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
Source: PubMed


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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    • "ers III and V of PFC[10,33]. These cytoarchitectural abnormalities are accompanied with changes in the molecular architecture of schizophrenic patients' brain and are related to neurotransmitters systems (dopaminergic and glutamatergic)[34,35,36]. Due to multiple affected regions and the diversity of symptoms found in schizophrenic patients, the existence of aberrant neural connectivity in the limbic system has been proposed, which participates in emotion, learning, memory, attention, and executive functions[37,38]. "
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    ABSTRACT: Schizophrenia, a severe and debilitating disorder with a high social burden, affects 1% of the adult world population. Available therapies are unable to treat all the symptoms, and result in strong side effects. For this reason, numerous animal models have been generated to elucidate the pathophysiology of this disorder. All these models present neuronal remodeling and abnormalities in spine stability. It is well known that the complexity in dendritic arborization determines the number of receptive synaptic contacts. Also the loss of dendritic spines and arbor stability are strongly associated with schizophrenia. This review evaluates changes in spine density and dendritic arborization in animal models of schizophrenia. By understanding these changes, pharmacological treatments can be designed to target specific neural systems to attenuate neuronal remodeling and associated behavioral deficits.
    No preview · Article · Dec 2015 · Behavioural brain research
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    • "What modulates the state of the NAcc neurons is an extra input from the hippocampus (HPC). That is, only the NAcc neurons that are stimulated by HPC neurons enter their depolarized state and subsequently , fire upon receiving input from the PFC (Grace, 2000). For this reason, these neurons are said to implement a type of AND gate, since they fire only if they receive input from both the PFC and the HPC (Gisiger and Boukadoum, 2011). "
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    ABSTRACT: A central question in artificial intelligence is how to design agents capable of switching between different behaviors in response to environmental changes. Taking inspiration from neuroscience, we address this problem by utilizing artificial neural networks (NNs) as agent controllers, and mechanisms such as neuromodulation and synaptic gating. The novel aspect of this work is the introduction of a type of artificial neuron we call “switch neuron”. A switch neuron regulates the flow of information in NNs by selectively gating all but one of its incoming synaptic connections, effectively allowing only one signal to propagate forward. The allowed connection is determined by the switch neuron’s level of modulatory activation which is affected by modulatory signals, such as signals that encode some information about the reward received by the agent. An important aspect of the switch neuron is that it can be used in appropriate “switch modules” in order to modulate other switch neurons. As we show, the introduction of the switch modules enables the creation of sequences of gating events. This is achieved through the design of a modulatory pathway capable of exploring in a principled manner all permutations of the connections arriving on the switch neurons. We test the model by presenting appropriate architectures in nonstationary binary association problems and T-maze tasks. The results show that for all tasks, the switch neuron architectures generate optimal adaptive behaviors, providing evidence that the switch neuron model could be a valuable tool in simulations where behavioral plasticity is required.
    Full-text · Article · Nov 2015 · Neural Networks
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    • "In experimental rodents, acute application of NMDA receptor antagonists is known to influence oscillations recorded in LFP (Ma and Leung 2000; Middleton et al. 2008; Roopun et al. 2008; Kocsis 2012) and electrocorticograms (Pinault 2008; Phillips et al. 2012). The nucleus accumbens (NAc) is a brain region that has been implicated widely in the pathophysiology of schizophrenia (Grace 2000). Previously, we identified a high-frequency oscillation (HFO; 130–180 Hz) recorded in the rat NAc that is enhanced substantially following systemic or local administration of NMDA receptor antagonists (Hunt et al. 2006). "
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    ABSTRACT: Rationale Abnormal oscillatory activity associated with N-methyl-D-aspartate (NMDA) receptor hypofunction is widely considered to contribute to the symptoms of schizophrenia. Objective This study aims to characterise the changes produced by NMDA receptor antagonists and antipsychotics on accumbal high-frequency oscillations (HFO; 130–180 Hz) in mice. Methods Local field potentials were recorded from the nucleus accumbens of freely moving mice. Results Systemic injection of ketamine and MK801 both dose-dependently increased the power of HFO and produced small increases in HFO frequency. The atypical antipsychotic drug, clozapine, produced a robust dose-dependent reduction in the frequency of MK801-enhanced HFO, whilst haloperidol, a typical antipsychotic drug, had little effect. Stimulation of NMDA receptors (directly or through the glycine site) as well as activation of 5-HT1A receptors, reduced the frequency of MK801-enhanced HFO, but other receptors known to be targets for clozapine, namely 5-HT2A, 5-HT7 and histamine H3 receptors had no effect. Conclusions NMDA receptor antagonists and antipsychotics produce broadly similar fundamental effects on HFO, as reported previously for rats, but we did observe several notable differences. In mice, HFO at baseline were weak or not detectable unlike rats. Post-injection of NMDA receptor antagonists HFO was also weaker but significantly faster. Additionally, we found that atypical antipsychotic drugs may reduce the frequency of HFO by interacting with NMDA and/or 5-HT1A receptors.
    Full-text · Article · Oct 2015 · Psychopharmacology
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