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.
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.
|Wolthusen, Rick P F; Coombs 3rd, Garth; Boeke, Emily A et al. (2018) Correlation Between Levels of Delusional Beliefs and Perfusion of the Hippocampus and an Associated Network in a Non-Help-Seeking Population. Biol Psychiatry Cogn Neurosci Neuroimaging 3:178-186|
|Ho, N F; Iglesias, J E; Sum, M Y et al. (2017) Progression from selective to general involvement of hippocampal subfields in schizophrenia. Mol Psychiatry 22:142-152|
|Ho, New Fei; Holt, Daphne J; Cheung, Mike et al. (2017) Progressive Decline in Hippocampal CA1 Volume in Individuals at Ultra-High-Risk for Psychosis Who Do Not Remit: Findings from the Longitudinal Youth at Risk Study. Neuropsychopharmacology 42:1361-1370|
|Mueller, Sophia; Wang, Danhong; Pan, Ruiqi et al. (2015) Abnormalities in hemispheric specialization of caudate nucleus connectivity in schizophrenia. JAMA Psychiatry 72:552-60|
|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|
|Linnman, Clas; Coombs 3rd, Garth; Goff, Donald C et al. (2013) Lack of insula reactivity to aversive stimuli in schizophrenia. Schizophr Res 143:150-7|
|Holt, Daphne J; Coombs, Garth; Zeidan, Mohamed A et al. (2012) Failure of neural responses to safety cues in schizophrenia. Arch Gen Psychiatry 69:893-903|