People who develop schizophrenia show deficits in emotional learning and memory, which have been linked to the symptoms of the disorder. Yet the neurobiological basis of these deficits is unknown. One challenging issue associated with this question is that the medications used to treat schizophrenia also cause some impairment in emotional function, so it has been difficult in previous studies to distinguish effects of the disorder from those of the medications used by the majority of the patients with the illness. One common method used to study emotional learning and memory in mammals, including humans, is called Pavlovian fear conditioning. In Pavlovian fear conditioning procedures, a person is exposed to a neutral stimulus, such as a tone or picture, which is followed by an unpleasant sensation, such as a loud noise or mild electrical stimulus. After a certain number of repetitions of this procedure, the person begins to experience some anticipatory anxiety or fear when exposed to the neutral stimulus by itself. A second type of learning can occur when this neutral stimulus is later presented several times without being followed by the unpleasant stimulus;this is called extinction learning and it requires the formation of a memory trace that is coded separately from the fear memory. These fear and extinction memories can be recalled at a later time, depending on the circumstances (called the "context") during the formation and recall of the memories. We have found evidence suggesting that the learning and later recall of fear and extinction memories is abnormal in schizophrenia. In this project, we will test the hypothesis that these abnormalities in fear and extinction learning and memory in schizophrenia are related to specific changes in the function of the brain regions known to drive these processes, and that these neural changes are linked to specific symptoms of schizophrenia. We will also determine whether any of the abnormalities in this system arise from, are worsened or improved by treatment with antipsychotic medications. This project has implications for understanding the fundamental pathophysiology of schizophrenia and for developing early markers and new treatments for the disorder. !

Public Health Relevance

The proposed research will test the hypothesis that the symptoms of schizophrenia arise from disruption of basic neural mechanisms governing emotional learning and memory. The findings of this project could lead to the identification of novel treatment targets for therapeutic agents aimed at ameliorating treatment-resistant symptoms of schizophrenia, and a quantitative neural phenotype for genetic and early detection studies of the disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Meinecke, Douglas L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Holt, Daphne J; Boeke, Emily A; Wolthusen, Rick P F et al. (2014) A parametric study of fear generalization to faces and non-face objects: relationship to discrimination thresholds. Front Hum Neurosci 8:624
Coombs 3rd, Garth; Loggia, Marco L; Greve, Douglas N et al. (2014) Amygdala perfusion is predicted by its functional connectivity with the ventromedial prefrontal cortex and negative affect. PLoS One 9:e97466