Dopamine System Dysregulation by the Ventral Subiculum as the Common Pathophysiological Basis for Schizophrenia Psychosis, Psychostimulant Abuse, and Stress

Department of Neuroscience, University of Pittsburgh, A210 Langley Hall, Pittsburgh, PA 15260, USA.
Neurotoxicity Research (Impact Factor: 3.54). 02/2010; 18(3-4):367-76. DOI: 10.1007/s12640-010-9154-6
Source: PubMed


The dopamine system is under multiple forms of regulation, and in turn provides effective modulation of system responses. Dopamine neurons are known to exist in several states of activity. The population activity, or the proportion of dopamine neurons firing spontaneously, is controlled by the ventral subiculum of the hippocampus. In contrast, burst firing, which is proposed to be the behaviorally salient output of the dopamine system, is driven by the brainstem pedunculopontine tegmentum (PPTg). When an animal is exposed to a behaviorally salient stimulus, the PPTg elicits a burst of action potentials in the dopamine neurons. However, this bursting only occurs in the portion of the dopamine neuron population that is firing spontaneously. This proportion is regulated by the ventral subiculum. Therefore, the ventral subiculum provides the gain, or the amplification factor, for the behaviorally salient stimulus. The ventral subiculum itself is proposed to carry information related to the environmental context. Thus, the ventral subiculum will adjust the responsivity of the dopamine system based on the needs of the organism and the characteristics of the environment. However, this finely tuned system can be disrupted in disease states. In schizophrenia, a disruption of interneuronal regulation of the ventral subiculum is proposed to lead to an overdrive of the dopamine system, rendering the system in a constant hypervigilant state. Moreover, amphetamine sensitization and stressors also appear to cause an abnormal dopaminergic drive. Such an interaction could underlie the risk factors of drug abuse and stress in the precipitation of a psychotic event. On the other hand, this could point to the ventral subiculum as an effective site of therapeutic intervention in the treatment or even the prevention of schizophrenia.

