Nucleus Reuniens-Elicited Delta Oscillations Disable the Prefrontal Cortex in Schizophrenia

Abstract

Schizophrenia (SZ) is a severe mental disorder associated with an array of symptoms characterized as positive, negative and cognitive dysfunctions. While SZ is a multifaceted disorder affecting several regions of the brain, altered thalamocortical systems have emerged as a leading contributor to SZ. Specifically, it has been shown that: (1) the thalamus is functionally disconnected from the prefrontal cortex (PFC) in SZ; (2) neural activity and blood flow to the PFC are greatly diminished in SZ (hypofrontality); and (3) delta oscillations are abnormally present in the PFC during the waking state in SZ. We suggest that the abnormal delta oscillations drive the other PFC signs of SZ. Specifically, decreases in energy required to maintain delta, would initiate the reduced PFC perfusion of SZ (hypofrontality), and contribute to the 'mismatched' thalamic and PFC activity of SZ. As SZ involves glutamate (NMDAR) hypofunction and dopamine hyperfunction, both NMDAR antagonists and dopamine agonists produce marked increases in delta oscillations in nucleus reuniens (RE) of the thalamus and its target structures, including the PFC. This would suggest that RE is a primary source for the elicitation of PFC delta activity, and the presence of delta during waking (together with associated signs) would indicate that the prefrontal cortex is disabled (or non-functional) in schizophrenia.

Keywords: cognition; dopamine; glutamate; hippocampus; memory; reticular thalamic nucleus; thalamus.

Figure 1

Schematic representation of the major interconnections of the nucleus reuniens of the ventral midline thalamus with subcortical and cortical structures. As depicted, the nucleus reuniens is reciprocally connected with the reticular nucleus of the thalamus, the hippocampus and the medial prefrontal cortex and receives projections from the ventral tegmental area. In addition, each of these structures are, in turn, interconnected to form loops that ultimately serve to drive delta oscillations in the prefrontal cortex. Abbreviations: DG, dentate gyrus of hippocampus; CA1, CA2, CA3, fields CA1–CA3 of Ammons horn of the hippocampus.