Christa K. McIntyre

Amygdala modulation of memory consolidation: Interaction with other brain systems

There is a strong consensus that the amygdala is involved in mediating influences of emotional arousal and stress on learning and memory. There is extensive evidence that the basolateral amygdala (BLA) is a critical locus of integration of neuromodulatory influences regulating the consolidation of several forms of memory. Many drug and stress hormone influences converge in activating the release of norepinephrine (NE) within the BLA. Evidence from studies using in vivo microdialysis and high-performance liquid chromatography indicates that increases in amygdala NE levels assessed following inhibitory avoidance training correlate highly with subsequent retention. Other evidence indicates that NE influences on memory consolidation require muscarinic cholinergic activation within the BLA provided by projections from the nucleus basalis magnocellularis (NB). Evidence from several experiments indicates that activation of the BLA plays an essential role in modulating memory consolidation processes involving other brain regions. These findings provide strong support for the hypothesis that the BLA plays a critical role in regulating the consolidation of lasting memories of significant experiences.

Amygdala norepinephrine levels after training predict inhibitory avoidance retention performance in rats.

Previous findings indicate that footshock and several drugs that modulate memory consolidation alter norepinephrine (noradrenaline) release in the amygdala, as assessed by in vivo microdialysis and high‐performance liquid chromatography. Such findings suggest that norepinephrine release in the amygdala may be critical for regulating memory consolidation. The present study was the first to examine the relationship between norepinephrine release in the amygdala assessed after inhibitory avoidance training and 24‐h retention performance within individual animals. Norepinephrine levels increased to > 300% of pretraining baseline 30 min after training and remained elevated for 2 h. In individual rats, the increase in norepinephrine levels after training correlated highly with 24‐h retention performance. These findings indicate that the degree of activation of the noradrenergic system within the amygdala in response to a novel, emotionally arousing experience predicts the extent of long‐term memory for that experience.

Glucocorticoid Effects on Memory Consolidation Depend on Functional Interactions between the Medial Prefrontal Cortex and Basolateral Amygdala

Considerable evidence indicates that the basolateral complex of the amygdala (BLA) interacts with efferent brain regions in mediating glucocorticoid effects on memory consolidation. Here, we investigated whether glucocorticoid influences on the consolidation of memory for emotionally arousing training depend on functional interactions between the BLA and the medial prefrontal cortex (mPFC), a brain region involved in higher-order cognitive and affective processing. The glucocorticoid receptor (GR) agonist 11β,17β-dihydroxy-6,21-dimethyl-17α-pregna-4,6-trien-20yn-3-one (RU 28362) administered unilaterally into the left mPFC of male Sprague Dawley rats immediately after inhibitory avoidance training enhanced 48 h retention performance. An ipsilateral, but not contralateral, lesion of the BLA blocked the memory enhancement. In a second experiment, RU 28362 infused into the mPFC after inhibitory avoidance training increased BLA levels of phosphorylated extracellular signal-regulated kinase 1/2 (pErk1/2). Blockade of this pErk1/2 activity in the BLA with the mitogen-activated protein kinase kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] prevented the memory enhancement, suggesting that GR agonist administration into the mPFC enhances memory consolidation via modulation of BLA activity. Conversely, GR agonist infusions administered into the BLA posttraining increased pErk1/2 levels in the mPFC in regulating memory consolidation. Moreover, as assessed with a two-phase inhibitory avoidance procedure designed to separate modulatory influences on memory of context and footshock, posttraining GR agonist infusions into either the BLA or mPFC enhanced memory of the contextual as well as aversive information acquired during inhibitory avoidance training. These findings indicate that glucocorticoid effects on memory consolidation depend on bidirectional interactions between the BLA and mPFC.

Role of the basolateral amygdala in memory consolidation.

Abstract: Memories of emotionally arousing events tend to be more vivid and to persist longer than do memories of neutral or trivial events. Moreover, memories of emotionally influenced information may endure after a single experience. Recent findings strongly suggest that the influence of emotional arousal on memory consolidation is mediated by the release of adrenal stress hormones (epinephrine and glucocorticoids) and neurotransmitters that converge in modulating the noradrenergic system within the amygdala. Considerable evidence also indicates that amygdala activation influences memory by regulating consolidation in other brain regions. The findings suggest further that this memory‐modulatory system may be involved in the formation of traumatic memories and posttraumatic stress disorder in human subjects.

Patterns of brain acetylcholine release predict individual differences in preferred learning strategies in rats

Acetylcholine release was measured simultaneously in the hippocampus and dorsal striatum of rats before and during training on a maze that could be learned using either a hippocampus-dependent spatial strategy or a dorsal striatum-dependent turning strategy. A probe trial administered after rats reached a criterion of 9/10 correct responses revealed that about half of the rats used a spatial strategy and half a turning strategy to solve the task. Acetylcholine release in the hippocampus, as well as the ratio of acetylcholine release in the hippocampus vs. the dorsal striatum, measured either before or during training, predicted these individual differences in strategy selection during learning. These findings suggest that differences in release of acetylcholine across brain areas may provide a neurobiological marker of individual differences in selection of the strategies rats use to solve a learning task.

