Faculty Bibliography

In rats, the superior colliculus (SC) is a main destination for retinal ganglion cells and is an important subcortical structure for vision. Electrophysiology studies have observed that many SC neurons are highly sensitive to moving objects, but complementary non-invasive functional imaging studies with larger fields of view have been rarely conducted. In this study, BOLD fMRI is used to measure the SC and nearby lateral geniculate nucleus' (LGN) hemodynamic responses, in normal adult Sprague Dawley (SD) rats, during a dynamic visual stimulus similar to those used in long-range apparent motion studies. The stimulation paradigm consists of four light spots arranged in a linear array and turned on and off sequentially at different rates to create five effective speeds of motion (7, 14, 41, 82, and 164 degrees /s across the visual field). Stationary periods (same light spot always on) are interleaved between the moving periods. The speed response function (SRF), the hemodynamic response amplitude at each speed tested, is measured. Significant responses are observed in the SC and LGN at all speeds. In the SC, the SRF increases monotonically from 7 to 82 degrees /s. The minimum response amplitude occurs at 164 degrees /s. The results suggest that the SC is sensitive to slow moving visual stimuli but the hemodynamic response is reduced at higher speeds. In the LGN, the SRF exhibits a similar trend to that of the SC, but response amplitude during 7 degrees /s stimulation is comparable to that during 164 degrees /s stimulation. These findings are in good agreement with previous electrophysiology studies conducted on albino rats like the SD strain. This work represents the first fMRI study of stimulus speed dependence in the SC and is also the first fMRI study of motion responsiveness in the rat.

UNLABELLED: To speed up the process of central nervous system (CNS) recovery after injury, the need for real-time measurement of axon regeneration in vivo is essential to assess the extent of injury, as well as the optimal timing and delivery of therapeutics and rehabilitation. It was necessary to develop a chronic animal model with an in vivo measurement technique to provide a real-time monitoring and feedback system. Using the framework of the 4 P's of CNS regeneration (Preserve, Permit, Promote and Plasticity) as a guide, combined with noninvasive manganese-enhanced magnetic resonance imaging (MEMRI), we show a successful chronic injury model to measure CNS regeneration, combined with an in vivo measurement system to provide real-time feedback during every stage of the regeneration process. We also show that a chronic optic tract (OT) lesion is able to heal, and axons are able to regenerate, when treated with a self-assembling nanofiber peptide scaffold (SAPNS). FROM THE CLINICAL EDITOR: The authors of this study demonstrate the development of a chronic injury model to measure CNS regeneration, combined with an in vivo measurement system to provide real-time feedback during every stage of the regeneration process. In addition, they determined that chronic optic tract lesions are able to heal with axonal regeneration when treated with a self-assembling nanofiber peptide scaffold (SAPNS).

BACKGROUND: The superior colliculus (SC) and lateral geniculate nucleus (LGN) are important subcortical structures for vision. Much of our understanding of vision was obtained using invasive and small field of view (FOV) techniques. In this study, we use non-invasive, large FOV blood oxygenation level-dependent (BOLD) fMRI to measure the SC and LGN's response temporal dynamics following short duration (1 s) visual stimulation. METHODOLOGY/PRINCIPAL FINDINGS: Experiments are performed at 7 tesla on Sprague Dawley rats stimulated in one eye with flashing light. Gradient-echo and spin-echo sequences are used to provide complementary information. An anatomical image is acquired from one rat after injection of monocrystalline iron oxide nanoparticles (MION), a blood vessel contrast agent. BOLD responses are concentrated in the contralateral SC and LGN. The SC BOLD signal measured with gradient-echo rises to 50% of maximum amplitude (PEAK) 0.2+/-0.2 s before the LGN signal (p<0.05). The LGN signal returns to 50% of PEAK 1.4+/-1.2 s before the SC signal (p<0.05). These results indicate the SC signal rises faster than the LGN signal but settles slower. Spin-echo results support these findings. The post-MION image shows the SC and LGN lie beneath large blood vessels. This subcortical vasculature is similar to that in the cortex, which also lies beneath large vessels. The LGN lies closer to the large vessels than much of the SC. CONCLUSIONS/SIGNIFICANCE: The differences in response timing between SC and LGN are very similar to those between deep and shallow cortical layers following electrical stimulation, which are related to depth-dependent blood vessel dilation rates. This combined with the similarities in vasculature between subcortex and cortex suggest the SC and LGN timing differences are also related to depth-dependent dilation rates. This study shows for the first time that BOLD responses in the rat SC and LGN following short duration visual stimulation are temporally different.

