Opposing effects of negative emotion on amygdalar and hippocampal memory for items and associations.
ABSTRACT: Although negative emotion can strengthen memory of an event it can also result in memory disturbances, as in post-traumatic stress disorder (PTSD). We examined the effects of negative item content on amygdalar and hippocampal function in memory for the items themselves and for the associations between them. During fMRI, we examined encoding and retrieval of paired associates made up of all four combinations of neutral and negative images. At test, participants were cued with an image and, if recognised, had to retrieve the associated (target) image. The presence of negative images increased item memory but reduced associative memory. At encoding, subsequent item recognition correlated with amygdala activity, while subsequent associative memory correlated with hippocampal activity. Hippocampal activity was reduced by the presence of negative images, during encoding and correct associative retrieval. In contrast, amygdala activity increased for correctly retrieved negative images, even when cued by a neutral image. Our findings support a dual representation account, whereby negative emotion up-regulates the amygdala to strengthen item memory but down-regulates the hippocampus to weaken associative representations. These results have implications for the development and treatment of clinical disorders in which diminished associations between emotional stimuli and their context contribute to negative symptoms, as in PTSD.
Project description:BACKGROUND:Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. METHODS:Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. RESULTS:Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. CONCLUSIONS:Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD.
Project description:Hippocampal structure is particularly sensitive to trauma and other stressors. However, previous findings linking hippocampal function with trauma-related psychopathology have been mixed. Heterogeneity in psychological responses to trauma has not been considered with respect to hippocampal function and may contribute to mixed findings. To address these issues, we examined associations between data-driven symptom dimensions and episodic memory formation, a key function of the hippocampus, in a trauma-exposed sample. Symptom dimensions were defined using principal components analysis (PCA) in 3881 trauma-exposed African-American women recruited from primary care waiting rooms of a large urban hospital. Hippocampal and amygdala function were subsequently investigated in an fMRI study of episodic memory formation in a subset of 54 women. Participants viewed scenes with neutral, negative, and positive content during fMRI, and completed a delayed cued recall task. PCA analysis produced five symptom dimensions interpreted as reflecting negative affect, somatic symptoms, re-experiencing, hyper-arousal, and numbing. <i>Re</i>-experiencing was the only symptom type associated with hippocampal function, predicting increased memory encoding-related activation in the hippocampus as well as the amygdala. In contrast, the negative affect component predicted lower amygdala activation for subsequently recalled scenes, and lower functional coupling with other important memory-related regions including the precuneus, inferior frontal gyrus, and occipital cortex. Symptom dimensions were not related to hippocampal volume. The fMRI findings for re-experiencing versus negative affect parallel differences in behavioral memory phenomena in PTSD versus MDD, and highlight a need for more complex models of trauma-related pathology.
Project description:Showing an emotional item in a neutral background scene often leads to enhanced memory for the emotional item and impaired associative memory for background details. Meanwhile, both top-down goal relevance and bottom-up perceptual features played important roles in memory binding. We conducted two experiments and aimed to further examine the effects of goal relevance and perceptual features on emotional items and associative memory. By manipulating goal relevance (asking participants to categorize only each item image as living or non-living or to categorize each whole composite picture consisted of item image and background scene as natural scene or manufactured scene) and perceptual features (controlling visual contrast and visual familiarity) in two experiments, we found that both high goal relevance and salient perceptual features (high salience of items vs. high familiarity of items) could promote emotional item memory, but they had different effects on associative memory for emotional items and neutral backgrounds. Specifically, high goal relevance and high perceptual-salience of items could jointly impair the associative memory for emotional items and neutral backgrounds, while the effect of item familiarity on associative memory for emotional items would be modulated by goal relevance. High familiarity of items could increase associative memory for negative items and neutral backgrounds only in the low goal relevance condition. These findings suggest the effect of emotion on associative memory is not only related to attentional capture elicited by emotion, but also can be affected by goal relevance and perceptual features of stimulus.
Project description:When our experience violates our predictions, it is adaptive to upregulate encoding of novel information, while down-weighting retrieval of erroneous memory predictions to promote an updated representation of the world. We asked whether mnemonic prediction errors promote hippocampal encoding versus retrieval states, as marked by distinct network connectivity between hippocampal subfields. During fMRI scanning, participants were cued to internally retrieve well-learned complex room-images and were then presented with either an identical or a modified image (0-4 changes). In the left hemisphere, we find that CA1-entorhinal connectivity increases, and CA1-CA3 connectivity decreases, with the number of changes. Further, in the left CA1, the similarity between activity patterns during cued-retrieval of the learned room and during the image is lower when the image includes changes, consistent with a prediction error signal in CA1. Our findings provide a mechanism by which mnemonic prediction errors may drive memory updating-by biasing hippocampal states.
Project description:Intimate partner violence (IPV) is one of the most common causes of posttraumatic stress disorder (PTSD) in women. Victims of IPV are often preoccupied by the anticipation of impending harm. This investigation tested the hypothesis that IPV-related PTSD individuals show exaggerated insula reactivity to the anticipation of aversive stimuli.Fifteen women with a history of IPV and consequent PTSD (IPV-PTSD) and 15 non-traumatized control (NTC) women performed a task involving cued anticipation to images of positive and negative events during functional magnetic resonance imaging.Both groups showed increased activation of bilateral anterior insula during anticipation of negative images minus anticipation of positive images. Activation in right anterior/middle insula was significantly greater in the IPV-PTSD relative to the NTC group. Functional connectivity analysis revealed that changes in activation in right middle insula and bilateral anterior insula were more strongly associated with amygdala activation changes in NTC than in IPV-PTSD subjects.This study revealed increased activation in the anterior/middle insula during negative anticipation in women with IPV-related PTSD. These findings in women with IPV could be a consequence of the IPV exposure, reflect pre-existing differences in insular function, or be due to the development of PTSD. Thus, future longitudinal studies need to examine these possibilities.
