持良好,与对照组比较差异有显著性(P<0.001和P<0.05);第2周后恐惧记忆逐渐消退,与对照组比较差异无显著性(P>0.05)。结论 本实验明确了大鼠条件恐惧记忆模型影响因素的主次,优化了实验条件,为模型的标准化、规范化及后续研究提供了可借鉴的实验的依据。     

外侧杏仁核在恐惧性条件化学习和记忆中的作用

恐惧性条件化学习的行为范式是研究情绪信息编码和储存的神经生物学机制的一个重要手段。杏仁核,尤其是外侧杏仁核(lateral nucleus of amygdala,LA),在恐惧性条件化的建立、恐惧信息的表达,以及恐惧性事件信息的存贮过程中起着非常重要的作用。本文着重论述外侧杏仁核在恐惧性条件化学习过程中的神经可塑性变化和相关的LTP机制,以及决定这种可塑性变化的分子信号转导通路。     

Involvement of isoproterenol-induced intracellular Zn2+ dynamics in the basolateral amygdala in conditioned fear memory

BioMetals - Beta-adrenergic receptors in the basolateral amygdala play an essential role in fear memory, while the physiological role of intracellular Zn2+ remains to be clarified. Intracellular...     

Effects of alcoholic beverage treatment on spatial learning and fear memory in mice

Although chronic ethanol treatment is known to impair learning and memory, humans commonly consume a range of alcoholic beverages. However, the specific effects of some alcoholic beverages on behavioral performance are largely unknown. The present study compared the effects of a range of alcoholic beverages (plain ethanol solution, red wine, sake and whiskey; with a matched alcohol concentration of 10%) on learning and memory. 6-week-old C57BL6J mice were orally administered alcohol for 7 weeks. The results revealed that red wine treatment exhibited a trend toward improvement of spatial memory and advanced extinction of fear memory. Additionally, red wine treatment significantly increased mRNA levels of brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate (NMDA) receptors in mice hippocampus. These results support previous reports that red wine has beneficial effects.     

Effects of conditioned fear and environmental novelty on plasma beta-endorphin in the rat

The levels of rat plasma beta-endorphin-like immunoreactivity following a 30 min exposure to (1) an unfamiliar operant chamber, (2) an unfamiliar operant chamber providing a VI-5 second schedule of 3 mA, 1 sec footshocks, or (3) a familiar chamber providing no shocks, but previously paired with unavoidable shocks were compared to control values from animals left undisturbed in their familiar home cages. The shocked group showed ten-fold elevations of beta-endorphin-like immunoreactivity compared to the undisturbed control animals, while conditioned rats showed a smaller two-fold elevation when re-exposed to a chamber in which they had previously been shocked. Two of five rats exposed merely to an unfamiliar chamber showed elevations, but there was no statistically reliable group effect. Such procedures may be useful for controlled and parametric studies of the mobilization of pituitary or brain pools of beta-endorphin under conditions involving merely anticipation of pain rather than the actual activation of ascending nervous pain pathways.     

(+)-Borneol suppresses conditioned fear recall and anxiety-like behaviors in mice

Fear- and anxiety-related psychiatric disorders have been one of the major chronic diseases afflicting patients for decades, and new compounds for treating such disorders remain to be developed. (+)-Borneol, a bicyclic monoterpene found in several species of Artemisia and Dipterocarpaceae, is widely used for anxiety, pain and anesthesia in Chinese medicine. Meanwhile, it can potentiate GABA (γ-aminobutyric acid) activity directly in recombinant GABAA receptors. The present study was to investigate the effects of (+)-Borneol on both contextual and cued fear recall. Interestingly, microinjection of (+)-Borneol into the dorsal hippocampus inhibited 24 h and 7 d contextual fear, whereas its infusion into ventral hippocampus only reduced 24 h cued fear responses. Moreover, microinjection of (+)-Borneol into dorsal but not ventral hippocampus suppressed anxiety-like behaviors in the open field test, light/dark exploration and the elevated plus maze test. As selective GABA_A receptor antagonist bicuculline reversed the effect of (+)-Borneol on contextual fear paradigm and the drug potentiated GABA-evoked currents in acute hippocampus slices, modulation of the GABAergic neurotransmission may explain the effects of (+)-Borneol. Our findings suggest that (+)-Borneol can serve as a new therapeutic in fear- and anxiety-related disorders.     

