Elizabeth A. Phelps - US grants

Recently it has been proposed that the hippocampus in rats and non-human primates does not encode only spatial information, but rather is responsible for the encoding of associations between the multiple cues present in the environment, whether spatial, temporal, visual, auditory, etc. (Eichenbaum et al., 1990; Sutherland & Rudy, 1989; Rolls et al., 1989). The goal of the proposed research is to examine whether a "relational" approach can also explain the amnesic deficit seen in humans following hippocampal damage. Amnesics generally show impaired performance on explicit memory tests of recognition, cued recall, and recall, but are intact on implicit memory tests such as priming and skill learning. While describing the amnesic deficit as one of explicit access to declarative information accurately characterizes the behavioral consequences of hippocampal damage in humans, it does not explain the processing mechanism that leads to this deficit. It has been suggested that a deficit in relational processing may underlie the behavioral deficit found in amnesia, that is difficulty with explicit memory tasks (Eichenbaum, 1992; Squire, 1992). The present proposal defines the deficit in relational processing as an impairment in forming long lasting, multiple relations between cues present during encoding. In the proposed research amnesics and controls will be given several variations of three types of learning tasks; conditioning tasks, implicit memory tasks, and explicit memory tasks. It is expected that increasing the relational demands on all types of tasks assessing long term memory will detrimentally effect amnesics' performance more than normal controls. In addition, it is expected that amnesics will encode fewer relations with the original learning context than controls and, therefore, will: 1) show less interference than controls when tested in a misleading context, and 2) benefit relatively more than controls from having aspects the original learning context reinstated in the testing environment. Finally, it is hypothesized that the memory representation for amnesics is less complex and complete than controls, and, therefore, will be less flexible in novel situations. Results from the proposed experiments will help determine if a relational approach could accurately describe the deficit seen in human amnesia.

DESCRIPTION: (Adapted from applicant's abstract): Animal models suggest that the amygdala has a broad role in modulating emotional learning and memory, as well learned emotional responses. The human amygdala is commonly characterized as being important for most forms of emotional learning and memory. However, the research on the human amygdala to date has only examined a few paradigms and does not support this broader interpretation. The overarching goal of this proposal is to determine the extent of the human arnygdala's involvement in emotional learning and memory and to characterize its role. By examining the role of the human amygdala in a range of emotional learning and memory tasks, we can begin to discover the extent to which these animal models (and popular descriptions) of the amygdala accurately reflect the human amygdala. Two techniques will be used to examine amygdala function in humans. Studies on patients with amygdala damage will indicate if this structure is critical for normal performance on a given task. FMR about studies in normal subjects will provide additional support for the involvement of the amygdala in these tasks and will also indicate other brain regions that may be important. There are three primary goals. First, we hope to confirm the findings of hippocampal modulation with additional paradigms and expand this research by varying the timing and source of emotional stimulus presentation (Section 1). Second, we want to determine how widespread the amvgdala's modulation of memory is; specifically does it extend to other memory systems that underlie skill/habit learning (Section 2), perceptual priming (Section 3) and working memory (Section 4). Third, we hope to specify the amygdala's role in modulating learned emotional responses to stimuli whose emotional significance is learned by means other than fear conditioning. We propose to examine the emotional learning circumstances under which the amygdala is (or is not) critical for normal skin conductance, heart rate, eyeblink startle and subjective emotional responses (Section 5).

