Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies

Abstract

Magnetic resonance imaging (MRI) is widely used in basic and clinical research to map the structural and functional organization of the brain. An important need of MR research is for contrast agents that improve soft-tissue contrast, enable visualization of neuronal tracks, and enhance the capacity of MRI to provide functional information at different temporal scales. Unchelated manganese can be such an agent, and manganese-enhanced MRI (MEMRI) can potentially be an excellent technique for localization of brain activity (for review see Silva et al., 2004). Yet, the toxicity of manganese presents a major limitation for employing MEMRI in behavioral paradigms. We have tested systematically the voluntary wheel running behavior of rats after systemic application of MnCl 2 in a dose range of 16-80 mg/kg, which is commonly used in MEMRI studies. The results show a robust dose-dependent decrease in motor performance, which was accompanied by weight loss and decrease in food intake. The adverse effects lasted for up to 7 postinjection days. The lowest dose of MnCl 2 (16 mg/kg) produced minimal adverse effects, but was not sufficient for functional mapping. We have therefore evaluated an alternative method of manganese delivery via osmotic pumps, which provide a continuous and slow release of manganese. In contrast to a single systemic injection, the pump method did not produce any adverse locomotor effects, while achieving a cumulative concentration of manganese (80 mg/kg) sufficient for functional mapping. Thus, MEMRI with such an optimized manganese delivery that avoids toxic effects can be safely applied for longitudinal studies in behaving animals.

Structural and functional neuroimaging phenotypes in dysbindin mutant mice

“…The pituitary gland is outside the BBB and its signal shows strong dose-dependent contrast enhancement. Therefore, it was used as an internal reference for any systemic effects, a technique also employed by other groups using MEMRI in mice (Chuang and Koretsky, 2009;Eschenko et al, 2010). In our sample, pituitary contrast enhancement between genotypes differed by 3.3% (p= 0.517) indicating no systematic differences in manganese uptake in the pituitary.…”

Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

“…We chose to examine the ability of MEMRI to detect changes between MPTP and DPBS controls during this time. MEMRI provides information relevant to assessments of neural anatomy, function, and connectivity [38,39]. Mn 2+ enters neurons through voltage-gated calcium Ca 2+ channels, owing to its similarities with Ca 2+ , linking Mn 2+ accumulation to MEMRI signal intensity [40].…”

Impaired associative taste learning and abnormal brain activation in kinase-defective eEF2K mice

“…When administered systemically, Mn 2+ reaches the brain and enters the cells via voltage-gated Ca 2+ channels and then propagates transsynaptically. Most importantly, because the transfer of manganese is through voltage-gated channels at relatively low rates, its accumulation inside cells and in the surrounding extracellular space is proportional to neural activity (Lin and Koretsky 1997;Eschenko et al 2009). We chose this MEMRI mode, which measures accumulation of Mn 2+ in active brain regions over several days, to provide a global view of patterns of brain activation associated with repeated CTA training.…”

“…Thus, this mode of Mn 2+ application was expected to result in a final spatial distribution pattern that reflected the differential cumulative activation of brain regions that is associated with CTA. Similar protocols have been applied to studying activation of the rat brain by voluntary running (Eschenko et al 2009), auditory stimulation (Yu et al 2011), and retrieval of novel taste (Inui-Yamamoto et al 2010).…”