Association between neural discoordination and impaired cognitive control in a schizophrenia-related animal model.

Abstract

The neural mechanisms underling cognitive dysfunction have been studied for decades, but it is still poorly understood. The neural discoordination hypothesis of schizophrenia asserts that cognitive deficits, such as impaired cognitive control, result from failures to coordinate the activation of distinct neural representations. The hypothesis that neural discoordination underlies impaired cognitive control predicts that altered neural coordination of cell assemblies is associated with impaired cognitive control and thus the inability to use relevant information while ignoring irrelevant information.

To examine this prediction, we investigated cognitive control and neural coordination in the acute phencyclidine (PCP) model of schizophrenia. Cognitive control was evaluated by measuring behavioral performance in an active place avoidance task, which challenges subjects to use relevant cues while ignoring the irrelevant cues. PCP selectively impaired place avoidance when cognitive control was required, but not memory and navigation. Neural coordination was measured by assaying local field potentials and spike trains of place cells in the CA1 region of hippocampus in freely moving rats. The dose of PCP that impaired place avoidance also changed local field potentials by increasing the amplitude of gamma oscillation and increasing the modulation of gamma amplitude by the phase of concurrent theta oscillation. PCP also altered the timing of place cells signals by altering the reliability of place cell discharge when the rat was in the firing field, by changing the relationship of coupled discharge between pairs of cells, and by corrupting the pattern of place cell ensemble discharge with minimal effects on the discharge properties of place cells.

The two main findings of our study are: 1) a moderate dose of PCP impairs cognitive control without disturbing the capacity to navigate or recall established memories; 2) the same dose of PCP that impaired cognitive control discoordinates the timing of hippocampal signals measured at the levels of local field potentials as well as action potential spike trains. These findings provide strong support for the discoordination hypothesis that neural discoordination underlies impaired cognitive control.