Severe Cross-Modal Object Recognition Deficits in Rats Treated Sub-Chronically with NMDA Receptor Antagonists are Reversed by Systemic Nicotine: Implications for Abnormal Multisensory Integration in Schizophrenia

Abstract

Schizophrenia is a complex and debilitating disorder, characterized by positive, negative, and cognitive symptoms. Among the cognitive deficits observed in patients with schizophrenia, recent work has indicated abnormalities in multisensory integration, a process that is important for the formation of comprehensive environmental percepts and for the appropriate guidance of behavior. Very little is known about the neural bases of such multisensory integration deficits, partly because of the lack of viable behavioral tasks to assess this process in animal models. In this study, we used our recently developed rodent cross-modal object recognition (CMOR) task to investigate multisensory integration functions in rats treated sub-chronically with one of two N-methyl-D-aspartate receptor (NMDAR) antagonists, MK-801, or ketamine; such treatment is known to produce schizophrenia-like symptoms. Rats treated with the NMDAR antagonists were impaired on the standard spontaneous object recognition (SOR) task, unimodal (tactile or visual only) versions of SOR, and the CMOR task with intermediate to long retention delays between acquisition and testing phases, but they displayed a selective CMOR task deficit when mnemonic demand was minimized. This selective impairment in multisensory information processing was dose-dependently reversed by acute systemic administration of nicotine. These findings suggest that persistent NMDAR hypofunction may contribute to the multisensory integration deficits observed in patients with schizophrenia and highlight the valuable potential of the CMOR task to facilitate further systematic investigation of the neural bases of, and potential treatments for, this hitherto overlooked aspect of cognitive dysfunction in schizophrenia.

Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: Implications for neurodevelopmental psychiatric disorders

“…PolyI:C treatment also selectively impaired multisensory integration, as sal-polyI:C rats showed significant memory on the visual and tactile tests, but were impaired on the crossmodal test. This finding compliments a recent report showing an impaired crossmodal recognition memory following acute treatment with an NMDA receptor antagonist (Jacklin et al, 2012), and indicates that the polyI:C model is useful for studying the developmental factors that may alter multisensory integration in schizophrenia (Stekelenburg et al, 2013;Stone et al, 2011;Williams et al, 2010). Similar to previous observations in Long-Evans rats , polyI:C treatment did not alter "simpler" forms of recognition memory in the visual or tactile tests.…”

“…4H), rats were tested for their ability to use information gained from a tactile experience during the sample phase to guide the exploration of visual stimuli during the test phase. Sal-sal control rats showed evidence of significant memory (t(22) = 4.42, p < 0.001), similar to results described previously (Jacklin et al, 2012;Winters and Reid, 2010). Sal-polyI:C rats failed to show significant memory as reflected by a mean DR not different from chance (t(1 9) = 1.06, p = 0.30).…”

“…Behavioral tests were conducted according to published protocols (Floresco et al, 2008(Floresco et al, , 2009Howland et al, 2012;Jacklin et al, 2012;Thai et al, 2013;Winters and Reid, 2010;Zhang et al, 2012). Testing occurred in the following order: PPI during puberty and young adulthood (PNDs 56-57), recognition memory (PNDs 60-80) and operant testing (PNDs 80-100).…”

“…To the best of our knowledge, multisensory integration has not been examined in rodent models of MIA. Therefore, we tested the effects of polyI:C on crossmodal recognition memory, a recently developed test of multisensory integration, which includes visual, tactile and crossmodal components (Jacklin et al, 2012;Winters and Reid, 2010). Finally, behavioral flexibility was examined as patients typically exhibit decreased flexibility on tests of attentional set-shifting and reversal learning (Leeson et al, 2009;Pantelis et al, 1999;Waltz and Gold, 2007).…”

T-type calcium channels in the orbitofrontal cortex mediate sensory integration as measured using a spontaneous oddity task in rats

“…The effects of systemic Z944 treatment on MSI are similar to those observed following NMDA receptor antagonist administration (Jacklin et al 2012;Cloke and Winters 2015;Cloke et al 2016). However, impaired unimodal SI was not found in these studies except when the task included a 1 h delay (Jacklin et al 2012;Cloke and Winters 2015).…”