Schizophrenia-like reduced sensorimotor gating in intact inbred and outbred rats is associated with decreased medial prefrontal cortex activity and volume

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Abstract

Prepulse inhibition (PPI) of startle response is a measure of sensorimotor gating that is impaired in schizophrenia and in many other clinical conditions. Rat models using pharmacological or surgical strategies reveal that PPI is modulated by the cortico-striatal-pallido-thalamic (CSPT) circuit. Here, we explore whether spontaneous variation in PPI in intact inbred and outbred rats is associated with functional and structural differences in the CSPT circuit. Inbred Roman High-(RHA) and Low-avoidance (RLA) and outbred heterogeneous stock (HS) rats were assessed for PPI, brain activity, and brain volume. Brain activity was assessed by c-Fos expression and brain volume by magnetic resonance imaging. Relevant structures of the CSPT circuit were evaluated, such as the medial prefrontal cortex (mPFC), cingulate cortex, hippocampus (HPC), amygdala, nucleus accumbens (NAc), and dorsal striatum. RHA showed lower PPI than RLA rats, while HS rats were stratified by their PPI levels in three groups. Reduced PPI was accompanied by decreased mPFC activity in Roman and HS rats and increased NAc shell activity in HS rats. Low PPI was also associated with decreased mPFC and HPC volumes in Roman and HS rats. This study reports a consistent relationship between decreased function and volume of the mPFC and spontaneous low-PPI levels in inbred and outbred intact rats. Moreover, our findings suggest that, apart from a hypoactive and smaller mPFC, a hyperactive NAc and smaller HPC may underlie reduced PPI levels. Our results support the notion that sensorimotor gating is modulated by forebrain structures and highlight the importance of the mPFC in its regulation.

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Regional dissociations within the hippocampus--memory and anxiety.

D Bannerman, J. N. P. Rawlins, S B McHugh … (2004)

The amnestic effects of hippocampal lesions are well documented, leading to numerous memory-based theories of hippocampal function. It is debatable, however, whether any one of these theories can satisfactorily account for all the consequences of hippocampal damage: Hippocampal lesions also result in behavioural disinhibition and reduced anxiety. A growing number of studies now suggest that these diverse behavioural effects may be associated with different hippocampal subregions. There is evidence for at least two distinct functional domains, although recent neuroanatomical studies suggest this may be an underestimate. Selective lesion studies show that the hippocampus is functionally subdivided along the septotemporal axis into dorsal and ventral regions, each associated with a distinct set of behaviours. Dorsal hippocampus has a preferential role in certain forms of learning and memory, notably spatial learning, but ventral hippocampus may have a preferential role in brain processes associated with anxiety-related behaviours. The latter's role in emotional processing is also distinct from that of the amygdala, which is associated specifically with fear. Gray and McNaughton's theory can in principle incorporate these apparently distinct hippocampal functions, and provides a plausible unitary account for the multiple facets of hippocampal function.

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Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review.

M Geyer, K Krebs-Thomson, D Braff … (2001)

Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia. This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats. Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated. Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications. Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.