MAR 14, 2019 7:00 AM PDT

Vulnerability to Stress as a Risk Factor for Major Mental Disorders

Presented at: Neuroscience 2019
C.E. Credits: P.A.C.E. CE Florida CE
  • Distinguished Professor of Neuroscience, Professor of Psychiatry and Psychology Department of Neuroscience, University of Pittsburgh
      Dr. Anthony A. Grace is a Distinguished Professor of Neuroscience and a Professor of Psychiatry and Psychology at the University of Pittsburgh in Pittsburgh, PA. He received his Ph.D. from Yale University School of Medicine with Dr. Benjamin S. Bunney and had postdoctoral training with Dr. Rodolfo Llinas in the Department of Physiology and Biophysics at New York University School of Medicine. Dr. Grace has been involved in translational research related to the dopamine system for over 30 years. His early work pioneered the mode of action of antipsychotic drugs, and the identification and characterization of dopamine-containing neurons, and was the first to provide a means to quantify their activity state and pattern in a way that is the standard in the literature. His current work involves novel treatments for schizophrenia and its prevention, the role of dopamine in anhedonia and affective disorders, and the mode of action of ketamine and novel antidepressant drugs. Dr. Grace has received several awards for his research, including the Paul Janssen Schizophrenia Research Award and the Lilly Basic Scientist Award from the International College of Neuropsychopharmacology, the Efron Award from the American College of Neuropsychopharmacology, as well as a NIMH MERIT award, a Distinguished Investigator award from the National Alliance for Research in Schizophrenia and Depression, the Judith Silver Memorial Investigator Award from the National Alliance for the Mentally Ill, a Fellow of the American Association for the Advancement of Science, and appointment as a Distinguished Professor of Neuroscience at the University of Pittsburgh. He is also a past member of the governing council of the American College of Neuropsychopharmacology and is on the editorial board fornumerous leading journals in the field.


    Substantial evidence demonstrates that schizophrenia involves a dysregulated dopamine system, potentially driven by overactivity in the hippocampus. Postmortem studies of schizophrenia brains show a substantial loss of parvalbumin GABAergic interneurons in the hippocampus; loss of this neuron likely drives hippocampal hyperactivity and dysrhythmic activity, leading to an over-responsive dopamine system. Our studies suggest that when the hippocampus is hyperactive and dysrhythmic, the dopamine system is hyper-responsive to stimuli, which can underlie the resultant hallucinations and delusions. A major question is why there is interneuron loss in the hippocampus. Parvalbumin interneurons early in life are susceptible to damage due to stress. In a developmental disruption model of schizophrenia in the rat, we found that prepubertally these rats are more anxious, are hyper-responsive to stress, and show hyperactivity in the amygdala; furthermore relieving the stress early in life prevents the transition to “psychosis” in these rats. This suggests that schizophrenia susceptibility may be due to heightened sensitivity to the deleterious effects of stress. Indeed, multiple stressors given during this sensitive period to normal rats can lead to the schizophrenia phenotype. Moreover, elimination of the ability of the medial prefrontal cortex to regulate stress causes minor stressors to yield the schizophrenia phenotype.  In contrast, multiple stressors given to adult rats result in a phenotype resembling models of depression.  However, if the critical developmental period is first re-opened in the adult rat via histone decarboxylase inhibition, the same stressors now yield a schizophrenia phenotype.This leads to the intriguing possibility that genetic predisposition does not cause schizophrenia, but instead like the developmental disruption model causes the individual to be hypersensitive to the deleterious effects of stress. Moreover, stress susceptibility may be a common link in familial risk for schizophrenia and depression. Therefore, controlling stress early in life in susceptible individuals may be an effective means to prevent transition to schizophrenia later in life.

    Learning Objectives: 

    1. To understand how stress during adolescence can lead to pathological changes in the brain and the emergence of psychosis in the adult
    2. To understand how alterations in different regions of the dopamine system can underlie pathophysiological changes in schizophrenia and depression
    3. To understand why parvalbumin interneurons are particularly sensitive to the deleterious impact of stress during adolescence but not adulthood

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