Bicuculline‐induced brain activation in mice detected by functional magnetic resonance imaging

Abstract

Key words: functional magnetic resonance imaging; relative cerebral blood volume; bicuculline; pharmacological stimulation; mouse; iron-oxide nanoparticles; transcutaneous blood gas monitoring Genetic engineering and transgenic technology have led to advances in the generation of animal models that develop aspects of various brain pathologies, and have emphasized the need to develop accurate methods when phenotyping these animals. Such models would benefit from the development of noninvasive methods to study disease progression while allowing for a correlation with behavioral studies. The purpose of the present study was to assess the feasibility of functional magnetic resonance imaging (fMRI) in mice by monitoring changes in local relative cerebral blood volume (CBV rel ) during pharmacological stimulation under controlled physiological conditions, and hence to assess the potential of pharmacological fMRI as a noninvasive method to characterize transgenic and knock-out mice models. fMRI has proven its utility for the noninvasive mapping of brain function with high temporal and spatial resolution. Depending on the method applied, image contrast in fMRI is determined either by the oxygenation state of hemoglobin (BOLD) (1) or by changes in cerebral hemodynamics, i.e., cerebral blood flow (CBF) (2,3) and CBV (4). Using superparamagnetic iron-oxide nanoparticles as a blood-pool contrast agent, a local CBV rel increase is reflected by an increase in the amount of magnetite nanoparticles in the activated tissue and, correspondingly, by a decrease in the signal intensities in T 2 -weighted images. High-resolution CBV rel maps can be derived from the signal attenuation once the tracer has reached a steady-state blood concentration. Applying this CBV rel -fMRI method, activation in the rat sensory cortex caused by electrical stimulation of the forepaw was demonstrated (5,6). Hemodynamic changes associated with a pharmacological stimulation paradigm have been demonstrated in rats, and could be used to study drugs at the specific receptor level. Systemic infusion of the GABA A antagonist bicuculline led to an alteration in neuronal activity in cortical and subcortical brain structures. Dose-dependent CBV rel increases have been measured in various brain structures (e.g., the cortex, thalamus, and caudate putamen) in the rat (7).It is well known that physiological parameters, such as body temperature and blood gases, will affect CBV values. Mandeville et al. (6) reported CBV rel increases on the order of 50% in rats during hypercarbia by increasing arterial CO 2 tension (PaCO 2 ) from 25-55 mmHg. Although reports on the quantitative relationship between changes in CBV rel and PaCO 2 differ considerably, it is obvious that control and continuous monitoring of blood CO 2 and blood oxygenation are critical for detecting small alterations of cerebrovascular parameters in the mouse. Although larger animals can sustain frequent blood samplings, noninvasive monitoring of blood gases has been found to be essential when studying m...

Propofol allows precise quantitative arterial spin labelling functional magnetic resonance imaging in the rat

“…Functional MRI techniques are based on the close relationship between local neural activity, metabolism and changes in the cerebral blood flow (CBF) (Raichle and Mintun, 2006). A major advantage offered by these techniques is the possibility for non invasive longitudinal studies of brain plasticity (Dijkhuizen and Nicolay, 2003) and functional recovery processes in models of brain injury (Mueggler et al, 2001;Schroeter et al, 2009). The tight coupling of regional CBF and neuronal activity was remarked upon by Roy and Sherrington more than a century ago (Roy and Sherrington, 1890).…”

Current status of functional MRI on small animals: application to physiology, pathophysiology, and cognition

“…The interpretation favoured by the authors is a compromised vascular reserve capacity in APP23 mice. This interpretation is supported by a further study by the same group using bicuculine or azetazolamide challenge as a reporter for vascular response (23). However, they admit that alternatively/ additionally the response could be compromised at the neuronal level, prompting a reduced amplitude of associated vascular changes in local CBV.…”

“…Isoflurane has been used in fMRI studies that rely on CBV changes in mice (23) and in fMRI studies on the relationship between neural, vascular and BOLD signals (24) and on cerebral oxygen consumption during brain activity in rats (25).…”

“…In the past, this was achieved with invasive blood sampling for repetitive blood gas analysis throughout the fMRI experiment. The drawbacks of limited blood sample availability and blindness to pCO 2 fluctuations between sampling periods have now been eliminated by using the continuous and non-invasive recording of transcutaneous pCO 2 (23,30,37,38) or end-tidal pCO 2 values with MRI-compatible capnometry in intubated animals (39)(40)(41) or simply with an inhalation mask (42) for which linear correlations with arterial pCO 2 have been established (43).…”

In Vivo mouse imaging and spectroscopy in drug discovery

“…To our knowledge, up to now only a very few brain fMRI studies involving external stimuli or drugs have been reported in mice (60)(61)(62)(63). fMRI approaches would be of interest for gaining insight into the pathophysiology and disease processes of a number of transgenic mice models.…”