Progressive MRI brain volume changes in ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited lysosomal storage disorders characterized by progressive neurodegeneration leading to motor and cognitive dysfunction, seizure activity and blindness. The disease can be caused by mutations in 1 of 13 ceroid lipofuscinosis neuronal (CLN) genes. Naturally occurring sheep models of the CLN5 and CLN6 neuronal ceroid lipofuscinoses recapitulate the clinical disease progression and post-mortem pathology of the human disease. We used longitudinal MRI to assess global and regional brain volume changes in CLN5 and CLN6 affected sheep compared to age-matched controls over 18 months. In both models, grey matter volume progressively decreased over time, while cerebrospinal fluid volume increased in affected sheep compared with controls. Total grey matter volume showed a strong positive correlation with clinical scores, while cerebrospinal fluid volume was negatively correlated with clinical scores. Cortical regions in affected animals showed significant atrophy at baseline (5 months of age) and progressively declined over the disease course. Subcortical regions were relatively spared with the exception of the caudate nucleus in CLN5 affected animals that degenerated rapidly at end-stage disease. Our results, which indicate selective vulnerability and provide a timeline of degeneration of specific brain regions in two sheep models of neuronal ceroid lipofuscinoses, will provide a clinically relevant benchmark for assessing therapeutic efficacy in subsequent trials of gene therapy for CLN5 and CLN6 disease.

Blood oxygen level dependent fMRI and perfusion MRI in the sheep brain.

The ovine model could be an effective translational model but remains underexplored. Here, Blood Oxygen Level dependent functional MRI during visual stimulation and resting-state perfusion MRI were explored. We aimed at investigating the impact of isoflurane anesthesia during visual stimulation and evaluate resting cerebral blood flow and cerebral blood volume parameters in the lamb and adult sheep brain. BOLD fMRI and perfusion MRI after a bolus of DOTAREM were conducted in 4 lambs and 6 adult ewes at 3 T. A visual stimulation paradigm was delivered during fMRI at increasing isoflurane doses (1-3%). Robust but weak BOLD responses (0.21 ± 0.08%) were found in the lateral geniculate nucleus (LGN) up to 3% isoflurane anaesthesia. No significant differences were found beween BOLD responses in the range 1 to 3% ISO (p > 0.05). However, LGN cluster size decreased and functional localization became less reliable at high ISO doses (2.5-3% ISO). BOLD responses were weaker in adult sheep than in lambs (4.6 ± 1.5 versus 13.6 ± 8.5; p = 0.08). Relative cerebral blood volumes (rCBV) and relative cerebral blood flows (rCBF) were significantly higher (p < 0.0001) in lambs than in adult sheep for both gray and white matter. The impact of volatile anesthesia was explored for the first time on BOLD responses demonstrating increased reliability of functional localization of brain activity at low doses. Perfusion MRI was conducted for the first time in both lambs and adult ewes. Assessment of baseline cerebrovascular values are of interest for future studies of brain diseases allowing an improved interpretation of BOLD responses.

Brain orchestration of pregnancy and maternal behavior in mice: A longitudinal morphometric study.

Reproduction induces changes within the brain to prepare for gestation and motherhood. However, the dynamic of these central changes and their relationships with the development of maternal behavior remain poorly understood. Here, we describe a longitudinal morphometric neuroimaging study in female mice between pre-gestation and weaning, using new magnetic resonance imaging (MRI) resources comprising a high-resolution brain template, its associated tissue priors (60-µm isotropic resolution) and a corresponding mouse brain atlas (1320 regions of interest). Using these tools, we observed transient hypertrophies not only within key regions controlling gestation and maternal behavior (medial preoptic area, bed nucleus of the stria terminalis), but also in the amygdala, caudate nucleus and hippocampus. Additionally, unlike females exhibiting lower levels of maternal care, highly maternal females developed transient hypertrophies in somatosensory, entorhinal and retrosplenial cortices among other regions. Therefore, coordinated and transient brain modifications associated with maternal performance occurred during gestation and lactation.

In vivo magnetic resonance imaging reveals the effect of gonadal hormones on morphological and functional brain sexual dimorphisms in adult sheep.

Sex differences in the brain and behavior are produced by the perinatal action of testosterone, which is converted into estradiol by the enzyme aromatase in the brain. Although magnetic resonance imaging (MRI) has been widely used in humans to study these differences, the use of animal models, where hormonal status can be properly manipulated, is necessary to explore the mechanisms involved. We used sheep, a recognized model in the field of neuroendocrinology, to assess brain morphological and functional sex differences and their regulation by adult gonadal hormones. To this end, we performed voxel-based morphometry and a resting-state functional MRI approach to assess sex differences in gonadally intact animals. We demonstrated significant sex differences in gray matter concentration (GMC) at the level of the gonadotropic axis, i.e., not only within the hypothalamus and pituitary but also within the hippocampus and the amygdala of intact animals. We then performed the same analysis one month after gonadectomy and found that some of these differences were reduced, especially in the hypothalamus and amygdala. By contrast, we found few differences in the organization of the functional connectome between males and females either before or after gonadectomy. As a whole, our study identifies brain regions that are sexually dimorphic in the sheep brain at the resolution of the MRI and highlights the role of gonadal hormones in the maintenance of these differences.

Artifact Induced by a Transponder During In Vivo Magnetic Resonance Imaging on Horse Brain.

