Central cannabinoid receptors modulate acquisition of eyeblink conditioning

Delay eyeblink conditioning is established by paired presentations of a conditioned stimulus (CS) such as a tone or light, and an unconditioned stimulus (US) that elicits the blink reflex. Conditioned stimulus information is projected from the basilar pontine nuclei to the cerebellar interpositus nucleus and cortex. The cerebellar cortex, particularly the molecular layer, contains a high density of cannabinoid receptors (CB1R). The CB1Rs are located on the axon terminals of parallel fibers, stellate cells, and basket cells where they inhibit neurotransmitter release. The present study examined the effects of a CB1R agonist WIN55,212-2 and antagonist SR141716A on the acquisition of delay eyeblink conditioning in rats. Rats were given subcutaneous administration of 1, 2, or 3 mg/kg of WIN55,212-2 or 1, 3, or 5 mg/kg of SR141716A before each day of acquisition training (10 sessions). Dose-dependent impairments in acquisition were found for WIN55,212-2 and SR141716A, with no effects on spontaneous or nonassociative blinking. However, the magnitude of impairment was greater for WIN55,212-2 than SR141716A. Dose-dependent impairments in conditioned blink response (CR) amplitude and timing were found with WIN55,212-2 but not with SR141716A. The findings support the hypothesis that CB1Rs in the cerebellar cortex play an important role in plasticity mechanisms underlying eyeblink conditioning.     

Posttraining activation of CB1 cannabinoid receptors in the CA1 region of the dorsal hippocampus impairs object recognition long-term memory

Evidence indicates that brain endocannabinoids are involved in memory processing. However, the participation of CB1 and CB2 cannabinoid receptors in recognition memory has not been yet conclusively determined. Therefore, we evaluated the effect of the posttraining activation of hippocampal cannabinoid receptors on the consolidation of object recognition memory. Rats with infusion cannulae stereotaxically aimed to the CA1 region of the dorsal hippocampus were trained in an object recognition learning task involving exposure to two different stimulus objects. Memory retention was assessed at different times after training. In the test sessions, one of the objects presented during training was replaced by a novel one. When infused in the CA1 region immediately after training, the non-selective cannabinoid receptor agonist WIN-55,212-2 and the endocannabinoid membrane transporter inhibitor VDM-11 blocked long-term memory retention in a dose-dependent manner without affecting short-term memory, exploratory behavior, anxiety state or the functionality of the hippocampus. The amnesic effect of WIN-55,212-2 and VDM-11 was not due to state-dependency and was completely reversed by co-infusion of the CB1 receptor antagonist AM-251 and mimicked by the CB1 receptor agonist ACEA but not by the CB2 receptor agonists JWH-015 and palmitoylethanolamide. Our data indicate that activation of hippocampal CB1 receptors early after training hampers consolidation of object recognition memory.     

胚胎期糖皮质激素系统在光照改善小鸡记忆中的作用

该研究采用胚胎期药物注射法和小鸡一次性被动回避反应行为模型,观察了皮质酮和地塞米松对暗孵化小鸡记忆的影响,以及两类皮质激素受体颉颃剂RU-486和Spironolactone对光照以及皮质酮效应的阻断作用。结果表明,糖皮质激素可明显改善暗孵化小鸡的记忆;两类受体颉颃剂均阻断了光照和皮质酮对暗孵化小鸡记忆的改善作用,但糖皮质激素受体对小鸡记忆的作用是特异性的,盐皮质激素主要通过对小鸡的基本状态的改变来影响记忆活动。因此,糖皮质激素及其受体系统参与了光照对小鸡记忆的作用过程。     

Influence of chronic corticosterone and glucocorticoid receptor antagonism in the amygdala on fear conditioning