[unreadable] DESCRIPTION (provided by applicant): One of affective neuroscience is the of detailed animal models for fear learning that have been confirmed and extended in investigations with humans. The neural systems identified in these animal models, which have relied on fear conditioning as a basic paradigm, have been implicated in the development of psychological disorders, such as anxiety disorders and drug addiction. Understanding the neural circuits important for the development of these disorders is a first step in linking basic science to their treatment. The next step is to understand how these learned emotional responses can be extinguished or altered by action. The goal of the proposed research is to explore the neural mechanisms underlying the extinction and active coping of conditioned fear across human and non-human species and as they are altered with anxiety disorders. [unreadable] [unreadable] There are three specific aims: [unreadable] Aim 1: To develop paradigms of extinction and fear coping that are similar across species allowing for the exploration of specific neural mechanisms in rodents that can be assessed using less invasive techniques in humans. [unreadable] Aim 2: To determine the link between the neural mechanisms of fear inhibition through extinction with the mechanisms underlying active coping/emotion regulation strategies. [unreadable] Aim 3: To assess how the behavioral expression and neural mechanisms underlying fear extinction and active coping differs between normal subjects and patients suffering from anxiety disorders. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Emotion's interaction with episodic memory plays an important role in both adaptive function and psychopathology. Given this, understanding the range of means by which emotion can influence episodic memory is vital in efforts to develop treatments for psychological disorders. The goal of the proposed research is to characterize the behavioral and neural mechanisms of emotion's influence on episodic memory at multiple stages of memory formation. Episodic memory formation is not an all or none process. There are several distinct stages, each of which may be altered by emotion. The first stage is encoding and it has been suggested that emotion may influence encoding through its modulation of attentional processes (e.g. Anderson &Phelps, 2001;Easterbrook, 1959). After encoding is storage, which is thought to be an active process in that over time episodic memories can become more stable through consolidation. Retrieval assesses the effects of both encoding and consolidation. Studies examining memory retrieval have suggested that emotion not only enhances memory accuracy (McGaugh et al., 2000), but also might alter the characteristics of these memories (Ochsner, 2000). The reactivation of memories with retrieval may also change the quality of these memories (Anderson et al., 2004;Dudai &Eisenberg, 2004). Following retrieval, memory is once again stored, and this additional storage, called reconsolidation, could also be modulated by emotion. The effects of reactivation and reconsolidation on memory can be assessed by a second retrieval, or re-retrieval. The primary neural mechanism that has been proposed for emotion's influence on episodic memory is the amygdala's modulation of hippocampal consolidation with arousal, specifically as it effects subsequent memory accuracy (see Phelps, 2004 for a review). Although understanding this aspect of emotional memory formation is important, it only captures a subset of emotion's overall influence on episodic memory in humans. The aim of the current proposed research is to explore the behavioral characteristics and neural systems underlying emotion's effect on episodic memory formation at encoding, retrieval, and re-retrieval. At each stage it is proposed the amygdala may play a critical role through its influence on hippocampal and parahippocampal function. There are three specific aims: Specific Aim 1 is to further specify how emotion influences attention and perception, and examine how this might affect the neural systems of memory encoding. Specific Aim 2 is to characterize emotion's impact on the behavioral and neural mechanisms of memory retrieval over time, specifically how emotion might alter factors related to recollection and familiarity. Specific Aim 3 is to explore if emotion has an impact on the re-retrieval of memories, with a goal of determining if the reactivation and reconsolidation of memory is influenced by emotion.

