Alterations in peripheral immune markers are observed in individuals with post-traumatic stress disorder (PTSD). PTSD is characterized in part by impaired extinction of fear memory for a traumatic experience. We hypothesized that fear memory extinction is regulated by immune signaling stimulated when fear memory is retrieved. The relationship between fear memory and the peripheral immune response was tested using auditory Pavlovian fear conditioning in mice. Memory for the association was quantified by the amount of conditioned freezing exhibited in response to the conditioned stimulus (CS), extinction and time-dependent changes in circulating inflammatory cytokines. Brief extinction training with 12 CS rapidly and acutely increased circulating levels of the cytokine interleukin-6 (IL-6), downstream IL-6 signaling, other IL-6 related pro-inflammatory cytokines. Transgenic manipulations or neutralizing antibodies that inhibit IL-6 activity did not affect conditioned freezing during the acquisition of fear conditioning or extinction but significantly reduced conditioned freezing 24 h after extinction training with 12 CS. Conversely, conditioned freezing after extinction training was unchanged by IL-6 inhibition when 40 CS were used during the extinction training session. In addition to effectively diminishing conditioned freezing, extinction training with 40 CS also diminished the subsequent IL-6 response to the CS. These data demonstrate that IL-6 released following fear memory retrieval contributes to the maintenance of that fear memory and that this effect is extinction dependent. These findings extend the current understanding for the role of the immune system in PTSD and suggest that IL-6 and other IL-6 related pro-inflammatory cytokines may contribute to the persistence of fear memory in PTSD where fear memory extinction is impaired.
Past reports suggest that threatening materials can impact the efficiency of goal-directed behavior. However, questions remain about whether a conditional stimulus (CS) can capture attention as previous results may have been influenced by voluntary prioritization of a to-be-ignored CS. In 2 experiments, eye tracking was used to evaluate whether neutral, perceptually simple materials capture attention when they take on aversive properties via probabilistic fear conditioning with strict methods in place to eliminate voluntary CS prioritization. During training, participants attempted to fixate search targets (i.e., horizontally or vertically oriented rectangles) as quickly as possible to avoid shock. In reality, shock administration was related to rectangle orientation so that 1 rectangle (CS+) predicted shock more often than the other (CS-). Subsequently rectangles became distractors and were to be ignored. At this point, participants were instructed to fixate a new target and incidences of CS capture were examined. Results showed that saccades were made more quickly to the CS+ than the CS- as training progressed, and that oculomotor capture by irrelevant rectangles occurred more often for the CS+ than the CS-. An independent physiological index (skin conductance response) confirmed that contingencies had been learned, as SCR magnitude was greater for CS+ than CS- trials early in the test phase. These effects were documented despite the absence of explicit contingency knowledge, assessed using a postexperimental questionnaire. Collectively, these outcomes indicate that a CS can capture attention despite being task-irrelevant, and that these effects do not depend on conscious awareness of learned contingencies. (PsycINFO Database Record
Although the amygdala is often directly linked with fear and emotion, amygdala neurons are activated by a wide variety of emotional and non-emotional stimuli. Different subregions within the amygdala may be engaged preferentially by different aspects of emotional and non-emotional tasks. To test this hypothesis, we measured and compared the effects of novelty and fear on amygdala activity. We used high-resolution blood oxygenation level-dependent (BOLD) imaging and streamline tractography to subdivide the amygdala into three distinct functional subunits. We identified a laterobasal subregion connected with the visual cortex that responds generally to visual stimuli, a non-projecting region that responds to salient visual stimuli, and a centromedial subregion connected with the diencephalon that responds only when a visual stimulus predicts an aversive outcome. We provide anatomical and functional support for a model of amygdala function where information enters through the laterobasal subregion, is processed by intrinsic circuits in the interspersed tissue, and is then passed to the centromedial subregion, where activation leads to behavioral output.
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