Neural circuitry underlying the regulation of conditioned fear and its relation to extinction

Recent efforts to translate basic research to the treatment of clinical disorders have led to a growing interest in exploring mechanisms for diminishing fear. This research has emphasized two approaches: extinction of conditioned fear, examined across species; and cognitive emotion regulation, unique to humans. Here, we sought to examine the similarities and differences in the neural mechanisms underlying these two paradigms for diminishing fear. Using an emotion regulation strategy, we examine the neural mechanisms of regulating conditioned fear using fMRI and compare the resulting activation pattern with that observed during classic extinction. Our results suggest that the lateral PFC regions engaged by cognitive emotion regulation strategies may influence the amygdala, diminishing fear through similar vmPFC connections that are thought to inhibit the amygdala during extinction. These findings further suggest that humans may have developed complex cognition that can aid in regulating emotional responses while utilizing phylogenetically shared mechanisms of extinction.     

环腺苷酸应答元件结合蛋白与学习记忆

环腺苷酸(cAMP)应答元件结合蛋白(cAMP response element binding protein,CREB)是一种核转录因子,可与cAMP反应元件结合,调节基因转录,具有调节精子生成,昼夜节律,学习记忆等功能.近年来关于其在学习记忆中的作用成为医学研究热点.CREB是神经元内多条信息传递途径的汇聚点,参与长时记忆形成和突触可塑性.长时记忆(long-term memory)形成需依赖CREB介导的基因转录,干扰或抑制CREB活性可破坏长时记忆.长时程增强(long-term potentiation,LTP)是研究学习记忆的理想模型,在LTP诱导和维持过程中均可观察到CREB活性持续升高.但增龄过程中,海马CREB活性下降,影响学习记忆功能,与许多神经退行性疾病发生有关.     

Effect of exposure to high pressure on subsequent spatial learning and memory in rats

The effects of high helium pressure on the subsequent acquisition of spatial memory were studied in male rats. Thirty-two rats were exposed to 65 ATA helium-oxygen pressure for 4.2 days, decompressed (total time in chamber 5 days), and then tested in an eight-arm radial maze. Thirty-two control rats were exposed in the chamber to 1 ATA air. Each rat had 20 sessions in the maze (2 sessions/day for 10 days), and the number of correct (visiting an arm not previously visited to obtain the reward pellet) and incorrect choices (visiting a previously visited arm) were recorded. Statistical analysis showed that the rats exposed to 65 ATA performed significantly better than 1-ATA controls during the first 8 of 20 sessions. This effect was most pronounced in sessions 5-8. Results for sessions 9-20 showed that the pressure-treated rats still made more correct choices but to an extent that did not always reach statistical significance. Possible explanations include the pressure-treated rats performing better because of hunger after a lower food consumption at pressure. Alternatively, pressure itself may enhance proposed mechanisms of spatial memory such as long-term potentiation.     

Effect of beta-lactotensin on acute stress and fear memory

β-Lactotensin (β-LT) is a bioactive peptide derived from bovine milk β-lactoglobulin and is a natural ligand for neurotensin receptors. We examined the effect of β-LT on restraint stress and fear memory in mice. Mice subjected to acute restraint stress exhibited a decreased number of head-dips and increased head-dip latency compared to non-stressed controls in the hole-board test, reflecting increased stress-induced behaviors. However, prior administration of β-LT improved the behaviors caused by stress. The anti-stress effect of β-LT was blocked by levocabastine, a neurotensin receptor subtype 2 (NTR2) antagonist. In the fear-conditioning test, the duration of freezing responses by cued fear conditioning was significantly reduced in mice administered β-LT compared with control mice. These results suggest that β-LT has an anti-stress effect and promotes the extinction of fear memory, which may be mediated by NTR2.     

Standardizing the analysis of conditioned fear in rodents: a multidimensional software approach

Data comparability between different laboratories strongly depends on the individually applied analysis method. This factor is often a critical source of variation in rodent phenotyping and has never been systematically investigated in Pavlovian fear conditioning paradigms. In rodents, fear is typically quantified in terms of freezing duration via manual observation or automated systems. While manual analysis includes biases such as tiredness or inter‐personal scoring variability, computer‐assisted systems are unable to distinguish between freezing and immobility. Consequently, the novel software called MOVE follows a semi‐automatized approach that prefilters video sequences of interest for the final human judgment. Furthermore, MOVE allows integrating additional data sources (e.g. force‐sensitive platform, EEG) to reach the most accurate and precise results. MOVE directly supports multi‐angle video recordings with webcams or standard laboratory equipment. The integrated manual key logger and internal video player complement this all‐in‐one software solution. Calculating the interlaboratory variability of manual freezing evaluation revealed significantly different freezing scores in two out of six laboratories. This difference was minimized when all experiments were analyzed with MOVE. Applied to a genetically modified mouse model, MOVE revealed higher fear responses of CB1 deficient mice compared to their wild‐type littermates after foreground context fear conditioning. Multi‐angle video analysis compared to the single‐camera approach reached up to 15% higher accuracy and two fold higher precision. Multidimensional analysis provided by integration of additional data sources further improved the overall result. We conclude that the widespread usage of MOVE could substantially improve the comparability of results from different laboratories.