Cognition and Reward Circuits in Schizophrenia: Synergistic, Not Separate

Abstract

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 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 which 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.

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…What appears is that the current molecular understanding of Glutamate NMDA - DA interactions in SCZ has improved, but it is still insufficient in particular in brain areas like the ventral striatum and in relation to negative symptoms. A better understanding of the circuit(s) will possibly further reduce boundaries between cognitive and negative SCZ symptoms domains ( Robison et al., 2020 ). The DA - NMDA research is also bringing the neurodevelopmental aspects of the SCZ disease to the core of current efforts and hopefully this will improve our understanding of SCZ disease onset and the relevance of DR research in SCZ animal models.…”

A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease

“…Diseases involving DA dysfunction span both neurological disorders such as parkinsonism and widespread neuropsychiatric diseases such as ADHD, ASD, bipolar disorder, schizophrenia, and depression (Cousins et al, 2009;Del Campo et al, 2011;Dichter et al, 2012;Howes & Kapur, 2009;Iversen & Iversen, 2007;Robison et al, 2020). DAT is a powerful regulator of DA neurotransmission, but the genetic and mechanistic link between insult to DAT function and DA-related pathologies is not clear.…”

“…Dopamine (DA) exerts strong effects on human behavior by supporting motor initiation and exploration, and through modulation of higher cognitive functions such as reinforcement learning and motivation (Berke, 2018;Iversen & Iversen, 2007). Disturbances in dopaminergic neurotransmission are widely implicated both in neurological diseases, such as Parkinson's disease (PD), and in psychiatric disorders including attention deficit hyperactivity disorder (ADHD), schizophrenia, bipolar disorder, and depression (Cousins et al, 2009;Del Campo et al, 2011;Dichter et al, 2012;Howes & Kapur, 2009;Iversen & Iversen, 2007;Robison et al, 2020). As a critical regulator of dopaminergic neurotransmission (Kristensen et al, 2011), the DA transporter (DAT) gene SLC6A3, has received enduring attention in candidate gene studies of both PD and psychiatric diseases (Gatt et al, 2015).…”

Drugs Based on NMDAR Hypofunction Hypothesis in Schizophrenia

“…(1) attention/vigilance, (2) cognitive control/executive function, (3) reasoning/problem solving, (4) social cognition, (5) speed of processing, (6) verbal learning, (7) visual learning, and (8) working memory. Cognition is generally regulated by the hippocampus, basal ganglia, the dorsolateral prefrontal cortex, the thalamus, and regions of the motor cortex (Robison et al, 2020). Cognitive dysfunction in schizophrenia is associated with the proactive control mechanism resulting from impaired function of the dorsolateral prefrontal cortex prefrontal cortex (DLPFC) (Guo et al, 2019).…”