Glucocorticoid receptor activation within the basolateral amygdala (BLA) during fear conditioning may mediate enhancement in rats chronically exposed to stress levels of corticosterone. Male Sprague-Dawley rats received corticosterone (400 microg/ml) in their drinking water (days 1-21), a manipulation that was previously shown to cause hippocampal CA3 dendritic retraction. Subsequently, rats were adapted to the fear conditioning chamber (day 22), then trained (day 23), and tested for conditioned fear to context and tone (day 25). Training consisted of two tone (20s) and footshock (500 ms, 0.25 mA) pairings. In Experiment 1, muscimol (4.4 nmol/0.5 microl/side), a GABAergic agonist, was microinfused to temporarily inactivate the BLA during training. Rats given chronic corticosterone showed enhanced freezing to context, but not tone, compared to vehicle-supplemented rats. Moreover, BLA inactivation impaired contextual and tone conditioning, regardless of corticosterone treatment. In Experiment 2, RU486 (0, 0.3, and 3.0 ng/0.2 microl/side) was infused on training day to antagonize glucocorticoid receptors in the BLA. Corticosterone treatment enhanced fear conditioning to context and tone when analyzed together, but not separately. Moreover, RU486 (3.0 ng/side) selectively exacerbated freezing to context in chronic corticosterone-exposed rats only, but failed to alter tone conditioning. Serum corticosterone levels were negatively correlated with contextual, not tone, conditioning. Altogether, these suggest that chronic corticosterone influences fear conditioning differently than chronic stress as shown previously. Moreover, chronic exposure to corticosteroids alters BLA functioning in a non-linear fashion and that contextual conditioning is influenced more than tone conditioning by chronic corticosterone and BLA glucocorticoid receptor stimulation.     

Dopamine D1 receptors are responsible for stress-induced emotional memory deficit in mice

It is established that stress impairs spatial learning and memory via the hypothalamus-pituitary-adrenal axis response. Dopamine D1 receptors were also shown to be responsible for a stress-induced deficit of working memory. However, whether stress affects the subsequent emotional learning and memory is not elucidated yet. Here, we employed the well-established one-trial step-through task to study the effect of an acute psychological stress (induced by tail hanging for 5, 10, or 20?min) on emotional learning and memory, and the possible mechanisms as well. We demonstrated that tail hanging induced an obvious stress response. Either an acute tail-hanging stress or a single dose of intraperitoneally injected dopamine D1 receptor antagonist (SCH23390) significantly decreased the step-through latency in the one-trial step-through task. However, SCH23390 prevented the acute tail-hanging stress-induced decrease in the step-through latency. In addition, the effects of tail-hanging stress and/or SCH23390 on the changes in step-through latency were not through non-memory factors such as nociceptive perception and motor function. Our data indicate that the hyperactivation of dopamine D1 receptors mediated the stress-induced deficit of emotional learning and memory. This study may have clinical significance given that psychological stress is considered to play a role in susceptibility to some mental diseases such as depression and post-traumatic stress disorder.     

Does stress enhance or impair memory consolidation?

Three experiments examined the hypothesis that stress-induced arousal enhances long-term memory for experiences associated with arousing events. Contrary to expectations, in each experiment exposure to a stressor (arm immersion in ice water) interfered with, rather than enhanced, long-term memory for associated material. Despite varying the stimuli (words, pictures), their emotional value (positive, negative, neutral), the time between learning and stress inductions (0 to 1 minute), and opportunities for post-learning rehearsal, each experiment produced a significant reversal of the hypothesised effect. That is, in each experiment, exposure to a stressor interfered with, rather than enhanced, long-term memory for associated material. We conclude that the relationship between stress and memory consolidation is more bounded than previously believed.     

Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala

Stress can profoundly affect memory and alter the functioning of the hippocampus and amygdala. Studies have also shown that the antidepressant tianeptine can block the effects of stress on hippocampal and amygdala morphology and synaptic plasticity. We examined the effects of acute predator stress and tianeptine on long-term potentiation (LTP; induced by 100 pulses in 1 s) and primed burst potentiation (PB; a low threshold form of LTP induced by only five physiologically patterned pulses) in CA1 and in the basolateral nucleus (BLA) of the amygdala in anesthetized rats. Predator stress blocked the induction of PB potentiation in CA1 and enhanced LTP in BLA. Tianeptine blocked the stress-induced suppression of PB potentiation in CA1 without affecting the stress-induced enhancement of LTP in BLA. In addition, tianeptine administered under non-stress conditions enhanced PB potentiation in the hippocampus and LTP in the amygdala. These findings support the hypothesis that acute stress impairs hippocampal functioning and enhances amygdaloid functioning. The work also provides insight into the actions of tianeptine with the finding that it enhanced electrophysiological measures of plasticity in the hippocampus and amygdala under stress, as well as non-stress, conditions.     

