In vivo auditory brain mapping in mice with Mn-enhanced MRI.

Nat Neurosci. 2005 Jul;8(7):961-8. PMID: 15924136

Yu X, Wadghiri YZ, Sanes DH, Turnbull DH.

The objective in this study was to develop a noninvasive imaging method of imaging changes in activity of murine brainstem nuclei related to brain development and hearing loss.  Using manganese enhanced MRI (MEMRI) shows differences in Mn²⁺ uptake caused by changes in neuronal activity.  This allows the measurement of changes in activity that result from hearing loss at different stages in neurodevelopment.

Results:

·         Mn²⁺ was enhanced in ventricles within 2hrs, but cleared over 24hrs concomitant with increased Mn²⁺ in parenchyma leading up to the 24hr point.  The greatest increase in signal was seen in the olfactory bulbs, hippocampus, midbrain, and cerebellum.
·         Animals with bilateral CHL showed significantly lower Mn enhancement of the auditory brainstem nuclei than control animals.  There were no significant differences in non-auditory areas.
·         Animals with unilateral CHL showed significant Mn²⁺ enhancement in the cochlear nucleus (CN) corresponding to the functional ear compared to the CN of the non-functional ear, which were similar to the differences in enhancement between experimental and control animals.  The enhancement also appeared in the inferior colliculi (IC) contralateral to the CN with Mn²⁺ enhancement, in agreement with the known axonal projections.
·         MEMRI was able to demonstrate frequency-dependent tonotopic enhancement in regions of the IC  that was in agreement with existing data from electrophysiological studies.
·         At the 6 week point, CHL induced at p10 (before the onset of hearing) resulted in decreased enhancement of both the CN and the IC, whereas CHL induced at p21 showed changes in the CN but not the IC.  This indicates that early hearing loss leads to persistent changes in auditory brain function.

Conclusions:

·         MEMRI has spatial resolution sufficiently high enough to allow for tonotopic mapping of the IC
·         MEMRI can demonstrate changes in neurodevelopment and function.
·         This method shows MEMRI can be done at non-toxic doses and less invasively than previous methods (no cannula or disruption of blood brain barrier) in order to measure activity-dependent Mn²⁺ uptake.

Methods: Unilateral or bilateral conductive hearing loss (CHL) was induced in mice at postnatal day 10, 21, or week 6 via puncture of the tympanic membrane and removal of the malleus. MnCl₂ was administered via IP injection at 0.4mm/kg as this dose was shown to be below the threshold of neurotoxicity. Mice were exposed to 24 hours of sound at frequencies within the range of their hearing. MRI data was then acquired and analyzed to find regions of interest as defined by and increased signal intensity due to Mn²⁺uptake. Signal intensity was normalized to the signal of the caudate putamen, which was a region unaffected by sound stimulation.

-DH