Larry Cahill

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.

Why sex matters for neuroscience

A rapidly burgeoning literature documents copious sex influences on brain anatomy, chemistry and function. This article highlights some of the more intriguing recent discoveries and their implications. Consideration of the effects of sex can help to explain seemingly contradictory findings. Research into sex influences is mandatory to fully understand a host of brain disorders with sex differences in their incidence and/or nature. The striking quantity and diversity of sex-related influences on brain function indicate that the still widespread assumption that sex influences are negligible cannot be justified, and probably retards progress in our field.

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.

Epinephrine enhancement of human memory consolidation: Interaction with arousal at encoding

Abundant evidence indicates that endogenous stress hormones like epinephrine and cortisol modulate memory consolidation in animals. Despite this evidence, there has been no demonstration that endogenous stress hormones modulate memory consolidation in humans. In the present study, healthy subjects viewed a series of 21 slides, and immediately after received an intravenous infusion of either saline or epinephrine (40 or 80 ng/kg/min). Memory for the first three (primacy) and last three (recency) slides viewed was assessed with an incidental free recall test one week later. Epinephrine dose-dependently increased memory for the primacy slides, but did not affect memory of the recency slides. A subsequent experiment involving new subjects revealed significantly higher electrodermal responses to the primacy compared with recency slides. These findings support the view (Gold & McGaugh, 1975) that endogenous stress hormones modulate memory consolidation for experiences that induce their release. Additionally, they suggest that in humans these hormones may interact with the degree of arousal at initial encoding of information to modulate memory consolidation processes for that information.

Sex influences on the neurobiology of learning and memory.

In essentially every domain of neuroscience, the generally implicit assumption that few, if any, meaningful differences exist between male and female brain function is being challenged. Here we address how this development is influencing studies of the neurobiology of learning and memory. While it has been commonly held that males show an advantage on spatial tasks, and females on verbal tasks, there is increasing evidence that sex differences are more widespread than previously supposed. Differing performance between the sexes have been observed on a number of common learning tasks in both the human and animal literature, many neither purely spatial nor verbal. We review sex differences reported in various areas to date, while attempting to identify common features of sexually dimorphic tasks, and to place these differences in a neurobiological context. This discussion focuses on studies of four classes of memory tasks for which sex differences have been frequently reported: spatial, verbal, autobiographical, and emotional memory. We conclude that the female verbal advantage extends into numerous tasks, including tests of spatial and autobiographical abilities, but that a small but significant advantage may exist for general episodic memory. We further suggest that for some tasks, stress evokes sex differences, which are not normally observed, and that these differences are mediated largely by interactions between stress and sex hormones.

Modulation of memory storage

For several decades, the concept of modulation of memory storage has significantly influenced research investigating neurobiological memory mechanisms. New evidence provides additional support for the view that stress hormones released during emotionally arousing situations modulate memory processes. Recent experiments have investigated the role of sympathetic adrenomedullary hormones in emotional memory in humans, as well as the role of adrenocortical hormones, primarily in animal studies. Further, it is becoming increasingly clear that the sympathetic adrenomedullary and the pituitary adrenocortical systems interact to modulate memory storage. Other new evidence emphasizes the role of peripheral influences to the brain on emotional memory, as well as the critical contribution of the amygdaloid complex in modulation of memory by emotional arousal.

Glucocorticoid Release and Memory Consolidation in Men and Women

Glucocorticoid hormones have been shown to enhance memory consolidation when applied at low doses posttraining, but are ineffective or impair memory at high doses. In a test of whether this quadratic relationship also exists for endogenously released glucocorticoids, healthy men and women received cold-pressor stress (CPS) or a control procedure immediately after reading a relatively neutral story and were tested for retention 1 week later. Cortisol levels in response to the stressor were assayed from saliva. CPS significantly elevated salivary cortisol in both sexes, but enhanced memory only in male subjects. Among CPS-treated male subjects, there was a significant quadratic correlation between cortisol release posttraining and subsequent memory. Thus, these findings represent the first demonstration of an inverted-U relationship between activity of endogenous stress hormones and human memory.