Effects of Aging on Functional Connectivity of the Amygdala for Subsequent Memory of Negative Pictures: A Network Analysis of Functional Magnetic Resonance Imaging Data

ABSTRACT— Aging is associated with preserved enhancement of emotional memory, as well as with age-related reductions in memory for negative stimuli, but the neural networks underlying such alterations are not clear. We used a subsequent-memory paradigm to identify brain activity predicting enhanced emotional memory in young and older adults. Activity in the amygdala predicted enhanced emotional memory, with subsequent-memory activity greater for negative stimuli than for neutral stimuli, across age groups, a finding consistent with an overall enhancement of emotional memory. However, older adults recruited greater activity in anterior regions and less activity in posterior regions in general for negative stimuli that were subsequently remembered. Functional connectivity of the amygdala with the rest of the brain was consistent with age-related reductions in memory for negative stimuli: Older adults showed decreased functional connectivity between the amygdala and the hippocampus, but increased functional connectivity between the amygdala and dorsolateral prefrontal cortices. These findings suggest that age-related differences in the enhancement of emotional memory might reflect decreased connectivity between the amygdala and typical subsequent-memory regions, as well as the engagement of regulatory processes that inhibit emotional responses.     

Trade-offs in visual attention and the enhancement of memory specificity for positive and negative emotional stimuli

Emotional influences on memory can lead to trade-offs in memory for gist or detail and trade-offs in memory for central or peripheral aspects of an event. Attentional narrowing has often been proposed as a theoretical explanation for this pattern of findings with negative emotion. These trade-offs have been less extensively investigated with positive emotion. In three experiments, we investigate memory for specific visual details of positive and negative stimuli, examine central–peripheral trade-offs in memory, and assess the hypothesis that attentional narrowing contributes to emotional enhancement of memory specificity. We found that memory for details was enhanced by negative and positive emotion. Central–peripheral trade-offs were found in memory for negative emotional stimuli but not in memory for positive emotional stimuli. These trade-offs with negative emotion were associated with attentional narrowing at the time of encoding, as measured by eye movements. There were no attentional effects at the time of encoding found with positive emotional stimuli. Evidence was found for the attentional narrowing hypothesis of memory specificity and central–peripheral trade-offs in memory for negative emotional events. Alternative explanations for the positive emotional enhancement of memory specificity are required.     

Memory enhancement induced by post-training intrabasolateral amygdala infusions of beta-adrenergic or muscarinic agonists requires activation of dopamine receptors: Involvement of right, but not left, basolateral amygdala

Previous findings indicate that the noradrenergic, dopaminergic, and cholinergic innervations of the basolateral amygdala (BLA) modulate memory consolidation. The current study investigated whether memory enhancement induced by post-training intra-BLA infusions of a beta-adrenergic or muscarinic cholinergic agonist requires concurrent activation of dopamine (DA) receptors in the BLA. Rats with implanted BLA cannulae were trained on an inhibitory avoidance (IA) task and, 48 h later, tested for retention. Infusions of the beta-adrenergic agonist clenbuterol into the right BLA, but not the left, enhanced retention, and concurrent infusions of the nonspecific DA receptor antagonist cis-Flupenthixol (Flu) blocked the enhancement. Post-training infusions of the muscarinic agonist oxotremorine into the right BLA also enhanced retention, and concurrent infusions of Flu blocked this effect. Additional experiments investigated whether memory modulation was lateralized to the right BLA. Post-training DA infusions into the right BLA, but not the left, enhanced retention. Post-training infusions of lidocaine or muscimol, which impair retention when infused bilaterally, had no effect when infused unilaterally into either the right or left BLA. These findings, together with earlier work, suggest that the dopaminergic system in the BLA is critically involved in memory modulation induced by noradrenergic and cholinergic influences. Additionally, these findings indicate that the enhancement, but not impairment, of memory consolidation is lateralized to the right BLA.     