[unreadable] DESCRIPTION (provided by applicant): Detailed animal studies provide strong evidence that emotional memories are reconsolidated each time after retrieval, and that protein synthesis inhibitors or beta-adrenergic antagonists can impair this process (e.g., Nadar et al., 2000; Debiec and Ledoux, 2004). In contrast to the notion that memories are stable once they have passed the labile state of formation to being fully consolidated, this basic finding suggests there might be a window of opportunity to impair old emotional memories, and more importantly, traumatic memories. However, to date, there is no evidence that such a process exists in humans. The aim of the current proposed research is to find evidence for reconsolidation of emotional memory in humans, and to elucidate its underlying brain mechanisms. Our strategy will be to examine reconsolidation in normal healthy human volunteers, using procedures that mirror those used in animals. These procedures will be aimed at detecting specific contributions of the amygdala and the hippocampus, two brain regions implicated in anxiety and emotional disorders, to reconsolidation processes. Specifically, we would attempt to provide the first evidence for reconsolidation of human amygdala and hippocampal dependent memories by examining the effects of the beta-adrenergic blocker propranolol on fear conditioning and its contextual modulation. There are two specific aims: Specific Aim 1: a) We will examine the effects of beta-adrenergic receptor blockade on reconsolidation of amygdala-dependent memories in humans, using a cue fear-conditioning paradigm; b) We will investigate the neural mechanisms underlying alterations in re-retrieval of amygdala-dependent memories induced by beta-adrenergic blockade effects on reconsolidation. Specific Aim 2: a) We will examine the effects of beta-adrenergic receptor blockade on reconsolidation of hippocampal-dependent memories in humans, using a context-mediated fear reinstatement paradigm; b) We will investigate the neural mechanisms underlying alterations in re-retrieval of hippocampal-dependent memories induced by beta-adrenergic blockade effects on reconsolidation. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): One of the primary achievements of affective neuroscience is the development of detailed animal models of affective learning and extinction that have been confirmed and extended in investigations with humans (Schultz, 2006;Phelps &LeDoux, 2005). The neural systems identified in these animal models have been implicated in the development of psychological disorders, such as anxiety disorders (Rauch, 2003). However in human experience, social interaction and affective learning are inherently intertwined, and there are a number of ways in which these animal models fail to reflect everyday human function in a social and cultural context. First, the nature of the UCS often differs. Typical reinforcers in human experience are often socially defined, such as money or praise. Second, how stimuli are linked to reinforcers does not always depend on emotional experience. Social means of affective learning can effectively convey the emotional qualities of a stimulus, without directly experiencing an emotional event. Third, diminishing a learned emotional response to a stimulus does not always require that the stimulus is repeatedly exposed. Instead, strategies for changing the emotional value of a stimulus can be conveyed through social interaction. The proposed studies will assess how, or if, animal models of affective learning can be extended to human experience in a social environment. Specific Aim 1: Using simple affective learning paradigms modeled on classical conditioning, we will explore the neural mechanisms of social means of affective learning. Previous research on the acquisition of affective responses has highlighted the importance of the amygdala and striatum. We will examine if the social acquisition of affective responses recruits similar neural mechanisms. Specific Aim 2: We will build on models of extinction learning in classical conditioning to explore if a socially conveyed emotion regulation strategies for controlling learned affective responses depend on overlapping neural mechanisms. Specifically, we will assess the interaction of the lateral and ventral medial prefrontal cortex, amygdala, and striatum. Specific Aim 3: We will explore the overlap in the neural mechanisms underlying the regulation of learned affective responses across a range of social, emotion regulation strategies. Emotional responses can be regulated by a number of social means, such as social support from a friend or training in a therapeutic context. We will explore if these different techniques utilize a similar neural circuitry. The goal of this proposal is to understand how the brain learns emotional responses in a social environment and how they can be controlled and modified using a range of techniques. The ability to control our emotional reactions is critical in everyday adaptive function and the treatment of a range of psychological disorders, such as anxiety disorders.

[unreadable] DESCRIPTION (provided by applicant): None provided; information taken from the Conference Plan. [unreadable] The goal of the proposed conference is to explore the relation between affect, learning and decision-making. The conference will bring together researchers who study affect, learning and decision-making. The goal is to bridge these lines of research that are clearly related, but have often been pursued independently. The hope is that scientists who study the representation of affect and affective learning, who now speculate on the adaptive role of these responses, gain some insight into the processes underlying decisions and choices. At same time, researchers who have primarily examined the neural circuitry and computational models of decision-making, a field that has often focused only on reward in guiding behavior (as opposed to aversive reactions), will gain some exposure and insight into the representation of affect more broadly. By bringing together both senior and junior investigators studying affective learning and decision making from a number of perspectives, it is hoped that we will foster future research that examines the link between affective learning and choice behavior more directly. Furthermore, by exposing basic science researchers to investigators using these models to understand drug addiction and other types of psychopathology, we hope to promote translational research. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The goal of the proposed research is to understand and develop successful means of behavior change that could assist in treatment compliance broadly for a range of health problems, as well as specific treatments for disorders characterized by poor choices, such as obesity and addiction. To achieve this goal, we will combine techniques and insights from neuroeconomics and affective neuroscience. Specifically, we will use behavioral economic paradigms and models to isolate and quantify specific individual factors that influence decisions, including the rate at which future rewards are discounted in value and the relative sensitivity to loss or risk when assessing value. We will link these specific decision variables to specific components of emotion that may contribute to the value computation, such as the arousal response to a loss or gain. We will then build on recent advances in affective neuroscience examining means to change emotion -- including cognitive emotion regulation techniques and pharmacological manipulations - to explore how these impact the different decision variables. Finally, we will examine how another common emotional response known to impact health decisions, namely stress, alters both the specific decision variables and the effectiveness of the proposed techniques used to alter emotional responses and choice behavior. PUBLIC HEALTH RELEVANCE: It is not uncommon for individuals to make decisions that can be detrimental to their health and well-being, such as in obesity and addiction. The proposed research will combine insights from the science of decision making and emotion to develop new means to encourage behavior change.

