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Grace AA. Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res Brain Res Rev 31: 330-341

Department of Neuroscience, University of Pittsburgh, 458 Crawford Hall, Pittsburgh, PA, USA.
Brain Research Reviews (Impact Factor: 5.93). 04/2000; 31(2-3):330-41. DOI: 10.1016/S0165-0173(99)00049-1
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ABSTRACT Although first thought of as a dopaminergic disorder, there is little direct evidence to support a primary pathology in the dopamine system as the etiological factor in schizophrenia. In contrast, evidence is amassing in support of a cortical disturbance in this disorder; one consequence of which is a disruption in the cortical regulation of subcortical dopamine systems. Our studies show that the hippocampus plays a major role in this interaction, in that, along with the dopamine system, it provides a gating influence over information flow from the prefrontal cortex at the level of the nucleus accumbens. Moreover, chemically-induced disruption of the development of the hippocampus and entorhinal cortex were found to lead to pathophysiological changes in these interactions in the limbic system of adult rats. Therefore, schizophrenia is proposed to be a developmentally-related disorder, in which disruption of the hippocampal influence over the limbic system during ontogeny results in a pathological alteration of corticoaccumbens interactions in the adult organism.

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    • "It has been reported that memories of fearful experiences can lead to pathogenic conditions such as anxiety and phobias (Orsini & Maren, 2012). According to previous researches, stimulation of the hippocampus with NMDA may disrupt particular hippocampal functions (Bast & Feldon, 2003; Berke & Eichenbaum, 2001), and impair processing of sensory stimuli, which is the core deficit in neuropsychiatric disorders such as schizophrenia and anxiety disorders (Bast & Feldon, 2003; Benes, 2000; Grace, 2000). Previous reports in animal models have also shown that intra-VH infusions of NMDA agonists increase locomotor activity (Bast, Zhang & Feldon, 2001; Swerdlow et al., 2001), and their antagonists decrease level of anxiety (Rezvanfard, Zarrindast & Bina, 2009). "
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    ABSTRACT: Introduction: In this study, we investigated the role of N-Methyl-D-Aspartate (NMDA) receptors in the ventral hippocampus (VH) and their possible interactions with GABA A system on anxiety-like behaviors. Methods: We used an elevated-plus maze test (EPM) to assess anxiety-like behaviors and locomotor activity in male Wistar rats. Results: The results showed that intra-VH infusions of different doses of NMDA (0.25 and 0.5 µg/rat) increased locomotor activity, and also induced anxiolytic-like behaviors, as revealed by a tendency to increase percentage of open arm time (%OAT), and a significant increase in percentage of open arm entries (%OAE). The results also showed that intra-VH infusions of muscimol (0.5 and 1 µg/rat) or bicuculline (0.5 and 1 µg/rat) did not significantly affect anxiety-like behaviors, but bicuculline at dose of 1 µg/rat increased locomotor activity. Intra-VH co-infusions of muscimol (0.5 µg/rat) along with low doses of NMDA (0.0625 and 0.125 µg/rat) showed a tendency to increase %OAT, %OAE and locomotor activity; however, no interaction was observed between the drugs. Interestingly, intra-VH co-infusions of bicuculline (0.5 µg/rat) along with effective doses of NMDA (0.25 and 0.5 µg/rat) decreased %OAT, %OAE and locomotor activity, and a significant interaction between two drugs was observed. Discussion: It can be concluded that GABAergic system may mediate the anxiolytic-like effects and increase in locomotor activity induced by NMDA in the VH.
    Autonomic neuroscience: basic & clinical 11/2014; 5(4). · 1.37 Impact Factor
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    • "It is notable that many of the cognitive processes known to be abnormal in patients with schizophrenia have been associated with the functioning of the limbic system, such as emotion regulation, emotion processing, self-monitoring, memory and attention. This observation has led to a number of theories that have emphasized the role of limbic system dysfunction in the etiology of schizophrenia, potentially via its role in the integration of cognition and emotion (Anticevic and Corlett, 2012; Coltheart, 2010), and/or sensory and cognitive gating (Bogerts et al., 1985; Grace, 2000). The limbic system is a phylogenetically ancient neural system comprised of a number of structurally and functionally interconnected gray matter structures (Mega et al., 1997). "
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    ABSTRACT: The cingulum bundle (CB) connects gray matter structures of the limbic system and as such has been implicated in the etiology of schizophrenia. There is growing evidence to suggest that the CB is actually comprised of a conglomeration of discrete sub-connections. The present study aimed to use Diffusion Tensor tractography to subdivide the CB into its constituent sub-connections, and to investigate the structural integrity of these sub-connections in patients with schizophrenia and matched healthy controls. Diffusion Tensor Imaging scans were acquired from 24 patients diagnosed with chronic schizophrenia and 26 matched healthy controls. Deterministic tractography was used in conjunction with FreeSurfer-based regions-of-interest to subdivide the CB into 5 sub-connections (I1 to I5). The patients with schizophrenia exhibited subnormal levels of FA in two cingulum sub-connections, specifically the fibers connecting the rostral and caudal anterior cingulate gyrus (I1) and the fibers connecting the isthmus of the cingulate with the parrahippocampal cortex (I4). Furthermore, while FA in the I1 sub-connection was correlated with the severity of patients' positive symptoms (specifically hallucinations and delusions), FA in the I4 sub-connection was correlated with the severity of patients' negative symptoms (specifically affective flattening and anhedonia/asociality). These results support the notion that the CB is a conglomeration of structurally interconnected yet functionally distinct sub-connections, of which only a subset are abnormal in patients with schizophrenia. Furthermore, while acknowledging the fact that the present study only investigated the CB, these results suggest that the positive and negative symptoms of schizophrenia may have distinct neurobiological underpinnings.
    Clinical neuroimaging 06/2014; 5. DOI:10.1016/j.nicl.2014.06.003 · 2.53 Impact Factor
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    • "It is also important to clarify whether sensitivity of the nucleus accumbens and mesolimbic dopamine pathways is influenced by the limbic bursts detected during REM sleep and linked with PGO waves and dreaming. Current evidence suggests that there is a connection: researchers working with rats have reported a resemblance between rhythmic activity in the nucleus accumbens of rats and hippocampal theta activity (Grace, 2000; Leung & Yim, 1993; O'Donnell & Grace, 1995). Further evidence is required to flesh-out this potentially very important line of enquiry. "
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    ABSTRACT: This paper reviews scientific literature on four subjective states: the dream state, the dreamy state of temporal lobe epilepsy and temporal lobe stimulation, the acute psychotic state, and the psychedelic state. Evidence is cited showing that underlying the emergence of dreamlike phenomena in all four states is the occurrence of high-voltage bursts of theta and slow-wave activity (2–8 Hz) in the medial temporal lobes. The medial temporal regions are recognized to play an important role in memory and emotion. In the dream state, medial temporal lobe bursts are tightly correlated with PGO waves. It has been widely speculated that PGO waves are direct neuro-physiological correlates of dreaming. On a phenomenological level, the dream state, the dreamy state, the acute psychotic state, and the psychedelic state have all been viewed as conducive to the emergence of unconscious material into consciousness. An argument is made that bursts of electrical activity spreading from the medial temporal lobes to the association cortices are the primary functional correlate of discharging psychical energies, experienced on a subjective level as the emergence of unconscious material into consciousness. The implications of these findings for the scientific legitimacy of the psychodynamic model are discussed.
    01/2014; 9(2):183-211. DOI:10.1080/15294145.2007.10773557
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