Opposing actions of chronic Delta9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation

Memory deficits produced by marijuana arise partly via interaction of the psychoactive component, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), with cannabinoid receptors in the hippocampus. Although cannabinoids acutely reduce glutamate release and block hippocampal long-term potentiation (LTP), a potential substrate for learning and memory, the consequences of prolonged exposure to Delta(9)-THC for hippocampal function are poorly understood. Rats were injected with Delta(9)-THC (10 mg/kg, i.p., q.d.) for 1, 3, or 7 d, and electrophysiological recordings were performed in hippocampal slices 1d after the final injection. At this time, Delta(9)-THC was undetectable in hippocampus using liquid chromatography-mass spectrometry (LC-MS). Hippocampal LTP generated using high-frequency (HFS) or theta burst stimulation was not observed in brain slices from the 7-d Delta(9)-THC-treated animals. Delta(9)-THC also blocked HFS-LTP after 3 d, but not 1 d of treatment. The complete blockade of LTP persisted for 3 d after the last Delta(9)-THC injection, and full reversal of the LTP deficit was not observed up to 14 d following Delta(9)-THC withdrawal. The cannabinoid antagonist AM251 (2 mg/kg), administered before each Delta(9)-THC injection prevented the blockade of LTP, and 7-d treatment with AM251 alone significantly increased the level of LTP. Chronic Delta(9)-THC also produced tolerance to the inhibition of synaptic GABA, but not glutamate release by the agonist WIN55,212-2. These data define consequences of repeated Delta(9)-THC exposure for synaptic plasticity in the hippocampus that may help explain memory impairments in humans following chronic marijuana use.     

Activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the lateral amygdala

Previously, we found that in the lateral amygdala (LA) of the mouse, WIN55,212-2 decreases both glutamatergic and GABAergic synaptic transmission via activation of the cannabinoid receptor type 1 (CB1), yet produces an overall reduction of neuronal excitability. This suggests that the effects on excitatory transmission override those on inhibitory transmission. Here we show that CB1 activation by WIN55,212-2 and Delta(9)-THC inhibits long-term depression (LTD) of basal synaptic transmission in the LA, induced by low-frequency stimulation (LFS; 900 pulses/1 Hz). The CB1 agonist WIN55,212-2 blocked LTD via G(i/o) proteins, activation of inwardly rectifying K+ channels (K(ir)s), inhibition of the adenylate cyclase-protein kinase A (PKA) pathway, and PKA-dependent inhibition of voltage-gated N-type Ca2+ channels (N-type VGCCs). Interestingly, WIN55,212-2 effects on LTD were abolished in CB1 knock-out mice (CB1-KO), and in conditional mutants lacking CB1 expression only in GABAergic interneurons, but were still present in mutants lacking CB1 in principal forebrain neurons. LTD induction per se was unaffected by the CB1 antagonist SR141716A and was normally expressed in CB1-KO as well as in both conditional CB1 mutants. Our data demonstrate that activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the LA. These findings suggest that CB1 expressed on either glutamatergic or GABAergic neurons play a differential role in the control of synaptic transmission and plasticity.     

Involvement of the rostral anterior cingulate cortex in consolidation of inhibitory avoidance memory: interaction with the basolateral amygdala

Previous findings suggest that the rostral anterior cingulate cortex (rACC) is involved in memory for emotionally arousing training. There is also extensive evidence that the basolateral amygdala (BLA) modulates the consolidation of emotional arousing training experiences via interactions with other brain regions. The present experiments examined the effects of posttraining intra-rACC infusions of the cholinergic agonist oxotremorine (OXO) on inhibitory avoidance (IA) retention and investigated whether the BLA and rACC interact in enabling OXO effects on memory. In the first experiment, male Sprague-Dawley rats were implanted with bilateral cannulae above the rACC and given immediate posttraining OXO infusions. OXO (0.5 or 3 ng) induced significant enhancement of retention performance on a 48-h test. In the second experiment, unilateral posttraining OXO infusions (0.5, 3.0 or 10 ng) enhanced retention when infused into rACC, but not caudal ACC, consistent with previous evidence that ACC is composed of functionally distinct regions. A third experiment investigated the effects of posttraining intra-rACC OXO infusions (0.5 or 10 ng) in rats with bilateral sham or NMDA-induced lesions of the BLA. The BLA lesions did not impair IA retention, but blocked the enhancement induced by posttraining intra-rACC OXO infusions. Lastly, unilateral NMDA lesions of rACC blocked the enhancement of IA retention induced by posttraining ipsilateral OXO infusions into the BLA. These findings support the hypothesis that the rACC is involved in modulating the storage of emotional events and provide additional evidence that the BLA modulates memory consolidation through interactions with efferent brain regions, including the cortex.     

