Impaired limbic cortico-striatal structure and sustained visual attention in a rodent model of schizophrenia

Abstract

Background: N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology of schizophrenia. Accordingly, NMDAR antagonists such as phencyclidine (PCP) are used widely in experimental animals to model cognitive impairment associated with this disorder. However, it is unclear whether PCP disrupts the structural integrity of brain areas relevant to the profile of cognitive impairment in schizophrenia.

Methods: Here we used high-resolution magnetic resonance imaging and voxel-based morphometry to investigate structural alterations associated with sub-chronic PCP treatment in rats.

Results: Sub-chronic exposure of rats to PCP (5mg/kg twice daily for 7 days) impaired sustained visual attention on a 5-choice serial reaction time task, notably when the attentional load was increased. In contrast, sub-chronic PCP had no significant effect on the attentional filtering of a pre-pulse auditory stimulus in an acoustic startle paradigm. Voxel-based morphometry revealed significantly reduced grey matter density bilaterally in the hippocampus, anterior cingulate cortex, ventral striatum, and amygdala. PCP-treated rats also exhibited reduced cortical thickness in the insular cortex.

Conclusions: These findings demonstrate that sub-chronic NMDA receptor antagonism is sufficient to produce highly-localized morphological abnormalities in brain areas implicated in the pathogenesis of schizophrenia. Furthermore, PCP exposure resulted in dissociable impairments in attentional function.

Keywords: 5-CSRTT; PCP; VBM; anterior cingulate cortex; hippocampus.

Figure 1.

Experimental timeline. Rats were trained for approximately 3 months on the five-choice serial reaction time task (5-CSRTT). Once trained, behavioral assessment involved standard (SD = 1 s; ITI = 5 s) and challenge (variable SD and ITI) sessions on the 5-CSRTT and PPI. Animals were treated with PCP (n = 10) or saline (n = 10) twice daily for 7 days, followed by a 7-day washout period. After the 1-week treatment regimen, animals were re-assessed in the 5-CSRTT during baseline sessions and challenge sessions, followed by PPI (A). A separate cohort of animals was administered PCP (n = 10) or saline (n = 10) and perfused with 4% PFA to enable ex-vivo microscopy to be carried out. Animals were perfused 15-days post-PCP treatment to coincide with the completion of behavioral testing in the first group (B). Values shown are in weeks. BL, baseline 5-CSRTT session; vSD, variable stimulus duration challenge session; vITI, variable inter-trial interval challenge session; PPI, prepulse inhibition; d1 - d7, day 1 - day 7.

Figure 2.

Attentional impairment in rats treated sub-chronically with PCP. Rats were challenged with variable SD (top row) and variable ITI (bottom row) sessions. Response accuracy was reduced in PCP-treated animals in the variable SD session (A). This was mainly attributed to an increase in incorrect responding (B). Analysis of performance, as a function of stimulus duration, revealed a reduction in accuracy of PCP-treated animals when presented with stimuli of 1 and 0.75 s in duration (C). These deficits were restricted to the last half of the session (D). Response accuracy was also reduced in PCP-treated animals when challenged during an acute variable ITI session (E), an effect largely driven by an increase in incorrect responding (F). When performance was analyzed as a function of ITI, a reduction in accuracy was only evident when animals were presented with a 2 s ITI (G). Accuracy impairments were only evident during the second half of the session (H).,Between-subject differences: *p < 0.05 and **p < 0.01. Within-subject differences: #p < 0.05 and ##p < 0.01. Open white columns represent saline control animals; open shaded columns represent PCP animals before sub-chronic PCP treatment. Dashed white columns represent saline animals and dashed shaded columns represent PCP treated animals after PCP treatment. Open circles represent saline-treated animals and open-squares denote PCP-treated animals. Data are mean ± SEM.

Figure 3.

Pre-pulse inhibition of the startle response before (A) and after (B) sub-chronic PCP treatment. It can be seen that PCP had no significant effect on prepulse inhibition of the acoustic startle response. A main effect of prepulse effect: *p < 0.001. Open white columns represent saline control animals (n = 10); open shaded columns represent PCP animals (n = 10) before sub-chronic PCP treatment. Dashed white columns represent saline control animals; shaded dashed columns represent PCP-treated animals after PCP. Data are mean ± SEM.

Figure 4.

Average voxel-based cortical thickness in rats treated with PCP. Scale bar in mm (A). Areas of significantly reduced cortical thickness in PCP-treated animals compared with saline-treated animals; the scale bar shows student’s t-score based on 14 degrees of freedom. Results surviving a cluster-extent correction for family-wise error p < 0.05 are shown (B). Coronal sections indicating reduced cortical thickness in the insular cortex, left somatosensory cortex (S1; C; panel 1), granular and dysgranular insular cortex (panel 2), granular, dysgranular insular cortex, and ectorhinal cortex (panel 3). Regions identified using Paxinos and Watson (1997).

Figure 5.

Coronal sections showing areas of significant differences in grey matter between rats treated with saline and PCP. The horizontal scale bar is 2mm; the color scale shows the student’s t-score. Results shown are significant at a cluster-level corrected family-wise error of p < 0.05. The test performed was two-tailed, but only grey matter reductions were observed. ACC, anterior cingulate cortex; VS, ventral striatum; Amyg, amydaloid regions; Hipp, hippocampus.