Role of neuronal activity and kinesin on tract tracing by manganese-enhanced MRI (MEMRI)

Abstract

MEMRI offers the exciting possibility of tracing neuronal circuits in living animals by MRI. Here we use the power of mouse genetics and the simplicity of the visual system to test rigorously the parameters affecting Mn 2+ uptake, transport and trans-synaptic tracing. By measuring electrical response to light before and after injection of Mn 2+ into the eye, we determine the dose of Mn 2+ with the least toxicity that can still be imaged by MR at 11.7T. Using mice with genetic retinal blindness, we discover that electrical activity is not necessary for uptake and transport of Mn 2+ in the optic nerve but is required for trans-synaptic transmission of this tracer to distal neurons in this pathway. Finally, using a kinesin light chain 1 knock-out mouse, we find that conventional kinesin is a participant but not essential to neuronal transport of Mn 2+ in the optic tract. This work provides a molecular and physiological framework for interpreting data acquired by MEMRI of circuitry in the brain.

Manganese transport in the rat optic nerve evaluated with spatial‐ and time‐resolved magnetic resonance imaging

“…Various substances move at different rates independently of the electrical activity within the axons (3,4) and are grouped in fast and slow components with speeds of %4-16 mm/h and 4-250 mm/h, respectively, in the healthy axon, (3,5). The same ''fast'' molecular motors are involved in both fast and slow axonal transport, but during slow axonal transport there are prolonged pauses between periods of movements (6,7).…”

Combination of Mn2+‐enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve

“…The toxicity of Mn 2ϩ is well documented. After high doses and after long exposure, Mn 2ϩ induces both systemic and neurological effects (24,25). Thus, MEMRI should be performed with an Mn 2ϩ dose that produces satisfactory tissue contrast without inducing severe toxic effects.…”

Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats

“…However, it has been shown that 50 nmol of Mn 2+ injected into the vitreous body of a mouse eye disturbed neuronal electrophysiology measured in the visual cortex (Bearer et al, 2007). A similar dose (45 nmol of Mn 2+ ) caused degeneration of the dopaminergic ventral tegmental area (VTA) neurons after a direct intracerebral injection in rats (own unpublished data).…”

“…However, that study focused on cortical and not midbrain neurons. Furthermore, a signal change measured 24 h after an injection of only a few nmol of Mn 2+ was not detectable by an 11 T MR scanner (Bearer et al, 2007). Therefore, when doses below 10 nmol are used the MR acquisition either takes place directly after the injection (Canals et al, 2008) or requires a scanning time of several hours (Pautler et al, 2003).…”

“…Moreover, this neuronal transport is, at least partially, activity-dependent which enables functional imaging of brain connectivity (Van der Linden et al, 2004, Bearer et al, 2007, Yang et al, 2011, Wang et al, 2015. Due to these unique characteristics, manganese -enhanced MRI (MEMRI) has been widely used for anatomical measurements, as well as investigations of neuronal function and plasticity in rodents, birds, and primates (Saleem et al, 2002, Van der Linden et al, 2004, Watanabe et al, 2004, Canals et al, 2008, Doron and Goelman, 2010, Zhang et al, 2010.…”