Lawrence Cahill - US grants

This is a submission for a B/START award. The applicant requests one year of support for studies of the role of peripheral stress hormones (catecholamines) in human memory. Building on a strong base of both animal and human research, this proposal aims to determine for the first time whether catecholamine stress hormones (epinephrine and norepinephrine) affect long-term memory in humans. Subjects will receive intra-venous injections of one of the hormones (at physiological doses) or of placebo during or after viewing a series of slides. Memory for the slides will be tested in an incidental (surprise) memory test two weeks later. It is predicted that, if adrenergic stress hormones (which are known to be released during emotional situations) affect memory, then memory of the slides should be different in those receiving the stress hormone injections compared to those receiving the placebo injections. As in the animal studies, post-learning injections will be used in some experiments to rule out potential effects of the hormones on non-memory factors like attention. These experiments should provide the strongest evidence to date bearing on the question of whether endogenous stress hormones modulate memory for emotional events. The results will also have implications for the prevention and treatment of disorders of emotional memory, such as Post Traumatic Stress Disorder.

This is a resubmission of an application for a FIRST Award. The applicant has recently begun to extend an extensive animal literature regarding the neurobiology of emotional memory storage to humans. The experiments to date confirm in human subjects the theory, anchored in animal studies that enhanced long-term memory for emotionally arousing events depends on the activity of, at minimum, two key nervous system elements: 1) endogenous stress hormones and 2) the Amygdaloid Complex (AC). The experiments proposed here are designed to build upon the initial results. Three general categories of experiments are proposed. The first are experiments involving stimulation of catecholamine receptors and long-term memory. These experiments will test in humans a critical prediction from the animal literature regarding neural mechanisms of emotional memory in humans, namely, that appropriate stimulation of catecholamine receptors enhances long-term memory formation. The second category of experiments involves blockade of catecholamine receptors. These experiments are designed to more fully investigate the applicants finding that beta-adrenergic receptor blockade selectively impairs emotional memory. Finally, PET scanning will be used to confirm and extend the applicants finding of a correlation between activity of the AC and long-term emotional memory. PET scanning will also be combined with beta adrenergic blockade to study the interaction between the AC and catecholamine receptors in emotional memory. Collectively, the proposed experiments will help provide a more detailed account of neurobiological mechanisms of emotional memory storage in humans. In so doing, they should also help bridge the gap between our understanding of the normal brain mechanisms subserving memory for emotionally negative events, and our understanding of how these mechanisms may underlie disorders associated with traumatic negative events, such as Post Traumatic Stress Disorder.

DESCRIPTION (provided by applicant): This is an application for a CEBRA award from NIDA. Understanding neural mechanisms of addiction will likely involve determining how normal brain mechanisms of emotional memory formation contribute to the disorder. The amygdala is known to be crucial for emotional memory, and many intriguing links exist between addiction and amygdala function in emotional memory. For example, activity of dopamine (DA), a neurotransmitter heavily implicated in addiction, within the amygdala clearly influences emotional memory formation. However, despite their likely importance, dopaminergic mechanisms within the human amygdala remain almost completely unexplored at present, and their relations to emotional memory and addiction are not known. This gap in our knowledge results primarily from the fact that ligands used to date to study human dopaminergic function with positron emission tomography (PET) scanning lack sufficient sensitivity to accurately and reliably assess amygdala activity. Recently, however and colleagues (2002a) developed a specific D2/D3 ligand-18F-fallypride- capable of reliably detecting D2/D3 receptor related activity in the human amygdala. Development of this method has created a new opportunity to study DA mechanisms within the human amygdala (and related brain regions) with respect to both to normal mechanisms of emotional memory and to addiction. Here we propose to combine the expertise of the PI in human amygdala function in emotional memory, with that of the Co-PI in the 18F-fallypride PET method to investigate the responsiveness of DA within the human amygdala to emotional learning conditions in both men and women. The primary goal of this proposal is to determine whether endogenous dopamine release within the human amygdala (and related regions) in response to the emotional memory challenges used in our previous studies can be detected with the (18)F-fallypride method. In addition, we propose to begin determining how both the variables of sex and cerebral hemisphere influence these mechanisms. The data derived from these preliminary experiments should lay the foundation for a research program aimed at understanding how DA mechanisms within the human amygdala subserve both emotional memory and addiction.

DESCRIPTION (provided by applicant): Converging evidence from animal and human subject studies supports the hypothesis that endogenous stress hormones (e.g., epinephrine, cortisol) interact with the amygdala to modulate explicit memory consolidation for emotionally arousing events. Our recent work involving human subjects has developed this theoretical framework in several ways. Most relevant to this proposal, we found that post-learning stress hormone activation does not uniformly enhance long-term memory consolidation; rather, that it interacts with the degree of arousal at initial encoding of a stimulus to modulate consolidation. We have also demonstrated a relationship between spontaneous, intrusive recollections after viewing emotional films and the strength of long-term memory for the films. Finally, we have uncovered pronounced sex-related influences on brain and hormonal mechanisms of emotional memory. The primary goal of this proposal is to conduct cognitive and neurobiological studies to better understand brain and hormone mechanisms regulating consolidation of emotional memory. The specific experimental aims build on our recent findings, and fall into one of three general sections. The first section will examine stress- and sex-hormone mechanisms underlying enhanced memory consolidation induced by cold pressor stress. The second section will examine adrenocortical and adrenomedullary involvement in the relationship we have found between spontaneous, intrusive recollections after viewing emotional films and strength of memory for the films. The third section will use PET scanning and Structural Equation Modeling ("Path Analysis") to identify brain regions with which the amygdala interacts to influence emotional memory. Each of these studies will be conducted independently on women and men. Collectively, these investigations should substantially advance our understanding of how brain and hormone systems interact to regulate explicit memory consolidation for emotionally stressful events. In so doing they should further close the gap that exists between our knowledge of "normal" brain memory mechanisms for emotional events, and of pathological mechanisms following emotionally traumatic experiences that are central to the etiology of disorders such as Clinical Depression and Posttraumatic Stress Disorder.

long term memory; emotions; brain imaging /visualization /scanning; amygdala; gender difference; neural information processing; behavioral /social science research tag; positron emission tomography; human subject; clinical research;

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Investigate the effects of acute cardiovascular exercise on the noradrenergic system and memory for emotionally positive visual stimuli in men and women with mild cognitive impairments. We hypothesize that acute cardiovascular exercise will result in an increase in sAA in healthy aged men and women, as well as an enhancement in memory for positive emotional visual stimuli. We will also examine whether these relationships hold in persons with mild cognitive impairment (MCI) and cognitive impairment, no dementia (CIND). We will do this by comparing the memory and alpha-amylase responses in subjects who view positive emotional stimuli followed either by a rest period, or six minutes of exercise on a stationary bicycle. Saliva samples will be taken at different time points throughout the study for the assessment of adrenergic stress response. This will be followed by a surprise memory test shortly after the exercise or rest period. We anticipate finding a relationship between the extent to which the alpha-amylase response to exercise in spared in the patients, and the degree to which they retain the visual images in memory.