Quantitative pharmacologic MRI: Mapping the cerebral blood volume response to cocaine in dopamine transporter knockout mice

Abstract

The use of pharmacologic MRI (phMRI) in mouse models of brain disorders allows noninvasive in vivo assessment of drug-modulated local cerebral blood volume changes (ΔCBV) as one correlate of neuronal and neuro-vascular activities. In this report, we employed CBV weighted phMRI to compare cocaine-modulated neuronal activity in dopamine transporter (DAT) knockout (KO) and wild-type mice. Cocaine acts to block the dopamine, norepinephrine and serotonin transporters (DAT, NET and SERT) that clear their respective neurotransmitters from the synapses, helping to terminate cognate neurotransmission. Cocaine consistently reduced CBV, with a similar pattern of regional ΔCBV in brain structures involved in mediating reward in both DAT genotypes. The largest effects (−20% to −30% ΔCBV) were seen in the nucleus accumbens and several cortical regions. Decreasing response amplitudes to cocaine were noted in more posterior components of the cortico-mesolimbic circuit. DAT KO mice had significantly attenuated ΔCBV amplitudes, shortened times to peak response and reduced response duration in most regions. This study demonstrates that DAT knockout does not abolish the phMRI responses to cocaine, suggesting that adaptations to loss of DAT and/or retained cocaine activity in other monoamine neurotransmitter systems underlie these responses in DAT KO mice.

A receptor-based model for dopamine-induced fMRI signal

“…In the rat, the overall sign of the model response is reversed after a brief negative dip by changing only the D1/D2 receptor ratio in the model; this response in the rat matches fMRI data reported by our group and others (Chen et al, 2011; Marota et al, 2000; Schwarz et al, 2004). Moreover, recently reported mouse fMRI data show a cocaine-induced reduction in CBV in basal ganglia similar to the NHP (Perles-Barbacaru et al, 2011), as predicted by the model due to the similar density of D1 and D2 receptors in the mouse. The temporal response in the mouse study was delayed and protracted relative to the model results of Fig.…”

“…Glucose autoradiography reported cocaine-induced elevation of metabolism in rats (Porrino, 1993) but decreased metabolism in non-human primates (NHP) (Lyons et al, 1996) and mice (Zocchi et al, 2001). Similarly, IRON fMRI reported cocaine-induced elevation of CBV in rats (Chen et al, 2011; Marota et al, 2000; Schwarz et al, 2004) but decreased CBV in NHP (Mandeville et al, 2011) and wild-type mice (Perles-Barbacaru et al, 2011). Because the different fMRI responses in rats and NHP occur despite similar levels of evoked DA (Bradberry, 2000; Chen et al, 2010; Schwarz et al, 2004), we previously hypothesized that these different responses might be attributable to the ratio of D1 to D2 receptors (Mandeville et al, 2011), which is much higher in laboratory rats than in humans, NHP, or wild-type mice.…”

Robust deep brain stimulation functional MRI procedures in rats and mice using an MR-compatible tungsten microwire electrode

“…Given the genetic tractability of this species, such a protocol is highly desirable yet challenging due to the small size of the mouse brain. In addition to the use of a microwire electrode to minimize susceptibility artifacts in the relatively small mouse brain, a major strength of our mouse DBS protocol lies in the application of an exogenous MION contrast agent to visualize changes in CBV . Interestingly, the frequency tuning plot acquired in mouse was generally consistent with the rat plots, although the mouse seems to be more sensitive to lower frequency VPM‐DBS.…”

Hyper BOLD Activation in Dorsal Raphe Nucleus of APP/PS1 Alzheimer’s Disease Mouse during Reward-Oriented Drinking Test under Thirsty Conditions

“…Such methods, accompanied by opto-or chemogenetics, can further investigations in AD model mice. It is especially advantageous as similar manipulations cannot be performed on humans [34][35][36] . The ease of genetically manipulating mice makes them suitable for investigating the roles of specific genes in brain function.…”