Dopaminergic control of working memory and its relevance to schizophrenia: A circuit dynamics perspective

Department of Electrical and Electronics Engineering, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan.
Neuroscience (Impact Factor: 3.36). 05/2006; 139(1):153-71. DOI: 10.1016/j.neuroscience.2005.08.070
Source: PubMed


This article argues how dopamine controls working memory and how the dysregulation of the dopaminergic system is related to schizophrenia. In the dorsolateral prefrontal cortex, which is the principal part of the working memory system, recurrent excitation is subtly balanced with intracortical inhibition. A potent controller of the dorsolateral prefrontal cortical circuit is the mesocortical dopaminergic system. To understand the characteristics of the dopaminergic control of working memory, the stability of the circuit dynamics under the influence of dopamine has been studied. Recent computational studies suggest that the hyperdopaminergic state is usually stable but the hypodopaminergic state tends to be unstable. The stability also depends on the efficacy of the glutamatergic transmission in the corticomesencephalic projections to dopamine neurons. When this cortical feedback is hypoglutamatergic, the circuit of the dorsolateral prefrontal cortex tends to be unstable, such that a slight increase in dopamine releasability causes a catastrophic jump of the dorsolateral prefrontal cortex activity from a low to a high level. This may account for the seemingly paradoxical overactivation of the dorsolateral prefrontal cortex observed in schizophrenic patients. Given that dopamine transmission is abnormal in the brains of patients with schizophrenia and working memory deficit is a core dysfunction in schizophrenia, the concept of circuit stability would be useful not only for understanding the mechanisms of working memory processing but for developing therapeutic strategies to enhance cognitive functions in schizophrenia.

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Available from: Shoji Tanaka, Oct 08, 2015
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    • "Additionally, previous research suggests a reciprocal relationship between prefrontal and striatal dopaminergic dysfunction in schizophrenia. A number of researchers have suggested that prefrontal dopaminergic dysfunction may partly be the result of dysregulated input from the midbrain dopamine system (Braver et al., 1999; Braver and Cohen, 2000; Tanaka, 2006). On the other hand, according to the tonic-phasic dopamine theory introduced by Grace (1991), when the tonic activity is low, stressful stimuli are not optimally regulated by the PFC, resulting in increased phasic dopamine release in the striatum. "
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    ABSTRACT: The social defeat (SD) hypothesis of schizophrenia posits that repeated experiences of SD may lead to sensitization of the mesolimbic dopaminergic system and to precipitation of psychosis. Based on previous definitions adapted to a human experimental paradigm, we prepared a computer simulation of SD to mimic this subjective experience. We measured prefrontal cortex (PFC) activity in subjects with schizophrenia and healthy controls during exposure to a single SD experience with functional near infrared spectroscopy. PFC activity declined in both groups. Compared with the control condition, SD exposure was associated with a broader decline in left ventromedial, right medial and right lateral PFC activity in healthy controls (n=25), and a sharper decline in right ventrolateral PFC activity in subjects with schizophrenia (n=25). The activity in the right ventrolateral PFC, was significantly lower in patients compared with controls. This may be due to a deficiency in emotion regulation or self-control, or it may be related to impaired empathy in schizophrenia. Different patterns of brain activity during the SD experience in subjects with schizophrenia versus healthy controls may provide indirect evidence regarding the SD hypothesis of schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    07/2015; 233(3). DOI:10.1016/j.pscychresns.2015.07.017
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    • "By blocking D (2)-receptors through antipsychotics, the apoptotic mechanisms in the brain regions involved in cognition are impaired (71). The disturbed activity of working memory in the DLPFC in schizophrenia patients is influenced by the release of dopamine in the midbrain in schizophrenia patients, which is regulated by a deficit in glutamatergic projection from the DLPFC to midbrain dopamine neurons (72). Extrastriatal dopamine transmission is necessary for attention and working memory, and these deficits in the fronto–striato–thalamic pathway are involved in cognition in schizophrenia (73). "
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    ABSTRACT: Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia.The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia. This review provides an in-depth analysis of dopamine in animal models of schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them but also an outline of dopamine and its interaction with other neurochemical models of schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in schizophrenia patients, are also discussed.
    Frontiers in Psychiatry 05/2014; 5. DOI:10.3389/fpsyt.2014.00047
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    • "Hallucination severity further correlated positively with efficiency within the dorsolateral prefrontal parcel. The DLPFC region is one of the most consistently examined regions in MRI studies involving individuals with schizophrenia (Lewis et al., 2004) because of its implications at different levels of impairments, from working memory and executive functions to dopaminergic system malfunction (Tanaka, 2006). Neuromodulation of the DLPFC activity and its role in regulation of thought content is hypothesized to depend on its connectivity patterns with surrounding regions (Arnsten et al., 2012). "
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    ABSTRACT: Schizophrenia is postulated to be the prototypical dysconnection disorder, in which hallucinations are the core symptom. Due to high heterogeneity in methodology across studies and the clinical phenotype, it remains unclear whether the structural brain dysconnection is global or focal and if clinical symptoms result from this dysconnection. In the present work, we attempt to clarify this issue by studying a population considered as a homogeneous genetic sub-type of schizophrenia, namely the 22q11.2 deletion syndrome (22q11.2DS). Cerebral MRIs were acquired for 46 patients and 48 age and gender matched controls (aged 6-26, respectively mean age = 15.20 ± 4.53 and 15.28 ± 4.35 years old). Using the Connectome mapper pipeline ( that combines structural and diffusion MRI, we created a whole brain network for each individual. Graph theory was used to quantify the global and local properties of the brain network organization for each participant. A global degree loss of 6% was found in patients' networks along with an increased Characteristic Path Length. After identifying and comparing hubs, a significant loss of degree in patients' hubs was found in 58% of the hubs. Based on Allen's brain network model for hallucinations, we explored the association between local efficiency and symptom severity. Negative correlations were found in the Broca's area (p < 0.004), the Wernicke area (p < 0.023) and a positive correlation was found in the dorsolateral prefrontal cortex (DLPFC) (p < 0.014). In line with the dysconnection findings in schizophrenia, our results provide preliminary evidence for a targeted alteration in the brain network hubs' organization in individuals with a genetic risk for schizophrenia. The study of specific disorganization in language, speech and thought regulation networks sharing similar network properties may help to understand their role in the hallucination mechanism.
    Frontiers in Human Neuroscience 09/2013; 7:402. DOI:10.3389/fnhum.2013.00402 · 2.99 Impact Factor
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