Amygdala modulation of parahippocampal and frontal regions during emotionally influenced memory storage.

Considerable evidence from both animal and human subject research supports the hypothesis that the amygdala, when activated by emotional arousal, modulates memory storage processes in other brain regions. By this hypothesis, changes in the functional interactions of the amygdala with other brain regions during emotional conditions should underlie, at least in part, enhanced memory for emotional material. Here we examined the influence of the human amygdala on other brain regions under emotional and nonemotional learning conditions using structural equation modeling (SEqM). Eleven male subjects received two PET scans for regional cerebral glucose metabolism-one scan while viewing a series of emotionally provocative (negative) film clips and a second scan while viewing a series of more emotionally neutral film clips. Enhanced activity in the right amygdala was related to enhanced memory for the emotional films. To identify potential candidate voxels for SEqM, the functional connectivity of the maximally activated voxel within the right amygdala was investigated using partial least squares. A subset of regions identified by this analysis showing differences functional connectivity with the amygdala between the emotional versus neutral film conditions were then submitted to SEqM, which revealed significantly increased amygdala influences on the ipsilateral parahippocampal gyrus and ventrolateral prefrontal cortex during the emotional relative to the neutral film viewing condition. These findings support the view that increased influences from the amygdala, presumably reflecting its memory-modulation function, occur during emotionally arousing learning situations.

Amygdaloid complex lesions differentially affect retention of tasks using appetitive and aversive reinforcement.

The hypothesis that the amygdaloid complex (AC) is involved in the formation of stimulus-reward associations was examined. A series of experiments (1A-1C) directly compared the effects of lesions (produced by injection of the excitotoxin N-methyl-D-aspartic acid) on 1-trial appetitive and 1-trial aversive learning in rats. Experiments 1A and 1B, which used different degrees of reinforcement, revealed no effect of lesions on the appetitive task, whereas acquisition of the aversive task was significantly impaired. This impairment depended on the nature of the aversive reinforcement used: Impairment was seen when a highly aversive stimulus (footshock) was used but not when a less aversive stimulus (0.2% quinine solution) was used. Control experiments indicated that the effect of lesions was not due to reduced sensitivity to the foot-shock. In Experiment 2, a novel odor conditioning task examined further the effect of AC lesions on the acquisition of appetitive and aversive stimulus-reinforcement associations. As in Experiment 1, the AC lesions impaired learning of the aversive association but did not significantly influence the appetitive association. It is argued that, although the AC may be involved in some types of appetitively rewarded learning, the findings of a differential effect of AC lesions on aversively rewarded learning suggest a role in learning beyond the formation of stimulus-reinforcement associations.

Memory for emotional events: differential effects of centrally versus peripherally acting β-blocking agents

Abstract Substantial evidence from animal research indicates that enhanced memory associated with emotional experiences involves activation of the β-adrenergic system. This hypothesis is further supported by the finding in human subjects that blockade of β-adrenergic receptors with propranolol selectively reduced memory for emotional events. In the present study, we compared the effects of propranolol, a lipid soluble drug which crosses the blood-brain barrier easily, with those of nadolol, a water soluble drug which crosses the blood-brain barrier to a considerably lesser extent, to determine whether the effect involved peripheral or central β-adrenergic receptors. The effects of these drugs, taken before subjects watched a slide show that was either emotionally arousing or relatively neutral in content, were tested 1 week later with a surprise memory test. Consistent with previous results, propranolol impaired memory (recall and recognition) in the subjects who saw the emotional version of the slide show. In contrast, nadolol did not impair memory of the emotional slide show. These results indicate that the blockade of central β-adrenergic receptors is responsible for the reduction in storage of emotional events. The results support the view that memory of a mild emotional event involves activation of central, but not necessarily peripheral β-adrenergic receptors.