DESCRIPTION (provided by applicant): The prevalence of anxiety disorders is estimated to be up to 18% of the US adult population. A primary treatment for anxiety disorders is exposure therapy, which is based on the principles of fear extinction. Although extinction based therapies can be effective, their efficacy is limited, in part due to the nature of extinction learning itsel. There is abundant evidence that extinction learning does not result in a significant alteration of the original fear memory, but rather results in new learning that the previously feared event is now safe. One consequence is that the original fear memory and the extinction memory may compete for expression. A range of circumstances, such as the passage of time (spontaneous recovery), alterations in context (renewal), and stress (reinstatement), can result in the fear returning. This potential for fear memory recovery even after extensive extinction training highlights the need to discover more persistent and robust techniques to diminish fear. Using simple classical fear conditioning paradigms, research in non-human animals has identified two potential mechanisms to prevent the return of fear. The first is by manipulating the reconsolidation or re-storage of the original fear memory. The second is by allowing the animal experience with control over the stressor, which has been shown to have lasting effects on reducing the likelihood of fear recovery. The goal of the proposed research is to assess in humans the efficacy, specificity, and underlying neural mechanisms of techniques that have been shown to prevent the return of fear in non- human animals. Studies under Aim 1 examine techniques to disrupt or alter the reconsolidation of conditioned fear in humans. Specifically, the pharmacological disruption of reconsolidation is explored and the specificity and the psychological and neural consequences of behavioral interference techniques used to alter the reconsolidation of conditioned fear are examined. Aim 2 examines whether experience with control over a stressor can diminish the likelihood that a fear memory returns. Finally, the studies under Aim 3 examine the success of these techniques in patients who suffer from PTSD to determine if the neural consequences of this anxiety disorder alters the effectiveness of these procedures. The overarching goal of all the proposed studies is to discover how and when we might be able to prevent the return of fear in humans, which has the potential to lead to novel and more effective treatments for anxiety disorders. PUBLIC HEALTH RELEVANCE: The prevalence of anxiety disorders is estimated to be up to 18% of the US adult population and a primary treatment for these disorders is exposure therapy, which is based on the principles of fear extinction. One limitation of fear extinction is that the original memory is not altered and in some circumstances the fear can return. The proposed studies aim to discover how and when we might be able to improve on extinction-based therapies and prevent the return of fear in humans, potentially leading to novel and more effective treatments for anxiety disorders.

Project Summary Substance addiction is characterized by compulsive and destructive choices. Decisions regarding substance use are fundamentally decisions of uncertainty regarding the negative or positive consequences that may arise. The proposed research will identify and manipulate affective factors that may play a role in decisions under uncertainty. Bringing together insights, expertise and techniques from affective science, neuroeconomics and addiction, we will systematically explore and characterize how specific affect variables modulate discrete decision processes that may be particularly common in decisions involving substance use. Specifically, we will both assess and manipulate specific components of affect ? arousal, stress, and mood -- to characterize how they may uniquely modulate three quantifiable, independent variables that contribute to decisions under uncertainty. The significance of the proposed research lies in the premise that if we can more accurately characterize the impact of affective factors on decision-making, we can use this knowledge to develop more effective means to influence choices concerning substance use. Specific Aim 1 will examine how transient arousal to the choice options, acute stress and mood may independently influence sensitivity to risk and ambiguity. Research finds that individuals are more averse to ambiguity than risk, preferring gambles with known probabilities over gambles with unknown probabilities. Decisions regarding substance use are by their nature risky and some choices more ambiguous in that the choice outcome has unknown probabilities. The proposed research examines how arousal, mood and stress independently modulate sensitivity to risk and ambiguity. Specific Aim 2 will assess how arousal, acute and chronic stress and mood modulates assessments of uncertainty in sequential decisions, specifically whether one should persist in a current course of action, or desist and pursue alternatives. The decision of whether to persist or desist is fundamentally captured in foraging decisions. The concept of foraging comes from behavioral ecology and is used to describe how animals decide to either persist in exploiting a current, depleting food resource (or patch), or desist and search for a new, uncertain, but potentially more abundant food resource at a cost of time and effort. Importantly, the basic principles of foraging have been shown to capture a range of complex human decisions, and may extend to drug use when choosing whether to stay or persist with substance abuse behavior or desist and try an alternative course of action. Across domains, optimal foraging decisions are characterized by the marginal value theorem (MVT), which allows the assessment of how different affect variables contribute to optimal, or non-optimal choices. Specific Aim 3 outlines an exploratory investigation of how an addicted population differentially responds to decisions under uncertainty pre and post-treatment.