title: Sub-anesthetic ketamine modulates intrinsic BOLD connectivity within the hippocampal-prefrontal circuit in the rat.
abstract: Dysfunctional connectivity within the hippocampal-prefrontal circuit (HC-PFC) is associated with schizophrenia, major depression, and neurodegenerative disorders, and both the hippocampus and prefrontal cortex have dense populations of N-methyl-D-aspartate (NMDA) receptors. Ketamine, a potent NMDA receptor antagonist, is of substantial current interest as a mechanistic model of glutamatergic dysfunction in animal and human studies, a psychotomimetic agent and a rapidly acting antidepressant. In this study, we sought to understand the modulatory effect of acute ketamine administration on functional connectivity in the HC-PFC system of the rat brain using resting-state fMRI. Sprague-Dawley rats in four parallel groups (N=9 per group) received either saline or one of three behaviorally relevant, sub-anesthetic doses of S-ketamine (5, 10, and 25 mg/kg, s.c.), and connectivity changes 15- and 30-min post-injection were studied. The strongest effects were dose- and exposure-dependent increases in functional connectivity within the prefrontal cortex and in anterior-posterior connections between the posterior hippocampus and retrosplenial cortex, and prefrontal regions. The increased prefrontal connectivity is consistent with ketamine-induced increases in HC-PFC electroencephalographic gamma band power, possibly reflecting a psychotomimetic aspect of ketamine's effect, and is contrary to the data from chronic schizophrenic patients suggesting that ketamine effect does not necessarily parallel the disease pattern but might rather reflect a hyperglutamatergic state. These findings may help to clarify the brain systems underlying different dose-dependent behavioral profiles of ketamine in the rat.
authors.affiliation: Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gass
authors.affiliation: 1] Translational Medicine, Eli Lilly, Indianapolis, IN, USA [2] Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
authors.forename: Adam James
authors.initials: AJ
authors.lastname: Schwarz
authors.affiliation: 1] Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany [2] Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sartorius
authors.affiliation: Neuroscience Drug Discovery Unit, Institut de Recherches Servier, Croissy s/Seine, France.
authors.forename: Esther
authors.initials: E
authors.lastname: Schenker
authors.affiliation: CNS Biomarker, Pharmaceuticals Division, F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Risterucci
authors.affiliation: Neuroscience Drug Discovery Unit, Institut de Recherches Servier, Croissy s/Seine, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Spedding
authors.affiliation: 1] Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany [2] Experimental Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.affiliation: Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weber-Fahr
mesh_terms: D000700:Analgesics / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006624:Hippocampus / Q000098:blood supply* / Q000187:drug effects*; D007091:Image Processing, Computer-Assisted; D007649:Ketamine / Q000097:blood / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D009415:Nerve Net / Q000098:blood supply* / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D017397:Prefrontal Cortex / Q000098:blood supply* / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013223:Statistics as Topic
chemical_list: D000700:Analgesics; D007649:Ketamine; D010100:Oxygen