Subanaesthetic ketamine treatment alters prefrontal cortex connectivity with thalamus and ascending subcortical systems

Neil Dawson, B.J. Morris, Judith Pratt

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Acute treatment with subanaesthetic doses of NMDA receptor antagonists, such as ketamine, provides a translational model with relevance to many of the symptoms of schizophrenia. Previous studies have focused specifically on the prefrontal cortex (PFC) because this region is implicated in many of the functional deficits associated with this disorder and shows reduced activity (hypofrontality) in schizophrenia patients. Chronic NMDA antagonist treatment in rodents can also induce hypofrontality, although paradoxically acute NMDA receptor antagonist administration induces metabolic hyperfrontality.
In this study, we use 2-deoxyglucose imaging data in mice to characterize acute ketamine-induced alterations in regional functional connectivity, a deeper analysis of the consequences of acute NMDA receptor hypofunction.
We show that acute ketamine treatment increases PFC metabolic activity while reducing metabolic activity in the dorsal reticular thalamic nucleus (dRT). This is associated with abnormal functional connectivity between the PFC and multiple thalamic nuclei, including the dRT, mediodorsal (MDthal), and anteroventral (AVthal) thalamus. In addition, we show that acute NMDA receptor blockade alters the functional connectivity of the serotonergic (dorsal raphe [DR]), noradrenergic (locus coeruleus [LC]), and cholinergic (vertical limb of the diagonal band of broca [VDB]) systems.
Together with other emerging data, these findings suggest that the reticular nucleus of the thalamus, along with the diffusely projecting subcortical aminergic/cholinergic systems, represent a primary site of action for ketamine in reproducing the diverse symptoms of schizophrenia. Our results also demonstrate the added scientific insight gained by characterizing the functional connectivity of discrete brain regions from brain imaging data gained in a preclinical context.
Original languageEnglish
Pages (from-to)366-377
Number of pages12
JournalSchizophrenia Bulletin
Volume39
Issue number2
Early online date22 Nov 2011
DOIs
Publication statusPublished - 2 Mar 2013

Keywords

  • ketamine
  • prefrontal cortex connectivity
  • thalamus
  • subcortical systems
  • NMDA receptor 2-deoxyglucose autoradiographic imaging
  • partial least squares regression

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