Magnetic resonance imaging (MRI) is now widely used in equine veterinary practice. However, the mandatory European legislation regarding horse identification imposes the implantation of a transponder within the fatty tissue of the neck cervical ligament. While performing brain MRI for scientific purposes in ponies, we faced artifacts produced by such transponder and reported here this problem. Indeed, pony mares were anesthetized for 2 hours and placed, bedded on their back, in a 3T MRI scanner. A four-element flexible antenna positioned around the head was used. Three MRI sequences were performed on each animal: three-dimensional T1, three-dimensional T2, and two-dimensional T1. The anesthesia allowed the acquisition of MRI for 2 hours. The images for the three MRI sequences for each pony exhibited great quality on all the anterior parts of the brain but began to become distorted posteriorly to the pineal pituitary axis and completely disappeared at the level of the cerebellum. To find the origin of the artifact, the transponder used for the identification of the animal was inserted in an inert gel and imaged in the same conditions as the ponies. The images obtained looked similar to the observed artifact. Our study thus advocates for the further exploration of such kind of artifact when using 3T MRI in brain imaging in horses.

Computation of a high-resolution MRI 3D stereotaxic atlas of the sheep brain.

The sheep model was first used in the fields of animal reproduction and veterinary sciences and then was utilized in fundamental and preclinical studies. For more than a decade, magnetic resonance (MR) studies performed on this model have been increasingly reported, especially in the field of neuroscience. To contribute to MR translational neuroscience research, a brain template and an atlas are necessary. We have recently generated the first complete T1-weighted (T1W) and T2W MR population average images (or templates) of in vivo sheep brains. In this study, we 1) defined a 3D stereotaxic coordinate system for previously established in vivo population average templates; 2) used deformation fields obtained during optimized nonlinear registrations to compute nonlinear tissues or prior probability maps (nlTPMs) of cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM) tissues; 3) delineated 25 external and 28 internal sheep brain structures by segmenting both templates and nlTPMs; and 4) annotated and labeled these structures using an existing histological atlas. We built a quality high-resolution 3D atlas of average in vivo sheep brains linked to a reference stereotaxic space. The atlas and nlTPMs, associated with previously computed T1W and T2W in vivo sheep brain templates and nlTPMs, provide a complete set of imaging space that are able to be imported into other imaging software programs and could be used as standardized tools for neuroimaging studies or other neuroscience methods, such as image registration, image segmentation, identification of brain structures, implementation of recording devices, or neuronavigation. J. Comp. Neurol. 525:676-692, 2017. © 2016 Wiley Periodicals, Inc.

Construction of an MRI 3D high resolution sheep brain template.

Sheep is a developing animal model used in the field of neurosciences for the study of many behavioral, physiological or pathophysiological mechanisms, including for example, the central control of social behavior, brain injury or neurodegenerative diseases. However, sheep remains an orphan species in the field of magnetic resonance imaging (MRI). Therefore, a mean image (template), resulting of registrations of multiple subject images is needed and currently does not exist. In this study, we: i) computed multimodal high resolution 3D in-vivo sheep brain templates of T1 weighted (T1W) and T2W images, ii) computed gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) prior probability maps using linear and optimized non-linear registrations iii) used prior probability maps to perform the segmentation of a single brain tissues. Computed multimodal sheep brain templates showed to preserve and underline all brain patterns of a single T1W or T2W image, and prior probability maps allowed to improve the segmentation of brain tissues. Finally, we demonstrated that these templates and prior probability maps were able to be portable in other publicly available imaging software and could be used as standardized spaces for multi-institution neuroimaging studies or other neuroscience methods.

Kisspeptin: a new neuronal target of primer pheromones in the control of reproductive function in mammals.

Pheromones are known to trigger either short-term behavioral responses, usually referred to as "releaser effects", or more long-term physiological changes, known as "primer effects", which especially affect reproductive function at the level of the gonadotrope axis. The precise mechanisms through which pheromones interact with the gonadotrope axis in the hypothalamus is not fully known. We propose that the neuropeptide Kisspeptin, could be a specific target of primer pheromones, allowing these pheromones to modulate the gonadotrope axis and GnRH activity. This emerging hypothesis is discussed in the context of puberty acceleration in female mice and the male effect in female ungulates (sheep or goat). These examples have been chosen to illustrate the diversity of the reproductive contexts in mammals and potential mechanisms affected by primer effects at the level of the gonadotrope axis.

Fast functional brain imaging using constrained reconstruction based on regularization using arbitrary projections.

This work describes a novel method for highly undersampled projection imaging using constrained reconstruction by Tikhonov-Phillips regularization and its application for high temporal resolution functional MRI (fMRI) at a repetition time of 80 ms. The high-resolution reference image used as in vivo coil sensitivity is acquired in a separate acquisition using otherwise identical parameters. Activation studies using a standard checkerboard activation paradigm demonstrate the inherent high sensitivity afforded by the possibility to separate activation-related effects from "physiological noise.". In this first proof-of-principle of the constrained reconstruction based on regularization using arbitrary projections (COBRA) technique, experiments are performed in a single-slice mode, which allows for a comparison with fast single-slice echo-planar imaging (EPI) at equal temporal resolution. The COBRA method can be extended to three-dimensional (3D) encoding without severe penalty in temporal performance. Analysis of the global signal change demonstrates the excellent reproducibility of COBRA compared to standard EPI. Activation analysis is considerably improved by the possibility to remove electrocardiogram (ECG)-related and breathing-related signal fluctuations by physiological correction of each individual breathing and ECG cycle, respectively.