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.
Keywords: Circuits; Cognition; Genetics; Reward; Schizophrenia; Translation.
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
The authors report no biomedical financial interests or potential conflicts of interest.
Dopaminergic Circuitry and Risk/Reward Decision Making: Implications for SchizophreniaCM Stopper et al. Schizophr Bull 41 (1), 9-14. PMID 25406370.Abnormal reinforcement learning and representations of reward value are present in schizophrenia, and these impairments can manifest as deficits in risk/reward decision m …
Addiction and Brain Reward and Antireward PathwaysEL Gardner. Adv Psychosom Med 30, 22-60. PMID 21508625. - ReviewAddictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly), and that they enhance the functioning of the reward cir …
Convergent Inputs From the Hippocampus and Thalamus to the Nucleus Accumbens Regulate Dopamine Neuron ActivitySM Perez et al. J Neurosci 38 (50), 10607-10618. PMID 30355626.Aberrant hippocampal activity is observed in individuals with schizophrenia and is thought to underlie the augmented dopamine system function associated with psychosis. T …
Functional Relationship Among Medial Prefrontal Cortex, Nucleus Accumbens, and Ventral Tegmental Area in Locomotion and RewardTM Tzschentke et al. Crit Rev Neurobiol 14 (2), 131-42. PMID 11513242. - ReviewProminent projections of the medial prefrontal cortex (mPFC) to the nucleus accumbens (NAS) and the ventral tegmental area (VTA) exist, but it has been difficult to assig …
Cannabinoid Transmission in the Hippocampus Activates Nucleus Accumbens Neurons and Modulates Reward and Aversion-Related Emotional SalienceM Loureiro et al. Biol Psychiatry 80 (3), 216-25. PMID 26681496.Together, these findings demonstrate a critical role for hippocampal cannabinoid signaling in the modulation of mesolimbic neuronal activity states and suggest that dysre …
- R01 DA040621/DA/NIDA NIH HHS/United States
- R01 MH112644/MH/NIMH NIH HHS/United States
- R01 MH111177/MH/NIMH NIH HHS/United States
- R01 NS085171/NS/NINDS NIH HHS/United States
- R01 MH059299/MH/NIMH NIH HHS/United States