Abstract
Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena – Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated neurons.
Highlights
Dynamic environments in the real world often involve multiple reference frames without stable mutual relationships
(B) Room-Rotating Place Avoidance on a rotating dry arena with a high demand for coordination of information from the dissociated spatial frames. 0.15 mg/kg MK-801 persistently impaired all measures of avoidance and increased locomotion on the Rotating arena compared to the saline controls and 0.10 mg/kg MK-801
Cognitive dysfunction precedes the manifestation of psychotic symptoms from early childhood (Reichenberg et al, 2010; Sørensen et al, 2010) and cognitive performance is the strongest predictor of the functional outcome in schizophrenia (Green, 1996; Green and Nuechterlein, 1999; Green et al, 2004; Bowie et al, 2006; Keefe et al, 2006; Rosenheck et al, 2006)
Summary
Dynamic environments in the real world often involve multiple reference frames without stable mutual relationships. Animals need to keep track of their positions within a group of conspecifics as well as within ambient environment. Representations to support context-relevant behavioral responses (Figures 1A,C). Impairment of this cognitive coordination could be responsible for cognitive disorganization in psychosis including inappropriate associations, deficits in contextual binding, and impaired discrimination between relevant and irrelevant information (Ellenbroek and Cools, 1990; Silverstein et al, 2000; Phillips and Silverstein, 2003; Uhlhaas et al, 2004; Hemsley, 2005). Most laboratory tests of hippocampal function occur in static environments or involve only one-off changes or between-session alternations
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