3. STRESS AND THE AMYGDALA-HIPPOCAMPAL-STRIATAL CIRCUIT: TOWARDS A MODEL OF BRAIN-ENVIRONMENT INTERACTIONS CONTRIBUTING TO THE PATHOGENESIS OF PSYCHOSIS

Abstract

There is increasing evidence from both preclinical and human studies that environmental factors, such as early life stress, when combined with a genetic predisposition, can lead to the onset of schizophrenia in late adolescence/ early adulthood. However, the neural mechanisms underlying these relationships remain poorly understood. This panel will present rodent model studies, along with human imaging and postmortem investigations, that converge upon a model of how environmental stress can lead to circuit-level disruptions of an amygdala-hippocampal-striatal pathway; stress-induced changes in this circuitry may increase susceptibility for the later development of psychosis. Dr. Grace will show that the timing of stressors is critical for driving pathophysiology, in that stress applied prepubertally leads to amygdala-driven parvalbumin interneuron loss in the hippocampus and a hyperdopaminergic state. This is facilitated by disrupting stress regulation by the medial prefrontal cortex-amygdala pathway and can be circumvented by prepubertal environmental enrichment. Dr. Meyer- Lindenberg will present data from humans showing that urban birth, urban living, and ethnic minority status converge on the perigenual cingulateamygdala- ventral striatal pathway as shown by structural and functional imaging, supporting a role for the amygdalostriatal system in psychosis risk. Moreover, environmental greenspace can mitigate these impacts. In postmortem studies, Dr. Sabina Berretta will show that anxiolytic and anxiogenic molecular factors in the human amygdala, such as somatostatin, are regulated by circadian rhythms and dysregulated in bipolar disorder and schizophrenia, identifying potential molecular mechanisms of the effects of environmental stress on this system in humans. Finally, Dr. Daphne Holt will present neuroimaging evidence for changes in connectivity of the amygdala and hippocampus in youth with persecutory beliefs. Links to childhood trauma and a behavioral bias to mislabel neutral information as negatively-valenced suggest potential mechanisms or consequences of these changes. Taken together, these data will provide insights about specific disruptions of the stress-regulating mechanisms of the brain mediating the relationship between environmental factors, including early life stress, and the pathophysiology of psychosis.