Ikemoto S. Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory. Neurosci Biobehav Rev 35: 129-150

Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, United States.
Neuroscience & Biobehavioral Reviews (Impact Factor: 8.8). 02/2010; 35(2):129-50. DOI: 10.1016/j.neubiorev.2010.02.001
Source: PubMed


Reductionist attempts to dissect complex mechanisms into simpler elements are necessary, but not sufficient for understanding how biological properties like reward emerge out of neuronal activity. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures-the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. In addition, studies found roles of non-dopaminergic mechanisms of the supramammillary, rostromedial tegmental and midbrain raphe nuclei in reward. To explain intracranial self-administration and related effects of various drug manipulations, I outlined a neurobiological theory claiming that there is an intrinsic central process that coordinates various selective functions (including perceptual, visceral, and reinforcement processes) into a global function of approach. Further, this coordinating process for approach arises from interactions between brain structures including those structures mentioned above and their closely linked regions: the medial prefrontal cortex, septal area, ventral pallidum, bed nucleus of stria terminalis, preoptic area, lateral hypothalamic areas, lateral habenula, periaqueductal gray, laterodorsal tegmental nucleus and parabrachical area.

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    • "Our results converge with these findings and suggest a possible role of limbic white matter structures in PNS. The limbic system is central to motivation, emotions, hedonic impact and reward as well as cognition (Bush et al., 2000, Ikemoto, 2010, Keedwell et al., 2012). Given that our sample had more prominent anhedonia symptoms, which are also part of the " amotivation " construct, this may have contributed to the group difference and the correlations with white matter tracts of the limbic system. "
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    ABSTRACT: Aberrant white matter structures in fronto-temporal regions have previously been identified in patients with schizophrenia. However, scant research has focused on white matter integrity in patients presenting with a first episode of psychosis (FEP) with persistent negative symptoms (PNS). This study aimed to explore microstructure in the neurocircuitry proposed to be involved in PNS, by using a region-of-interest approach. Secondly, the relationship between individual negative symptoms and white matter were explored. Fractional anisotropy (FA) was measured in the fornix and three other tracts bilaterally including the uncinate fasciculus, superior longitudinal fasciculus and the cingulum bundle. Twelve patients with PNS were compared to a non-PNS group (52) and a healthy control group (51). Results showed that the PNS group had significantly lower FA values in the fornix when compared to healthy controls and that the non-PNS group had significantly lower FA values in the right uncinate fasciculus compared to healthy controls. Significant correlations were observed between SANS global score for anhedonia-asociality and lower FA values in the right cingulum bundle. Our results suggest that fronto-temporal white matter might be more closely related to PNS and that this relationship may possibly be mediated by greater anhedonia in PNS patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research: Neuroimaging 07/2015; 233(3). DOI:10.1016/j.pscychresns.2015.06.017 · 2.42 Impact Factor
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    • "The conduction velocities of these fibers are too slow [9] [10] [11] and the refractory periods too long [6] [7] to provide a good match to the inferred properties of the directly stimulated substrate for self-stimulation of the MFB. Moreover, the direction of the DA projections along the MFB is caudal–rostral [15], whereas the behaviorally relevant direction of conduction in at least some of the reward-relevant neural projections is rostral–caudal [11]. The importance of descending diencephalic projections in BSR had been proposed earlier by Huston et al. [16] [17]. "
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    ABSTRACT: The rewarding effect of electrical brain stimulation has been studied extensively for 60 years, yet the identity of the underlying neural circuitry remains unknown. Previous experiments have characterized the directly stimulated ("first-stage") neurons implicated in self-stimulation of the medial forebrain bundle. Their properties are consistent with those of fine myelinated axons, at least some of which project rostro-caudally. These properties do not match those of dopaminergic neurons. The present psychophysical experiment estimates an additional first-stage characteristic: maximum firing frequency. We test a frequency-following model that maps the experimenter-set pulse frequency into the frequency of firing induced in the directly stimulated neurons. As pulse frequency is increased, firing frequency initially increases at the same rate, then becomes probabilistic, and finally levels off. The frequency-following function is based on the counter model which holds that the rewarding effect of a pulse train is determined by the aggregate spike rate triggered in first-stage neurons during a given interval. In 7 self-stimulating rats, we measured current-versus-pulse-frequency trade-off functions. The trade-off data were well described by the frequency-following model, and its upper asymptote was approached at a median value of 362Hz (IQR=46Hz). This value implies a highly excitable, non-dopaminergic population of first-stage neurons. Incorporating the frequency-following function and parameters in Shizgal's 3-dimensional reward-mountain model improves its accuracy and predictive power. Copyright © 2015. Published by Elsevier B.V.
    Behavioural brain research 06/2015; 292. DOI:10.1016/j.bbr.2015.06.008 · 3.03 Impact Factor
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    • "For example, future research will have to continue to identify clusters of GABAergic cells which make up value-processing microcircuits as well as their connections to other value-and non-value related clusters, including other cell types, such that a better understanding of their true function becomes clearer (and probably resulting in clearer delineations between multiple " systems " ). Analogous advances in network neuroscience have been made to identify many major nodes/hubs (i.e., clusters), edges (i.e., connections), and the interactions within and between such brain networks (Behrens and Sporns, 2012)—while most of this work is being done in humans, progress on the vast animal literature has also been made (Ikemoto, 2010). At this point, the greatest advances at the molecular-cellular level of understanding are likely being made through the identification and spatiotemporal electrochemical characterization of value-related microcircuits, for instance in the traditional mesocorticolimbic circuit (e.g., Nieh et al., 2013; Lammel et al., 2014). "
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    ABSTRACT: Affect is the fundamental neuropsychological state combining value- and arousal-related processes underpinning emotion and mood. A major goal of the emerging field of affective science is to explain the mechanisms of valuation within the brain. A core network of brain activity is seen across mammals in response to appetitive or aversive stimuli, and appears to be largely independent of stimulus modality (Bissonette et al., 2014; Hayes et al., 2014a). However, the underlying mechanisms of valuation (i.e., appetitive- and aversive-related brain activity) are unclear, and there is particularly little information about how these two valuative networks interact. One candidate which is likely central to the activity of both networks is the neurotransmitter γ-aminobutyric acid (GABA). Here, I briefly discuss some of the evidence pointing to GABA as a central player in mediating appetitive and aversive activity throughout the brain. The broader implication is that the role of GABA in valuative processing may be at the heart of affective regulation, and thus also important for a wide variety of psychological phenomena, from emotion (Stan et al., 2014) and impulsivity (Hayes et al., 2014b) to sense of self (Wiebking et al., 2014a,b).
    Frontiers in Systems Neuroscience 05/2015; 9. DOI:10.3389/fnsys.2015.00076
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