Mapping of CBV changes in 5-HT1A terminal fields by functional MRI in the mouse brain

Mueggler, Thomas; Razoux, Florence; Russig, Holger; Buehler, Anna; Franklin, Tamara B.; Baltes, Christof; Mansuy, Isabelle M.; Rudin, Markus

doi:10.1016/j.euroneuro.2010.06.010

« Previous Next »European Neuropsychopharmacology
Volume 21, Issue 4 , Pages 344-353, April 2011

Mapping of CBV changes in 5-HT_1A terminal fields by functional MRI in the mouse brain

Thomas Mueggler
- Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland
- Current address: F. Hoffmann-La Roche Ltd., Pharmaceutical Research Neuroscience, CH-4070 Basel, Switzerland. Tel.: +41 61 687 4027; fax: +41 61 687 1910.
- Contributed equally to this work.
Florence Razoux
- Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland
- Contributed equally to this work.
Holger Russig
- Brain Research Institute, University and ETH Zurich, Zurich, Switzerland
Anna Buehler
- Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland
Tamara B. Franklin
- Brain Research Institute, University and ETH Zurich, Zurich, Switzerland
Christof Baltes
- Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland
Isabelle M. Mansuy
- Brain Research Institute, University and ETH Zurich, Zurich, Switzerland
Markus Rudin
- Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland
- Institute of Pharmacology and Toxicology, University Zurich, Zurich, Switzerland
- Corresponding author. Institute for Biomedical Engineering, University and ETH Zurich, Institute of Pharmacology and Toxicology, University of Zurich, HIT E.22.4, Wolfgang Pauli Strasse 27, CH-8093 Zurich, Switzerland. Tel.: +41 44 633 7604; fax: +41 44 633 1187.

Received 11 December 2009; received in revised form 14 June 2010; accepted 19 June 2010. published online 26 July 2010.

Abstract

Visualization of brain activity in humans and animals using functional magnetic resonance imaging (fMRI) is an established method for translational neuropsychopharmacology. It is useful to study the activity of defined brain structures, however it requires further refinement to allow more specific cellular analyses, like for instance, the activity of selected pools of brain cells. Here, we investigated brain activity in serotonergic pathways in the adult mouse brain by using acute pharmacological challenge of 5-hydroxytryptamine (5-HT) 1A receptors. We show that administration of the 5-HT_1A receptor agonist 8-OH-DPAT prompts a dose-dependent reduction in local cerebral blood volume (CBV) in brain areas rich in neurons expressing post-synaptic 5-HT_1A receptor, including the prefrontal cortex, hippocampus and amygdalar nuclei. Region-specific inhibition of the response by co-injection of 8-OH-DPAT with the selective 5-HT_1A receptor antagonist WAY-100635, or in 5-HT_1A knock-out mice, suggests that 5-HT_1A receptors are the primary targets of the agonist. Overall, the data demonstrate the feasibility of mapping region-specific serotonergic transmission in the adult mouse brain in vivo by non-invasive fMRI. The method opens novel perspectives for investigating 5-HT_1A receptor functions in mouse models of human pathologies resulting from a dysfunction of the 5-HT_1A receptor or the serotonergic system, including depression and anxiety.

Abbreviations:: 5-HT-R, 5-hydroxy-tryptamine (serotonergic) receptor, 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino) tetralin, BLA, basolateral amygdala, BM, basomedial amygdala, CBV, cerebral blood volume, Cg, cingulate cortex, DHC, dorsal hippocampus, DR, dorsal raphe nucleus, FMRI, functional magnetic resonance imaging, LA, lateral amygdala, LS, lateral septum, PAG, periaqueductal gray, PET, positron emission tomography, RF, radiofrequency, ROI, region-of-interest, SNR, signal-to-noise ratio, SE-RARE, Spin-echo rapid acquisition with relaxation enhancement technique, tcpCO₂, transcutaneously assessed partial pressure of carbon dioxide, VHC, ventral hippocampus, WAY-10063, N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide