Elsevier

NeuroImage

Volume 54, Issue 1, 1 January 2011, Pages 389-395
NeuroImage

In vivo retinotopic mapping of superior colliculus using manganese-enhanced magnetic resonance imaging

https://doi.org/10.1016/j.neuroimage.2010.07.015Get rights and content

Abstract

The superior colliculus (SC) is a dome-shaped subcortical laminar structure in the mammalian midbrain, whose superficial layers receive visual information from the retina in a topological order. Despite the increasing number of studies investigating retinotopic projection in visual brain development and disorders, in vivo, high-resolution 3D mapping of topographic organization in the subcortical visual nuclei has not yet been available. This study explores the capability of 3D manganese-enhanced MRI (MEMRI) at 200 μm isotropic resolution for in vivo retinotopic mapping of the rat SC upon partial transection of the intraorbital optic nerve. One day after intravitreal Mn2+ injection into both eyes, animals with partial transection at the right superior intraorbital optic nerve in Group 1 (n = 8) exhibited a significantly lower T1-weighted signal intensity in the lateral region of the left SC compared to the left medial SC and right control SC. Partial transection toward the temporal or nasal region of the right intraorbital optic nerve in Group 2 (n = 7) led to T1-weighted hypointensity in the rostral or caudal region of the left SC, whereas a clear border was observed separating 2 halves of the left SC in all groups. Previous histological and electrophysiological studies showed that the retinal ganglion cell axons emanating from superior, inferior, nasal and temporal retina projected respectively to the contralateral lateral, medial, caudal and rostral SC in rodents. While this topological pattern is preserved in the intraorbital optic nerve, it was shown that partial transection of the superior intraorbital optic nerve led to primary injury predominantly in the superior but not inferior retina and optic nerve. The results of this study demonstrated the sensitivity of submillimeter-resolution MEMRI for in vivo, 3D mapping of the precise retinotopic projections in SC upon reduced anterograde axonal transport of Mn2+ ions from localized regions of the anterior visual pathways to the subcortical midbrain nuclei. Future MEMRI studies are envisioned that measure the topographic changes in brain development, diseases, plasticity and regeneration therapies in a global and longitudinal setting.

Introduction

The functions of the central nervous system depend upon precisely organized neuronal connections (Herrero et al., 2002, Humphries et al., 2010, Petersen, 2007, Romanelli et al., 2005, Scicolone et al., 2009, Silver and Kastner, 2009, Upadhyay et al., 2007). Among the complex neural networks, the superior colliculus (SC) is a dome-shaped subcortical laminar structure in the mammalian midbrain, which is important in coordinating visual, somatosensory and auditory stimuli to guide animal behavior (Baba et al., 2007, Dori et al., 1998, Tiao and Blakemore, 1976). In particular, the superficial layers of the SC receive visual information from the retina in a topological order (McLaughlin et al., 2003, Plas et al., 2005, Siminoff et al., 1966, Simon and O'Leary, 1991), whereby the retinal ganglion cell axons emanating from superior, inferior, nasal and temporal retina projected to the contralateral lateral, medial, caudal and rostral SC respectively in rodents (McLaughlin et al., 2003, Plas et al., 2005, Siminoff et al., 1966, Simon and O'Leary, 1991). Despite the increasing number of studies investigating the retinotopic projection in visual brain development and disorders (Chandrasekaran et al., 2005, Dunlop et al., 2007, Finlay et al., 1979, Haustead et al., 2008, Jeffery and Thompson, 1986, McLaughlin et al., 2003, O'Leary and McLaughlin, 2005, Scicolone et al., 2009, Simon and O'Leary, 1992, So, 1979), the majority of in vivo techniques on brain organization, such as electrophysiology and optical imaging, focus on the cortex (Issa et al., 2008, Kalatsky et al., 2005, Kim et al., 2006, Peterson et al., 1998). The precise topological projection in the subcortical structures remains difficult to assess in vivo, due to the low spatial resolution of electrophysiological techniques, the depth limitation from optical imaging, the small sizes of the subcortical nuclei, their deep locations, and their closeness to surrounding large pulsating vessels (Chen et al., 1999, Fortune and Hood, 2003). Development of a tool for in vivo, high-resolution 3D mapping of topographic organization in the subcortical visual nuclei would help open a new area for understanding the precise retinotopic organizations in the visual system globally, longitudinally and non-invasively in the same animal, which could be useful for monitoring the topographic changes in brain development, diseases, plasticity and regeneration therapies in a single setting.

Magnetic resonance imaging (MRI) provides a non-invasive tool to study the structural, metabolic and functional details of the inner-depths of the body in vivo. Among the MRI techniques, blood-oxygenation level dependent functional MRI (BOLD-fMRI) has recently been used to detect the subcortical organizations in the SC and lateral geniculate nucleus (LGN) together with cortical activations (Chan et al., 2010, Chen et al., 1999, Schneider and Kastner, 2005, Schneider et al., 2004). Nevertheless, the nature of BOLD-fMRI signals relies on the hemodynamic response, and is subject to a broad intrinsic hemodynamic point-spread function covering a larger area than the neuronally active area (Duong et al., 2000, Engel et al., 1997, Duong et al., 2001, Kim and Fukuda, 2008, Shmuel et al., 2007). In addition, while the BOLD signals in subcortical nuclei are prone to contamination from surrounding large pulsating vessels, the spatial resolution of the imaging protocol is typically traded off for better signal-to-noise ratio (SNR) and faster acquisition in order to capture the physiological responses in the order of seconds. These limit the precision and accuracy in mapping topographic projections in these small nuclei using BOLD-fMRI.

Recently, manganese-enhanced MRI (MEMRI) has been increasingly used for neuronal tract tracing (Chan et al., 2008, Lin et al., 2001, Pautler et al., 1998, Thuen et al., 2005, Watanabe et al., 2001) and functional brain mapping at lamina levels (Berkowitz et al., 2006, Bissig and Berkowitz, 2009) without the reliance on hemodynamic responses. Mn2+ ions are paramagnetic in nature and can shorten the T1 relaxation time of the surrounding water protons. They act as a calcium analogue and enter the intracellular space via L-type voltage-gated calcium channels upon neuronal activation (Merritt et al., 1989, Narita et al., 1990, Pautler, 2006). A fraction of the ions are then sequestered in the endoplasmic reticulum or Golgi apparatus, and actively transported along the microtubules via fast axonal transport (Pautler, 2006, Tjalve et al., 1996). In addition, Mn2+ ions accumulate at the target locations with a slow clearance rate, allowing sufficient time for high-resolution, 3D acquisition with a large field-of-view (FOV) and an optimal SNR using typical T1-weighted (T1W) imaging sequences (Aoki et al., 2004, Chan et al., 2008, Pautler, 2004, Pautler et al., 1998, Silva et al., 2004, Thuen et al., 2008, Van der Linden et al., 2007, Watanabe et al., 2004, Yang et al., 2008, Yang and Wu, 2008). Anatomical distortions from fast acquisition sequences such as echo-planar imaging can also be avoided. Given such potential advantages, this study explores the capability of 3D MEMRI at 200 μm isotropic resolution for in vivo retinotopic mapping of the SC using a rat model of partial transection of the intraorbital optic nerve, and compares the in vivo results with previous histological and electrophysiological findings.

Section snippets

Animal preparation

Sprague–Dawley female rats (200–250 g, n = 15) were divided into 2 groups, and were reared in a temperature-controlled room subjected to a 12 h light/12 h dark cycle with standard chow and water supply ad libitum. In Group 1 (n = 8), the superior region of the right intraorbital optic nerve was partially transected at about 2 mm from the eye with a custom-made thin blade using the ophthalmic artery lying inferior to the optic nerve as a landmark (Janes and Bounds, 1955, Levkovitch-Verbin et al., 2003,

Results

In the multi-planar reconstructed images in Fig. 1, the site of partial transection was demonstrated by hypointensity in the intraorbital optic nerve at about 2 mm from the right eye. Distal to the lesion, the T1W signal intensity was apparently lower compared to the proximal segment and the entire control left optic nerve. In the MIP images (Fig. 2, Fig. 3 and Supplementary information), intravitreal Mn2+ injection into the left control eye resulted in signal enhancement in the entire left

Discussion

Using in vivo axonal tracing by Mn2+, MEMRI correctly mapped out the retinotopic organization of SC in agreement with previous histological and electrophysiological studies in rodents (McLaughlin et al., 2003, Plas et al., 2005, Siminoff et al., 1966, Simon and O'Leary, 1991). While the retinotopic pattern is preserved in the intraorbital optic nerve (Baker and Jeffery, 1989), it had been shown that partial transection of the superior intraorbital optic nerve led to primary injury predominantly

Acknowledgments

This work was supported by the Hong Kong Research Grant Council (GRF HKU 7793/08 M and GRF HKU 7808/09 M).

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