Exposure to early life stress results in behavioural changes, and these dysfunctions may persist throughout adulthood. In this study, we investigated whether hippocampus volume and neurochemical changes were involved in the appearance of these effects in the maternal separation (MS) animal model using the noninvasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Sprague-Dawley rats exposed to MS for 180 min from postnatal days (PND) 2-14 demonstrated decreased sucrose preference, increased immobility in the forced swimming test (FST), and impaired memory in the Morris water maze in adulthood. Environmental enrichment (EE) (PND 21-60) could ameliorate the effects of MS on sucrose preference and learning and memory but not on immobility in the FST. In addition, EE significantly increased N-acetylaspartate (NAA) of MS animals. However, we did not find an effect of MS or EE on hippocampal volume. These results indicate the involvement of hippocampal neurochemistry in the behavioural changes that result from early stressful life events and their modification by post-weaning EE. Thus changes in NAA, as a measure of neuronal integrity, appear to be a sensitive correlate of these behavioural effects.

Neonatal monocular enucleation (ME) is often employed to study the developmental mechanisms underlying visual perception and the cross-modal changes in the central nervous system caused by early loss of the visual input. However, underlying biochemical or metabolic mechanisms that accompany the morphological, physiological and behavioral changes after ME are not fully understood. Male Sprague-Dawley rats (N=14) were prepared and divided into 2 groups. The enucleated group (N=8) underwent right ME (right eye removal) at postnatal day 10, while the normal group (N=6) was intact and served as a control. Three weeks after ME, single voxel proton magnetic resonance spectroscopy ((1)H MRS) was performed over the visual cortex of each hemisphere in all animals with a point-resolved spectroscopy (PRESS) sequence at 7 T. The taurine (Tau) and N-acetylaspartate (NAA) levels were found to be significantly lower in the left visual cortex (contralateral to enucleated eye) for enucleated animals. Such metabolic changes measured in vivo likely reflected the cortical degeneration associated with the reduction of neurons, axon terminals and overall neuronal activity. This study also demonstrated that (1)H MRS approach has the potential to characterize neonatal ME and other developmental neuroplasticity models noninvasively for the biochemical and metabolic processes involved.

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 mum isotropic resolution for in vivo retinotopic mapping of the rat SC upon partial transection of the intraorbital optic nerve. One day after intravitreal Mn(2+) 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 Mn(2+) 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.

It is generally accepted that cognitive processes, such as learning and memory, are affected in depression. The present study used a rat model of depression, chronic unpredictable mild stress (CUMS), to determine whether hippocampal volume and neurochemical changes were involved in learning and memory alterations. A further aim was to determine whether these effects could be ameliorated by escitalopram treatment, as assessed with the non-invasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Our results demonstrated that CUMS had a dramatic influence on spatial cognitive performance in the Morris water maze task, and CUMS reduced the concentration of neuronal marker N-acetylaspartate (NAA) in the hippocampus. These effects could be significantly reversed by repeated administration of escitalopram. However, neither chronic stress nor escitalopram treatment influenced hippocampal volume. Of note, the learning and memory alterations of the rats were associated with right hippocampal NAA concentration. Our results indicate that in depression, NAA may be a more sensitive measure of cognitive function than hippocampal volume.

