Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 52, Pages 26970-26979Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1910481116
Keywords
safety learning; threat; conditioned inhibition; hippocampus; anxiety
Categories
Funding
- NIH Director's Early Independence Award [DP5OD021370]
- Brain & Behavior Research Foundation (National Alliance for Research on Schizophrenia and Depression) Young Investigator Award
- Jacobs Foundation Early Career Research Fellowship
- NIH R01 [NS052819]
- Pritzker Neuropsychiatric Disorders Research Consortium Award
- New York Presbyterian Youth Anxiety Center
- DeWitt-Wallace Fund of the New York Community Trust
- National Institute of Mental Health Pathway to Independence Award [NIH K99MH119320]
- National Center for Advancing Translational Science of the NIH TL1 Award [TR0002386]
- National Science Foundation Graduate Research Fellowship Program Award [DGE1122492]
- Dr. Mortimer D. Sackler family
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Heightened fear and inefficient safety learning are key features of fear and anxiety disorders. Evidence-based interventions for anxiety disorders, such as cognitive behavioral therapy, primarily rely on mechanisms of fear extinction. However, up to 50% of clinically anxious individuals do not respond to current evidence-based treatment, suggesting a critical need for new interventions based on alternative neurobiological pathways. Using parallel human and rodent conditioned inhibition paradigms alongside brain imaging methodologies, we investigated neural activity patterns in the ventral hippocampus in response to stimuli predictive of threat or safety and compound cues to test inhibition via safety in the presence of threat. Distinct hippocampal responses to threat, safety, and compound cues suggest that the ventral hippocampus is involved in conditioned inhibition in both mice and humans. Moreover, unique response patterns within target-differentiated subpopulations of ventral hippocampal neurons identify a circuit by which fear may be inhibited via safety. Specifically, ventral hippocampal neurons projecting to the prelimbic cortex, but not to the infralimbic cortex or basolateral amygdala, were more active to safety and compound cues than threat cues, and activity correlated with freezing behavior in rodents. A corresponding distinction was observed in humans: hippocampal-dorsal anterior cingulate cortex functional connectivity-but not hippocampal-anterior ventromedial prefrontal cortex or hippocampal-basolateral amygdala connectivity-differentiated between threat, safety, and compound conditions. These findings highlight the potential to enhance treatment for anxiety disorders by targeting an alternative neural mechanism through safety signal learning.
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