Subcortical Dopamine and Cognition in Schizophrenia: Looking Beyond Psychosis in Preclinical Models

Abstract

Schizophrenia is characterized by positive, negative and cognitive symptoms. All current antipsychotic treatments feature dopamine-receptor antagonism that is relatively effective at addressing the psychotic (positive) symptoms of schizophrenia. However, there is no clear evidence that these medications improve the negative or cognitive symptoms, which are the greatest predictors of functional outcomes. One of the most robust pathophysiological observations in patients with schizophrenia is increased subcortical dopamine neurotransmission, primarily in the associative striatum. This brain area has an important role in a range of cognitive processes. Dopamine is also known to play a major part in regulating a number of cognitive functions impaired in schizophrenia but much of this research has been focused on cortical dopamine. Emerging research highlights the strong influence subcortical dopamine has on a range of cognitive domains, including attention, reward learning, goal-directed action and decision-making. Nonetheless, the precise role of the associative striatum in the cognitive impairments observed in schizophrenia remains poorly understood, presenting an opportunity to revisit its contribution to schizophrenia. Without a better understanding of the mechanisms underlying cognitive dysfunction, treatment development remains at a standstill. For this reason, improved preclinical animal models are needed if we are to understand the complex relationship between subcortical dopamine and cognition. A range of new techniques are facillitating the discrete manipulation of dopaminergic neurotransmission and measurements of cognitive performance, which can be investigated using a variety of sensitive translatable tasks. This has the potential to aid the successful incorporation of recent clinical research to address the lack of treatment strategies for cognitive symptoms in schizophrenia. This review will give an overview on the current state of research focused on subcortical dopamine and cognition in the context of schizophrenia research. We also discuss future strategies and approaches aimed at improving the translational outcomes for the treatment of cognitive deficits in schizophrenia.

Keywords: goal-directed behavior; operant tasks; reversal learning; rodent; translation.

FIGURE 1

Goal-directed action and schizophrenia. A simplified diagram of the circuitry, subcortical (reds) and cortical regions (blues), and their roles in goal-directed action. Impaired dopamine function and release in the caudate/associative striatum (dark red) of patients living with schizophrenia may be the cause of impairments in goal-directed behavior. Increased dopamine function in the associative striatum may directly alter associative learning and the understanding of action-specific values. Alternatively, increased dopamine function may impair the integration of incoming cortical inputs. In particular, subregions of the prefrontal cortex have differing roles in the encoding of outcome values. Other cortical regions such as the anterior cingulate cortex and posterior cingulate cortex have also shown to have differing roles in action selection. PFC, prefrontal cortex.

FIGURE 2

Goal-directed action and dopamine (preclinical studies). A simplified summary of the preclinical research on subcortical (reds) and cortical (blues) regions involved in goal-directed behavior with potential relevance to schizophrenia. Dopamine signaling driven by the nigrostriatal pathway projecting into the dorsomedial/associative striatum (dark red) is essential for associative learning. Aberrant functioning in the associative striatum could impact goal-directed behavior via multiple circuits. In particular, integrating and encoding inputs from cortical regions such as the anterior cingulate cortex, prelimbic and infralimbic cortices, which have distinct roles in terms of action selection, associative learning and habit formation. However, it is the corticostriatal circuit as a whole that is responsible for the acquisition of action-outcome associations. The thalamus also has an important role in mediating action selection with the thalamocortical circuit integrating causal relationships. Striatothalamic circuitry is important to managing learning in goal-directed behavior and also has a role in regulating striatal dopamine release.

FIGURE 3

Reversal learning and schizophrenia. A simplified diagram of the circuitry, subcortical (reds) and cortical regions (blues), and their roles in reversal learning. Impaired dopamine function and release in the caudate/associative striatum (dark red) of patients living with schizophrenia may be the cause of reversal learning impairments. The dopamine enriched substantia nigra is involved in modifying responding to changes in reward contingencies and dopamine release in the caudate is related to reversal learning errors. In contrast, the nucleus accumbens has a role in predicting reward outcome. The orbitofrontal cortex is responsible for monitoring changes in reward value that guide reversal learning behavior.

FIGURE 4

Reversal learning and dopamine (preclinical studies). A simplified summary of the preclinical research on subcortical (reds) and cortical (blues) regions involved in reversal learning with potential relevance to schizophrenia. Alterations in dopamine signaling in the dorsomedial/associative striatum (dark red; which is essential for reversal learning) could impair integration and encoding of inputs from other regions/circuits involved in probabilistic reversal learning behavior. This is most likely driven by the nigrostriatal circuit that modulates dopamine signaling in the striatum. In contrast, the nucleus accumbens is important for using probabilisitic reward feedback to guide choices (i.e., probabilistic learning). Corticostriatal circuitry monitors changes in reward value to guide choices. Specifically, the lateral orbitofrontal cortex allows the adaptation of behavior for reversal learning while the medial orbitofrontal cortex modulates reward feedback sensitivity for probabilistic learning.

FIGURE 5

Subcortical dopamine, cognition and schizophrenia. This is a simplified diagram of the cortico-striato-thalamic circuit loop that is disrupted in schizophrenia. Increased striatal dopamine signaling, as well as the impaired integration of cortical inputs into the striatum, may affect a number of cognitive components involved in decision-making including those linked with goal-directed and flexible behavior. The nigrostriatal pathway (red) is responsible for the increased dopamine synthesis and release in the associative striatum. This could result in a perturbation of the thalamostriatal pathway, impacting striatal dopamine release and impairing the integration of new and existing learning. The corticostriatal pathway is also affected in schizophrenia as there is compromised integration of cortical inputs into the striatum, potentially impacting on associative learning and value tracking processes. Finally, this may have flow on effects for the thalamocortical pathway which would result in an inability to understand the consequences of actions and to appropriately adapt behavior.