Effect of negative emotional content on working memory and long-term memory

In long-term memory, negative information is better remembered than neutral information. Differences in processes important to working memory may contribute to this emotional memory enhancement. To examine the effect that the emotional content of stimuli has on working memory performance, the authors asked participants to perform working memory tasks with negative and neutral stimuli. Task accuracy was unaffected by the emotional content of the stimuli. Reaction times also did not differ for negative relative to neutral words, but on an n-back task using faces, participants were slower to respond to fearful faces than to neutral faces. These results suggest that although emotional content does not have a robust effect on working memory, in some instances emotional salience can impede working memory performance.     

Emotional enhancement of immediate memory: Positive pictorial stimuli are better recognized than neutral or negative pictorial stimuli

We examined emotional memory enhancement (EEM) for negative and positive pictures while manipulating encoding and retrieval conditions. Two groups of 40 participants took part in this study. Both groups performed immediate implicit (categorization task) and explicit (recognition task) retrieval, but for one group the tasks were preceded by incidental encoding and for the other group by intentional encoding. As indicated by the sensitivity index (d'), after incidental encoding positive stimuli were easier to recognize than negative and neutral stimuli. Participants' response criterion was more liberal for negative stimuli than for both positive and neutral ones, independent of encoding condition. In the implicit retrieval task, participants were slower in categorizing positive than negative and neutral stimuli. However, the priming effect was larger for emotional than for neutral stimuli. These results are discussed in the context of the idea that the effect of emotion on immediate memory enhancement may depend on the intentionality to encode and retrieve information.     

The neural bases of sport fan reactions to teams: Evidence from a neuroimaging study

This study uses neuroimaging methods to identify patterns of brain activation among sport fans in reaction to team stimuli. In a whole-brain analysis without selected regions in advance, the purposes were to identify the structures involved when fans are exposed to positive, neutral, and negative events and to learn what events activate more limbic networks. A total of 53 individuals participated in and functional magnetic resonance imaging experiment involving the presentation of videos in various situations. Findings indicate the activation of the cingulate gyrus and other structures of the limbic system, as the hippocampus and parahippocampus. We also found involvement of the ventral tegmental area of the reward system. Additionally, brain activity in emotional regulation and memory areas were more influenced by positive than neutral and negative videos. It was also found the involvement of other areas not directly included in the limbic or reward systems. This study provides the neural basis of fan reactions to team-related stimuli. Sport clubs should be aware that negative content seems to be suppressed from emotional memory and positive videos trigger more emotion and memory areas than neutral and negative videos.     

Pre-training anandamide infusion within the basolateral amygdala impairs plus-maze discriminative avoidance task in rats

Endocannabinoids (eCBs) modulate a variety of brain functions via activation of the widely expressed CB1 receptor. One site of high density of this receptor is the basolateral amygdala (BLA), a structure involved in the formation of aversive memories. The activation and blockade of CB1 receptors by systemic or hippocampal drug administrations have been shown to modify memory processing. However, little is known about the role of the BLA endocannabinoid system in aversive memories. Additionally, BLA endocannabinoid transmission seems to be related to emotional states, but the relevance of these effects to memory formation is still unknown. In this study we investigated the effects of the eCB anandamide (AEA) and the CB1 antagonist/inverse agonist AM251 infused into the BLA on the acquisition of an aversive memory task, concomitantly evaluating basal anxiety levels in rats. Male rats received pre-training micro-injection of AEA, AM251 or vehicle bilaterally into the BLA, and were studied with the plus-maze discriminative avoidance task (a paradigm that allows concomitant and independent evaluation of anxiety-like behavior and the memory of an aversive task). Our results showed that AEA into the BLA before training prevented memory retrieval 24 h later, as evaluated by exploration of the aversive arm of the maze, while AM251 into the BLA did not interfere with animals' performance. In addition, AEA had no effect on anxiety-like behavior (as evaluated by open arm exploration and risk assessment), while AM251 induced an anxiogenic effect. Our data indicate an important role of BLA CB1 receptors in aversive memory formation, and suggest that this involvement is not necessarily related to a possible modulation of anxiety states.     

