TY - JOUR T1 - The effect of threat on right dlPFC activity during behavioral pattern separation. JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.0717-17.2017 SP - 0717-17 AU - Nicholas L. Balderston AU - Abigail Hsiung AU - Monique Ernst AU - Christian Grillon Y1 - 2017/08/21 UR - http://www.jneurosci.org/content/early/2017/08/21/JNEUROSCI.0717-17.2017.abstract N2 - It has long been established that individuals with anxiety disorders tend to overgeneralize attributes of fearful stimuli to non-fearful stimuli, but there is little mechanistic understanding of the neural system that supports overgeneralization. To address this gap in our knowledge, this study examined effect of experimentally-induced anxiety in humans on generalization using the behavioral pattern separation (BPS) paradigm. Healthy subjects of both sexes encoded and retrieved novel objects during periods of safety and threat of unpredictable shocks, while we recorded brain activity with fMRI. During retrieval, subjects were instructed to differentiate among new, old, and altered images. We hypothesized that the hippocampus and dorsolateral prefrontal cortex (dlPFC) would play a key role in the effect of anxiety on BPS. The dlPFC but not the hippocampus showed increased activity for altered images compared to old images when retrieval occurred during periods of threat compared to safe. In addition, accuracy for altered items retrieved during threat was correlated with dlPFC activity. Together these results suggest that overgeneralization in anxiety patients may be mediated by an inability to recruit the dlPFC, which mediates the cognitive control needed to overcome anxiety and differentiate between old and altered items during periods of threat.SIGNIFICANCE STATEMENTAnxiety and PTSD patients generalize fear to non-fearful fear stimuli, making it difficult to regulate anxiety. Understanding how anxiety affects generalization is key to understanding the overgeneralization experienced by these patients. We examined this relationship in healthy subjects by studying how threat of shock impacts neural responses to previously encountered stimuli. Although previous studies point to hippocampal involvement, we found that threat impacted activity in the dorsolateral prefrontal cortex (dlPFC), rather than the hippocampus, when subjects encountered slightly altered versions of the previously encountered items. Importantly this dlPFC activity predicted performance for these items. Together these results suggest that the dlPFC is important for discrimination during elevated anxiety, and that overgeneralization may reflect a deficit in dlPFC mediated cognitive control. ER -