Download full-text


Available from: Anthony Grace,
21 Reads
  • Source
    • "Improved accuracy and reproducibility in mapping hippocampal iFC is of clinical relevance, as subregional hippocampal dysfunction is implicated in epilepsy, schizophrenia, Alzheimer's disease, anxiety disorders, and major depressive disorder [Grace, 2010; Tanti and Belzung, 2013; Coras et al., 2014; Maruszak and Thuret, 2014; r Blessing et al. r r 2 r Stevens et al., 2014]. We therefore sought to determine whether human longitudinal hippocampal components can be reproducibly defined using a data-driven analysis, specifically, independent component analysis (ICA). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The hippocampus (HPC) is functionally heterogeneous along the longitudinal anterior-posterior axis. In rodent models, gene expression maps define at least three discrete longitudinal subregions, which also differ in function, and in anatomical connectivity with the rest of the brain. In humans, equivalent HPC subregions are less well defined, resulting in a lack of consensus in neuroimaging approaches that limits translational study. This study determined whether a data-driven analysis, namely independent component analysis (ICA), could reproducibly define human HPC subregions, and map their respective intrinsic functional connectivity (iFC) with the rest of the brain. Specifically, we performed ICA of resting-state fMRI activity spatially restricted within the HPC, to determine the configuration and reproducibility of functional HPC components. Using dual regression, we then performed multivariate analysis of iFC between resulting HPC components and the whole brain, including detailed connectivity with the hypothalamus, a functionally important connection not yet characterized in human. We found hippocampal ICA resulted in highly reproducible longitudinally discrete components, with greater functional heterogeneity in the anterior HPC, consistent with animal models. Anterior hippocampal components shared iFC with the amygdala, nucleus accumbens, medial prefrontal cortex, posterior cingulate cortex, midline thalamus, and periventricular hypothalamus, whereas posterior hippocampal components shared iFC with the anterior cingulate cortex, retrosplenial cortex, and mammillary bodies. We show that spatially masked hippocampal ICA with dual regression reproducibly identifies functional subregions in the human HPC, and maps their respective brain intrinsic connectivity. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 11/2015; DOI:10.1002/hbm.23042 · 5.97 Impact Factor
  • Source
    • "Prior studies suggest that hallucinations in PD patients can be due to either cortical or subcortical atrophy (Papapetropoulos et al., 2006). Specifically, psychosis and hallucinations can stem from dysfunction to either the prefrontal cortex (Corlett et al., 2007; Fletcher and Frith, 2008), basal ganglia (Frank, 2008; Howes et al., 2012), or hippocampal region (Bogerts et al., 1985; Weinberger, 1999; Goldman and Mitchell, 2004; Keri, 2008; Grace, 2010). Studies also report temporal lobe dysfunction in PD patients with visual hallucination (Botha and Carr, 2012) and also with studies showing that early onset of hallucinations in PD patients is associated with dysfunction to the parahippocampus and inferior temporal cortex (Harding et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is a neurological disorder, associated with rigidity, bradykinesia, and resting tremor, among other motor symptoms. In addition, patients with PD also show cognitive and psychiatric dysfunction, including dementia, mild cognitive impairment (MCI), depression, hallucinations, among others. Interestingly, the occurrence of these symptoms-motor, cognitive, and psychiatric-vary among individuals, such that a subgroup of PD patients might show some of the symptoms, but another subgroup does not. This has prompted neurologists and scientists to subtype PD patients depending on the severity of symptoms they show. Neural studies have also mapped different motor, cognitive, and psychiatric symptoms in PD to different brain networks. In this review, we discuss the neural and behavioral substrates of most common subtypes of PD patients, that are related to the occurrence of: (a) resting tremor (vs. nontremor-dominant); (b) MCI; (c) dementia; (d) impulse control disorders (ICD); (e) depression; and/or (f) hallucinations. We end by discussing the relationship among subtypes of PD subgroups, and the relationship among motor, cognitive, psychiatric factors in PD.
    Frontiers in Systems Neuroscience 12/2013; 7:117. DOI:10.3389/fnsys.2013.00117
  • Source
    • "The amygdala generates emotionally loaded information, which is labelled in time, place and context while processed in e.g. the hippocampal formation (Eichenbaum et al., 2007). In mutual feedback and feedforward loops the amygdala and hippocampus communicate with frontal brain regions, notably the mesolimbic – cortical DA pathways of reward and adversity, and the prefrontal cortex of which subregions are involved in specific higher cognitive functions, as well as mood, affect, emotional and stress regulation (Grace, 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is recognition that biomedical research into the causes of mental disorders and their treatment needs to adopt new approaches to research. Novel biomedical techniques have advanced our understanding of how the brain develops and is shaped by behaviour and environment. This has led to the advent of stratified medicine, which translates advances in basic research by targeting aetiological mechanisms underlying mental disorder. The resulting increase in diagnostic precision and targeted treatments may provide a window of opportunity to address the large public health burden, and individual suffering associated with mental disorders. While mental health and mental disorders have significant representation in the "health, demographic change and wellbeing" challenge identified in Horizon 2020, the framework programme for research and innovation of the European Commission (2014-2020), and in national funding agencies, clear advice on a potential strategy for mental health research investment is needed. The development of such a strategy is supported by the EC-funded "Roadmap for Mental Health Research" (ROAMER) which will provide recommendations for a European mental health research strategy integrating the areas of biomedicine, psychology, public health well being, research integration and structuring, and stakeholder participation. Leading experts on biomedical research on mental disorders have provided an assessment of the state of the art in core psychopathological domains, including arousal and stress regulation, affect, cognition social processes, comorbidity and pharmacotherapy. They have identified major advances and promising methods and pointed out gaps to be addressed in order to achieve the promise of a stratified medicine for mental disorders.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 10/2013; 24(1). DOI:10.1016/j.euroneuro.2013.09.010 · 4.37 Impact Factor
Show more