The role of the noradrenergic system in emotional memory

This contribution is an overview on the role of noradrenaline as neurotransmitter and stress hormone in emotional memory processing. The role of stress hormones in memory formation of healthy subjects can bear significance for the derailment of memory processes, for example, in post traumatic stress disorder (PTSD). Increased noradrenaline levels lead to better memory performance, whereas blocking the noradrenergic receptors with a betablocker attenuates this enhanced memory for emotional information. Noradrenaline appears to interact with cortisol in emotional memory processes, varying from encoding to consolidation and retrieval. Imaging studies show that confronting human subjects with emotional stimuli results in increased amygdala activation and that this activation is noradrenergic dependent. The role of noradrenaline in other brain areas, such as hippocampus and prefrontal cortex, is shortly summarized. Finally, the pros and cons of a therapeutic application of betablockers in the (secondary) prevention of PTSD will be discussed.     

Failure of positive but not negative emotional valence to enhance memory in schizophrenia

Abnormalities in the integration of emotion and cognition have long been considered hallmark characteristics of schizophrenia. Study authors used a well-established emotional memory model from the neuroscience literature to assess the facilitative impact of emotional valence of information on long-term memory consolidation in schizophrenia. Participants with schizophrenia (n=33) indicated somewhat higher levels of emotional intensity in response to emotional images than did healthy (n=28) participants. However, when recognition memory was tested 24 hr later, schizophrenia participants did not show enhancement of memory for positive images as was found in healthy participants. Their memory enhancement for negative images did not differ from that of healthy participants. Correlations between self-reported physical and social anhedonia were significantly inversely correlated with intensity ratings of positive stimuli during the encoding phase for healthy participants but were negligible for schizophrenia participants. These results suggest a failure to adequately integrate positive emotional experience in memory consolidation processes in schizophrenia participants, despite appropriate initial response to positive stimuli, which may contribute to symptoms such as anhedonia by reducing the long-term impact of positive experiences in motivating hedonic behavior in day-to-day life.     

双加工再认提取中的情绪记忆增强效应

根据双加工理论, 再认提取可以划分为两种不同的加工：熟悉性与回想。以往的研究普遍认为情绪对再认提取具有增强效应, 但是情绪对再认记忆中两种不同加工方式(熟悉性与回想)的增强效应的神经机制尚存争议。本研究以ERP作为测量手段, 采用修正的“记得/知道”范式对情绪图片进行再认测验, 旨在探究在学习?测验间隔较长的条件下, 情绪信息如何对熟悉性与回想产生增强效应。在行为结果中, 对于知道判断, 情绪图片的记忆表现显著高于中性图片, 情绪效价间没有差异; 对于记得判断, 负性情绪图片的记忆表现要显著高于正性与中性图片。在ERP数据上, 对于知道判断, 情绪图片的FN400新旧效应有增强作用。对于记得判断, 负性图片的LPC的新旧效应波幅显著高于中性与负性图片; 而正性图片的LPC新旧效应增强作用不显著。以上证据表明：学习?测验间隔较长的情况下, 熟悉性再认提取中, 情绪记忆增强效应主要体现在情绪唤醒对记忆强度的提高, 而不仅仅体现在情绪效价对熟悉判断反应倾向的影响。在回想的再认提取中, 情绪效价的调节占据主导地位, 负性情绪图片有显著的情绪记忆增强效应; 正性情绪图片则不具有增强效应。