Halima Chahboune

Consequences of Intraventricular Hemorrhage in a Rabbit Pup Model

Background and Purpose— Intraventricular hemorrhage (IVH) is a common complication of prematurity that results in neurological sequelae, including cerebral palsy, posthemorrhagic hydrocephalus, and cognitive deficits. Despite this, there is no standardized animal model exhibiting neurological consequences of IVH in prematurely delivered animals. We asked whether induction of moderate-to-severe IVH in premature rabbit pups would produce long-term sequelae of cerebral palsy, posthemorrhagic hydrocephalus, reduced myelination, and gliosis. Methods— The premature rabbit pups, delivered by cesarean section, were treated with intraperitoneal glycerol at 2 hours postnatal age to induce IVH. The development of IVH was diagnosed by head ultrasound at 24 hours of age. Neurobehavioral, histological, and ultrastructural evaluation and diffusion tensor imaging studies were performed at 2 weeks of age. Results— Although 25% of pups with IVH (IVH pups) developed motor impairment with hypertonia and 42% developed posthemorrhagic ventriculomegaly, pups without IVH (non-IVH) were unremarkable. Immunolabeling revealed reduced myelination in the white matter of IVH pups compared with saline- and glycerol-treated non-IVH controls. Reduced myelination was confirmed by Western blot analysis. There was evidence of gliosis in IVH pups. Ultrastructural studies in IVH pups showed that myelinated and unmyelinated fibers were relatively preserved except for focal axonal injury. Diffusion tensor imaging showed reduction in fractional anisotropy and white matter volume confirming white matter injury in IVH pups. Conclusion— The rabbit pups with IVH displayed posthemorrhagic ventriculomegaly, gliosis, reduced myelination, and motor deficits, like humans. The study highlights an instructive animal model of the neurological consequences of IVH, which can be used to evaluate strategies in the prevention and treatment of posthemorrhagic complications.

DTI abnormalities in anterior corpus callosum of rats with spike-wave epilepsy.

OBJECTIVE Absence epilepsy is a common seizure disorder in children which can produce chronic psychosocial sequelae. Human patients and rat absence models show bilateral spike-wave discharges (SWD) in cortical regions. We employed diffusion tensor imaging (DTI) in rat absence models to detect abnormalities in white matter pathways connecting regions of seizure activity. METHODS We studied Wistar albino Glaxo rats of Rijswijk (WAG/Rij), genetic absence epilepsy rats of Strasbourg (GAERS), and corresponding nonepileptic control strains. Ex vivo DTI was performed at 9.4 T with diffusion gradients applied in 16 orientations. We compared fractional anisotropy (FA), perpendicular (lambda(perpendicular)) and parallel (lambda(||)) diffusivity between groups using t-maps and region of interest (ROI) measurements. RESULTS Adult epileptic WAG/Rij rats exhibited a localized decrease in FA in the anterior corpus callosum. This area was confirmed by tractography to interconnect somatosensory cortex regions most intensely involved in seizures. This FA decrease was not present in young WAG/Rij rats before onset of SWD. GAERS, which have more severe SWD than WAG/Rij, exhibited even more pronounced callosal FA decreases. Reduced FA in the epileptic animals originated from an increased lambda(perpendicular) with no significant changes in lambda(||). INTERPRETATION Reduced FA with increased lambda(perpendicular) suggests that chronic seizures cause reduction in myelin or decreased axon fiber density in white matter pathways connecting regions of seizure activity. These DTI abnormalities may improve the understanding of chronic neurological difficulties in children suffering with absence epilepsy, and may also serve as a noninvasive biomarker for monitoring beneficial effects of treatment.