Project description:The hippocampus plays a prominent role in associative memory by supporting relational binding and recollection processes. Structural atrophy in the hippocampus is likely to induce associative memory deficits in older adults. Previous studies have primarily focused on average age-related differences in hippocampal structure and memory performance. To date, however, it remains unclear whether individual differences in hippocampal morphometry underlie differential associative memory performance, and whether there are sex differences in the structural correlates of associative memory in healthy older adults. Here, we used voxel-based morphometry (VBM) to examine the extent to which gray matter volume (GMV) of the hippocampus predicts associative memory performance in cognitively normal older adults. Seventy-one participants completed a cued recall paired-associative learning test (PALT), which consists of novel associations and semantically related associations, and underwent magnetic resonance imaging (MRI). We observed worse associative memory performance and larger variability for novel associations than for semantically related associations. The VBM results revealed that higher scores on associative memory for novel associations were related to greater hippocampal GMV across all older adults. When considering men and women separately, the correlation between hippocampal GMV and associative memory performance for novel associations reached significance only in older women. These findings suggest that hippocampal structural volumes may predict individual differences in novel associative memory in older women but not men.
Project description:Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are often comorbid. Drinking tends to increase following trauma, which may exacerbate PTSD-related symptoms. Despite a clear relationship between excessive alcohol use and PTSD, how alcohol impacts the expression of traumatic fear remains unclear. This study aims to determine the neurobehavioral impact of chronic alcohol (ethanol; EtOH) on the expression of established fear memories in C57BL/6?N mice. We show that chronic EtOH selectively augments cued fear memory generalization and impairs fear extinction retrieval, leaving the expression of the original cued response intact. Immunohistochemistry for Arc/arg3.1 (Arc) revealed EtOH-induced decreases in Arc expression in the infralimbic cortex (IL) and basolateral amygdala complex (BLA) that were associated with cued fear memory overgeneralization. Chemogenetic stimulation of IL pyramidal neurons reversed EtOH-driven fear memory overgeneralization, identifying a role for the IL in cued fear memory precision. Considering the modulatory influence of the IL over conditioned fear expression, these data suggest a model whereby chronic EtOH-driven neuroadaptations in the IL promote fear memory overgeneralization. These findings provide new mechanistic insight into how excessive alcohol use, following exposure to a traumatic event, can exacerbate symptoms of traumatic fear.
Project description:People with schizophrenia (PSZ) exhibit signs of reduced working memory (WM) capacity. However, this may reflect an impairment in managing its content, e.g. preventing irrelevant information from taking up available storage space, rather than a true capacity reduction. We tested the ability to eliminate and update WM content in 38 PSZ and 30 healthy control subjects (HCS). Images of real-world objects were presented consecutively, and a tone cued the item most likely to be tested for memory. On half the trials, randomly intermixed, a second tone occurred. Participants were informed that the item cued by the second tone was now the most likely to be tested, and the item cued by the first tone now the least likely, providing incentive to eliminate the first cued item from WM. Both HCS and PSZ displayed a robust performance advantage for cued items. Unexpectedly, PSZ more efficiently removed the no-longer-essential item from WM than HCS. The magnitude of the WM clearance of this first cued item correlated with memory performance for the newly prioritized second cued item in PSZ, indicating that it was adaptive. However, WM clearance was not associated with WM capacity, ruling out the need to budget limited resources as an explanation for greater clearance in PSZ. A robust correlation between WM clearance and poverty of speech in PSZ instead suggests that the propensity to rapidly clear non-essential information and minimize the number of items in WM may be the reflection of a negative symptom trait. This finding may reflect a more general tendency of PSZ to focus processing more narrowly than HCS.
Project description:Smaller hippocampal volume is associated with increased risk for PTSD following trauma, but the hippocampal functions involved remain unknown. We propose a conceptual model that identifies broad impairment in hippocampus-dependent associative learning as a vulnerability factor for PTSD. Associative learning of foreground cues and background context is required to form an integrated representation of an event. People with poor associative learning may have difficulty remembering who or what was present during a trauma, where the trauma occurred, or the sequence of events, which may contribute to PTSD symptoms. We argue that associative learning difficulties in PTSD exist for cues and context, regardless of the emotional nature of the information. This contrasts with PTSD models that focus exclusively on threat-processing or contextual-processing. In a meta-analysis, people with PTSD exhibited poor associative learning of multiple information types compared to those without PTSD. Differences were of medium effect size and similar magnitude for neutral and negative/trauma-related stimuli. We provide evidence for associative learning difficulties as a neurocognitive pathway that may contribute to PTSD.
Project description:We examined whether hippocampal activity in recognition relates to the strength of the memory or to recollective experience, a subject of considerable current debate. Participants studied word pairs and then made two successive recognition decisions on each item: first on the uncued target and then on the target presented with the studied cue word. We compared recollection and familiarity patterns of activation in fMRI for these decisions. Critically, our analyses attempted in two ways to equate perceived memory strength while varying the associative information available. First, activity for targets judged familiar before cueing was contrasted with activity for the same items in the second decision as a function of whether the targets converted to recollection or remained familiar when the context cues were provided. We found increased hippocampal activity following cueing only with recollective conversion. Second, we investigated whether hippocampal activity was modulated by the rated familiarity strength of cued items or whether it increased uniquely in recollection. Hippocampal activation was not modulated parametrically by familiarity strength and recollected items were associated with greater activity relative to highly familiar items. Together, our results support the notion that it is recollection of context, rather than memory strength, that underlies hippocampal engagement at retrieval.