Journal
BIOLOGICAL PSYCHIATRY
Volume 87, Issue 3, Pages 204-214Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2019.09.021
Keywords
Circuits; Cognition; Genetics; Reward; Schizophrenia; Translation
Categories
Funding
- National Institutes of Mental Health [MH111604, MH112644, MH115297, MH111177, MH059299]
- National Institutes of Neurological Disease and Stroke [NS085171]
- National Institutes of Drug Abuse [DA040621, DA040621-03S1]
- Avielle Foundation
- Cohen Neuroscience Endowment
- Jack Dorsey Neuroscience Endowment
- Children's Hospital of Michigan Foundation
- Prechter World Bipolar Foundation
- Ethel and James Flinn Foundation
- Detroit Medical Center Foundation
- LycakiYoung Funds from the State of Michigan
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Schizophrenia has been studied from the perspective of cognitive or reward-related impairments, yet it cannot be wholly related to one or the other process and their corresponding neural circuits. We posit a comprehensive circuit-based model proposing that dysfunctional interactions between the brain's cognitive and reward circuits underlie schizophrenia. The model is underpinned by how the relationship between glutamatergic and dopaminergic dysfunction in schizophrenia drives interactions between cognition and reward circuits. We argue that this interaction is synergistic: that is, deficits of cognition and reward processing interact, and this interaction is a core feature of schizophrenia. In adopting this position, we undertake a focused review of animal physiology and human clinical data, and in proposing this synergistic model, we highlight dopaminergic afferents from the ventral tegmental area to nucleus accumbens (mesolimbic circuit) and frontal cortex (mesocortical circuit). We then expand on the role of glutamatergic inputs to these dopamine circuits and dopaminergic modulation of critical excitatory pathways with attention given to the role of glutamatergic hippocampal outputs onto nucleus accumbens. Finally, we present evidence for how in schizophrenia, dysfunction in the mesolimbic and mesocortical circuits and their corresponding glutamatergic inputs gives rise to clinical and cognitive phenotypes and is associated with positive and negative symptom dimensions. The synthesis attempted here provides an impetus for a conceptual shift that links cognitive and motivational aspects of schizophrenia and that can lead to treatment approaches that seek to harmonize network interactions between the brain's cognition and reward circuits with ameliorative effects in each behavioral domain.
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