James L. McGaugh

Mechanisms of emotional arousal and lasting declarative memory

Neuroscience is witnessing growing interest in understanding brain mechanisms of memory formation for emotionally arousing events, a development closely related to renewed interest in the concept of memory consolidation. Extensive research in animals implicates stress hormones and the amygdaloid complex as key, interacting modulators of memory consolidation for emotional events. Considerable evidence suggests that the amygdala is not a site of long-term explicit or declarative memory storage, but serves to influence memory-storage processes in other brain regions, such as the hippocampus, striatum and neocortex. Human-subject studies confirm the prediction of animal work that the amygdala is involved with the formation of enhanced declarative memory for emotionally arousing events.

Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice

Progressive memory loss and cognitive dysfunction are the hallmark clinical features of Alzheimers disease (AD). Identifying the molecular triggers for the onset of AD-related cognitive decline presently requires the use of suitable animal models, such as the 3xTg-AD mice, which develop both amyloid and tangle pathology. Here, we characterize the onset of learning and memory deficits in this model. We report that 2-month-old, prepathologic mice are cognitively unimpaired. The earliest cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Abeta in the hippocampus and amygdala. Plaque or tangle pathology is not apparent at this age, suggesting that they contribute to cognitive dysfunction at later time points. Clearance of the intraneuronal Abeta pathology by immunotherapy rescues the early cognitive deficits on a hippocampal-dependent task. Reemergence of the Abeta pathology again leads to cognitive deficits. This study strongly implicates intraneuronal Abeta in the onset of cognitive dysfunction.

Role of adrenal stress hormones in forming lasting memories in the brain

Recent experiments investigating the effects of adrenal stress hormones on memory provide extensive evidence that epinephrine and glucocorticoids modulate long-term memory consolidation in animals and human subjects. Release of norepinephrine and activation of beta-adrenoceptors within the basolateral amygdala is critical in mediating adrenal stress hormone regulation of memory consolidation.

Memory consolidation and the amygdala: a systems perspective

The basolateral region of the amygdala (BLA) plays a crucial role in making significant experiences memorable. There is extensive evidence that stress hormones and other neuromodulatory systems activated by arousing training experiences converge in regulating noradrenaline-receptor activity within the BLA. Such activation of the BLA modulates memory consolidation via BLA projections to many brain regions involved in consolidating lasting memory, including the hippocampus, caudate nucleus, nucleus basalis and cortex. Investigation of the involvement of BLA projections to other brain regions is essential for understanding influences of the amygdala on different aspects and forms of memory.

A Novel Demonstration of Enhanced Memory Associated with Emotional Arousal

The relationship between emotional arousal and long-term memory is addressed in two experiments in which subjects viewed either a relatively emotionally neutral short story (presented as a brief slide show) or a closely matched but more emotionally arousing story and were tested for retention of the story 2 weeks later. Experiment 1 provides an essential replication of the results of Heuer and Reisberg (1990) and illustrates the common interpretive problem posed by the use of different stimuli (slides) in the neutral versus emotional stories. In Experiment 2, identical slides (and sequence) were used in both the neutral and arousal stories. Two different stories were created by varying the narration that accompanied each slide. In both experiments, subjects who viewed the arousal story both experienced a greater emotional reaction to the story than did the subjects who viewed the neutral story, and subsequently exhibited enhanced memory for the story. Subjects in Experiment 2 who viewed the arousal story also recalled more slides than did the subjects who viewed the neutral story. This effect was greatest for story phase 2, the phase in which the emotional slide narration occurred. Because this enhanced retention of the story slides cannot be explained by any differences in the slides themselves, the results provide new evidence to support the contention that emotional arousal influences long-term memory in normal human subjects.

Glucocorticoids Increase Amyloid-β and Tau Pathology in a Mouse Model of Alzheimer’s Disease

Various environmental and genetic factors influence the onset and progression of Alzheimer’s disease (AD). Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, which controls circulating levels of glucocorticoid hormones, occurs early in AD, resulting in increased cortisol levels. Disturbances of the HPA axis have been associated with memory impairments and may contribute to the cognitive decline that occurs in AD, although it is unknown whether such effects involve modulation of the amyloid β-peptide (Aβ) and tau. Using in vitro and in vivo experiments, we report that stress-level glucocorticoid administration increases Aβ formation by increasing steady-state levels of amyloid precursor protein (APP) and β-APP cleaving enzyme. Additionally, glucocorticoids augment tau accumulation, indicating that this hormone also accelerates the development of neurofibrillary tangles. These findings suggest that high levels of glucocorticoids, found in AD, are not merely a consequence of the disease process but rather play a central role in the development and progression of AD.