Interacting brain systems modulate memory consolidation

Emotional arousal influences the consolidation of long-term memory. This review discusses experimental approaches and relevant findings that provide the foundation for current understanding of coordinated interactions between arousal activated peripheral hormones and the brain processes that modulate memory formation. Rewarding or aversive experiences release the stress hormones epinephrine (adrenalin) and glucocorticoids from the adrenal glands into the bloodstream. The effect of these hormones on memory consolidation depends upon binding of norepinephrine to beta-adrenergic receptors in the basolateral complex of the amygdala (BLA). Much evidence indicates that the stress hormones influence release of norepinephrine in the BLA through peripheral actions on the vagus nerve which stimulates, through polysynaptic connections, cells of the locus coeruleus to release norepinephrine. The BLA influences memory storage by actions on synapses, distributed throughout the brain, that are engaged in sensory and cognitive processing at the time of amygdala activation. The implications of the activation of these stress-activated memory processes are discussed in relation to stress-related memory disorders.

Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions

Considerable evidence indicates that glucocorticoid hormones enhance the consolidation of memory for emotionally arousing events through interactions with the noradrenergic system of the basolateral complex of the amygdala (BLA). We previously reported that intra-BLA administration of a beta-adrenoceptor agonist immediately after inhibitory avoidance training enhanced memory consolidation and increased hippocampal expression of the protein product of the immediate early gene activity-regulated cytoskeletal-associated protein (Arc). In the present experiments corticosterone (3 mg/kg, i.p.) was administered to male Sprague-Dawley rats immediately after inhibitory avoidance training to examine effects on long-term memory, amygdala norepinephrine levels, and hippocampal Arc expression. Corticosterone increased amygdala norepinephrine levels 15 min after inhibitory avoidance training, as assessed by in vivo microdialysis, and enhanced memory tested at 48 h. Corticosterone treatment also increased expression of Arc protein in hippocampal synaptic tissue. The elevation in BLA norepinephrine appears to participate in corticosterone-influenced modulation of hippocampal Arc expression as intra-BLA blockade of beta-adrenoceptors with propranolol (0.5 microg/0.2 microL) attenuated the corticosterone-induced synaptic Arc expression in the hippocampus. These findings indicate that noradrenergic activity at BLA beta-adrenoceptors is involved in corticosterone-induced enhancement of memory consolidation and expression of the synaptic-plasticity-related protein Arc in the hippocampus.

Cooperation between memory systems: acetylcholine release in the amygdala correlates positively with performance on a hippocampus-dependent task.

The present experiment examined the relationship between release of acetylcholine (ACh) in the amygdala and performance on a hippocampus-dependent spatial working memory task. Using in vivo microdialysis, the authors measured ACh release in rats during testing on a spontaneous alternation task. Amygdala ACh release was positively correlated with performance on the hippocampus-dependent task. These findings suggest that activation of the amygdala promotes processing in other neural systems important for learning and memory.

Intra-amygdala infusions of scopolamine impair performance on a conditioned place preference task but not a spatial radial maze task

Lesions of the amygdala impair performance on a conditioned place preference (CPP) but not a spatial radial maze task. The role of cholinergic receptors within the amygdala in performance of these tasks was evaluated using intra-amygdala injections of the muscarinic receptor antagonist, scopolamine. Food deprived rats were trained on a CPP task, which consisted of four training trials on two arms of a radial eight-arm maze. One arm was consistently paired with a large amount of food (14 g) while the other arm was never baited. Prior to the fourth trial, rats received bilateral intra-amygdala infusions of the muscarinic receptor antagonist, scopolamine (SCOP; 5 microg/0.5 microl) or vehicle. On a retention test 24 h later, unoperated and vehicle-infused rats, but not SCOP-treated rats, spent significantly more time in the paired arm than chance (50%). Therefore, the scopolamine treatment appeared to block learning and/or memory on trial 4. The same rats were then trained on a radial maze task on the same apparatus, in which rats had access to all eight arms but only four were baited with food (1 pellet). Rats were trained until they reached criterion and then infusions were given prior to testing. SCOP treatment did not affect performance on the radial maze task. Thus, intact cholinergic mechanisms in the amygdala are necessary for learning or memory on a CPP task with a high reward component but not performance on a spatial radial maze task with a lower reward component.

Rapid Remission of Conditioned Fear Expression with Extinction Training Paired with Vagus Nerve Stimulation

BACKGROUND Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations. In human subjects, as well as rats, posttraining stimulation of the vagus nerve enhances memory consolidation. Subjects with posttraumatic stress disorder show impaired extinction of conditioned fear. The objective of this study was to determine whether vagus nerve stimulation (VNS) can enhance the consolidation of extinction of conditioned fear. METHODS Male Sprague-Dawley rats were trained on an auditory fear conditioning task followed by 1 to 10 days of extinction training. Treatment with vagus nerve or sham stimulation was administered concurrently with exposure to the fear conditioned stimulus. Another group was given VNS and extinction training but the VNS was not paired with exposure to conditioned cues. Retention of fear conditioning was tested 24 hours after each treatment. RESULTS Vagus nerve stimulation paired with exposure to conditioned cues enhanced the extinction of conditioned fear. After a single extinction trial, rats given VNS stimulation demonstrated a significantly lower level of freezing, compared with that of sham control rats. When extinction trials were extended to 10 days, paired VNS accelerated extinction of the conditioned response. CONCLUSIONS Extinction paired with VNS is more rapid than extinction paired with sham stimulation. As it is currently approved by the Federal Food and Drug Administration for depression and seizure prevention, VNS is a readily available and promising adjunct to exposure therapy for the treatment of severe anxiety disorders.