This study explored the feasibility of high-resolution Mn-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) for in vivo assessments of the development and reorganization of retinal and visual callosal pathways in normal neonatal rodent brains and after early postnatal visual impairments. Using MEMRI, intravitreal Mn(2+) injection into one eye resulted in maximal T1-weighted hyperintensity in neonatal contralateral superior colliculus (SC) 8 hours after administration, whereas in adult contralateral SC signal increase continued at 1 day post-injection. Notably, mild but significant Mn(2+) enhancement was observed in the ipsilateral SC in normal neonatal rats, and in adult rats after neonatal monocular enucleation (ME) but not in normal adult rats. Upon intracortical Mn(2+) injection to the visual cortex, neonatal binocularly-enucleated (BE) rats showed an enhancement of a larger projection area, via the splenium of corpus callosum to the V1/V2 transition zone of the contralateral hemisphere in comparison to normal rats. For DTI, the retinal pathways projected from the enucleated eyes possessed lower fractional anisotropy (FA) 6 weeks after BE and ME. Interestingly, in the optic nerve projected from the remaining eye in ME rats a significantly higher FA was observed compared to normal rats. The results of this study are potentially important for understanding the axonal transport, microstructural reorganization and functional activities in the living visual brain during early postnatal development and plasticity in a global and longitudinal setting.

Early life stress is a potential precursor of eventual neuropsychiatric diseases and may result in altered neurodevelopment and function of the hippocampus, which thus provides a site at which potential interventions to modify the effects of early life stress may act. In this study, Sprague-Dawley rat pups comprising male and female animals underwent maternal separation (MS) for 180 min from postnatal days (PND) 2 to 14, or were left with their dams. They subsequently received daily administration of saline (0.9%), escitalopram (10 mg/kg), or no treatment during adolescence (PND 43-60). All adult animals underwent brain magnetic resonance imaging (MRI) and bilateral hippocampal proton magnetic resonance spectroscopy ((1)H-MRS). Neither MS nor escitalopram treatment had a significant effect on hippocampal volume. Adult rats that experienced MS displayed significantly increased choline-containing compounds (Cho) and decreased N-acetylaspartate (NAA), glutamate (Glu) and Myo-inositol (MI) relative to the stable neurometabolite creatine (Cr) in hippocampus. Administration of escitalopram during adolescence could modify the alterations of NAA/Cr, Glu/Cr and MI/Cr. The effects of MS on hippocampal neurochemistry were most significant in the right hippocampus. These results indicate that MS in rats has long-term consequences on hippocampal neurochemistry reflective of neural density/functional integrity, especially on the right hippocampus, and adolescent administration with escitalopram can at least partially ameliorate these neurochemical alterations. Furthermore, these metabolite changes seem to be more sensitive indicators of the results from early life stress than volume changes.

The integrity of the neuronal connections between eye and brain plays an important role in the performance of the mammalian visual system. However, the developmental and pathophysiological mechanisms in the visual system are largely unexplored due to the lack of a sensitive technique for directly assessing both anterior and posterior visual pathways longitudinally under the same experimental conditions. This paper reviewed the recent use of magnetic resonance imaging and spectroscopic (MRI/MRS) methods (contrast-enhanced MRI, diffusion MRI, proton MRS and functional MRI) at high magnetic field strengths, for in vivo and global assessments of the structure, metabolism and function of the visual system in normal, developing and injured rodent brains. Using animal models of ocular diseases, optic neuropathies, developmental plasticity and neonatal hypoxic-ischemic brain injury, focus is put on the feasibility of MRI/MRS to evaluate axonal transport and cellular activity along segregated fibers of the visual pathways, to characterize lesion-induced neurodegeneration in the retina and the optic nerve and tract, to detect steady-state metabolite changes in the posterior visual nuclei, and blood-ocular dynamic exchanges in the eye, and to understand the neurovascular coupling and functions in the retina and the visual brain nuclei. These studies suggested the significant values of high-field multiparametric MRI/MRS for providing early diagnoses and comprehensive therapeutic strategies for promoting functional recovery upon partial vision loss.