Modulating effects of posttraining epinephrine on memory: Involvement of the amygdala noradrenergic system

These experiments examined the effects, on retention, of posttraining intra-amygdala administration of norepinephrine (NE), and propranolol. Rats were trained on a one-trial step-through inhibitory avoidance task and tested for retention 24 h later. Injections were administered bilaterally (1.0 microliter/injection) through chronically-implanted cannulae. Low doses of NE (0.1 or 0.3 microgram) administered shortly after training enhanced retention while higher doses (1.0 or 5.0 micrograms) were ineffective. Retention was not affected by NE administered 3 h after training. The effect of intra-amygdala NE on retention is blocked by simultaneous administration of propranolol (0.2 microgram). This finding suggests that the memory-enhancing effect of NE may be mediated by beta-receptors. Posttraining intra-amygdala NE also attenuated the retention deficit produced by adrenal demedullation. Further, intra-amygdala injections of propranolol (0.2 microgram) blocked the enhancing effect, on retention, of posttraining s.c. injections of epinephrine. These findings suggest that activation of noradrenergic receptors in the amygdala may be involved in memory processing and may play a role in the memory-modulating effect of peripheral epinephrine.

Glucocorticoids interact with emotion-induced noradrenergic activation in influencing different memory functions

Extensive evidence from rat and human studies indicates that glucocorticoid hormones influence cognitive performance. Posttraining activation of glucocorticoid-sensitive pathways dose-dependently enhances the consolidation of long-term memory. Glucocorticoid effects on memory consolidation rely on noradrenergic activation of the basolateral amygdala and interactions of the basolateral amygdala with other brain regions. Glucocorticoids interact with the noradrenergic system both at a postsynaptic level, increasing the efficacy of the beta-adrenoceptor-cyclic AMP/protein kinase A system, as well as presynaptically in brainstem noradrenergic cell groups that project to the basolateral amygdala. In contrast, memory retrieval and working memory performance are impaired with high circulating levels of glucocorticoids. Glucocorticoid-induced impairment of these two memory functions also requires the integrity of the basolateral amygdala and the noradrenergic system. Such critical interactions between glucocorticoids and noradrenergic activation of the basolateral amygdala have important consequences for the role of emotional arousal in enabling glucocorticoid effects on these different memory functions.

Basolateral Amygdala Lesions Block the Memory‐enhancing Effect of Glucocorticoid Administration in the Dorsal Hippocampus of Rats

These experiments examined the effects of bilateral amygdala nuclei lesions on modulation of memory storage induced by bilateral intrahippocampal microinfusions of glucocorticoids in male Sprague‐Dawley rats. Post‐training infusions of the glucocorticoid receptor (type II) agonist RU 28362 (3.0 or 10.0 ng) enhanced inhibitory avoidance retention, and infusions of the glucocorticoid receptor antagonist RU 38486 (3.0 or 10.0 ng) administered shortly before training in a water maze spatial task did not affect acquisition, but impaired retention. In both tasks, neurochemically induced lesions of the basolateral but not of the central amygdala blocked the memory‐modulatory effects of the intrahippocampal infusions of the drugs affecting glucocorticoid receptors. Lesions of the central amygdala alone impaired inhibitory avoidance retention, but basolateral amygdala lesions alone did not affect acquisition or retention in either task. These findings are consistent with previous evidence indicating that lesions of the basolateral amygdala block the memory‐modulatory effects of systemically administered glucocorticoids, and provide further evidence that the basolateral amygdala is a critical area involved in regulating glucocorticoid effects in other brain regions involved in memory storage.

Retrieval of memory for fear-motivated training initiates extinction requiring protein synthesis in the rat hippocampus

Evidence that protein synthesis inhibitors induce amnesia in a variety of species and learning paradigms indicates that the consolidation of newly acquired information into stable memories requires the synthesis of new proteins. Because extinction of a response also requires acquisition of new information, extinction, like original learning, would be expected to require protein synthesis. The present experiments examined the involvement of protein synthesis in the hippocampus in the extinction of a learned fear-based response known to involve the hippocampus. Rats were trained in a one-trial inhibitory avoidance task in which they received footshock after stepping from a small platform to a grid floor. They were then given daily retention tests without footshock. The inhibitory response (e.g., remaining on the platform) gradually extinguished with repeated testing over several days. Footshock administered in a different context, instead of a retention test, prevented the extinction. Infusions of the protein synthesis inhibitor anisomycin (80 μg) into the CA1 region of the hippocampus (bilaterally) 10 min before inhibitory avoidance training impaired retention on all subsequent tests. Anisomycin infused into the hippocampus immediately after the 1st retention test blocked extinction of the response. Infusions administered before the 1st retention test induced a temporary (i.e., 1 day) reduction in retention performance and blocked subsequent extinction. These findings are consistent with other evidence that anisomycin blocks both the consolidation of original learning and extinction.