Hypoxic Injury during Neonatal Development in Murine Brain: Correlation between In Vivo DTI Findings and Behavioral Assessment

Preterm birth results in significant neurodevelopmental disability. A neonatal rodent model of chronic sublethal hypoxia (CSH), which mimics effects of preterm birth, was used to characterize neurodevelopmental consequences of prolonged exposure to hypoxia using tissue anisotropy measurements from diffusion tensor imaging. Corpus callosum, cingulum, and fimbria of the hippocampus revealed subtle, yet significant, hypoxia-induced modifications during maturation (P15-P51). Anisotropy differences between control and CSH mice were greatest at older ages (>P40) in these regions. Neither somatosensory cortex nor caudate putamen revealed significant differences between control and CSH mice at any age. We assessed control and CSH mice using tests of general activity and cognition for behavioral correlates of morphological changes. Open-field task revealed greater locomotor activity in CSH mice early in maturation (P16-P18), whereas by adolescence (P40-P45) differences between control and CSH mice were insignificant. These results may be associated with lack of cortical and subcortical anisotropy differences between control and CSH mice. Spatial-delayed alternation and free-swim tasks in adulthood revealed lasting impairments for CSH mice in spatial memory and behavioral laterality. These differences may correlate with anisotropy decreases in hippocampal and callosal connectivities of CSH mice. Thus, CSH mice revealed developmental and behavioral deficits that are similar to those observed in low birth weight preterm infants.

Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD

BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD), a major cause of end-stage renal failure, results from genetic mutation of either polycystin-1 (Pkd1) or polycystin-2 (Pkd2). In order to develop novel therapies to treat the advancement of disease progression, numerous rodent models of different genetic backgrounds are available to study cyst development. METHODS Here, a Pkd1-floxed inducible mouse model using the interferon responsive Mx1Cre-recombinase was utilized to test the effect of the small molecule triptolide. Relative to other Pkd1 inactivation models, cyst progression in this neonatal to adult transition model is attenuated. Following the characterization of inducible cyst formation in these mice, the development of kidney cysts from triptolide or vehicle-treated animals was analysed. RESULTS Although Pkd1 deletion on postnatal Days P10 and P12 resulted in numerous cysts by P35, daily injections with triptolide beginning on Day P16 significantly reduced the total number of cysts per kidney, with a pronounced effect on the number of microcysts and the overall cystic burden. Additionally, renal function as assessed by blood urea nitrogen levels was also improved in triptolide-treated mice at both the P22 and P35 time points. As the Pkd1(flox/flox);Mx1Cre model has not been previously used for drug development studies, the feasibility of a 6-month adult Pkd1 inactivation study was also tested. While kidney cyst formation was minimal and focal in nature, livers of these Pkd1-deficient mice were severely cystic, enlarged and pale. CONCLUSIONS These results suggest that the Pkd1(flox/flox);Mx1Cre model of ADPKD is amenable to short-term kidney cyst formation drug studies; however, it may be problematic for long-term therapeutic research where widespread liver cysts and fibrosis could compromise drug metabolism.

Micro-spectrometer for NMR: analysis of small quantities in vitro

This paper reports the design, fabrication and preliminary tests of planar microcoils associated with a micromachined channel in silicon. These microcoils are used as nuclear magnetic resonance (NMR) radio frequency detection coils. They allow in vitro NMR analysis of small quantities introduced into the microchannel. It is a real challenging task to develop microsystems for NMR spectrum extraction for smaller and smaller sample volumes. Moreover, it is advantageous that these microsystems could be integrated in a micro total analysing system (µ-TAS) as an analysing stage. In this paper the description, fabrication process and electrical characterization of planar microcoil receivers are described. Results obtained on NMR microspectroscopy experiments have been performed in water and ethanol, using a 500 µm × 500 µm planar microcoil tuned and matched at 85.13 MHz (proton frequency at 2 T).

Induced Clustered Nanoconfinement of Superparamagnetic Iron Oxide in Biodegradable Nanoparticles Enhances Transverse Relaxivity for Targeted Theranostics

Combined therapeutic and diagnostic agents, “theranostics” are emerging valuable tools for noninvasive imaging and drug delivery. Here, we report on a solid biodegradable multifunctional nanoparticle that combines both features.

Denoising EMG and EEG for monitoring small animal models during NMR experiments

The present growing field of molecular imaging, including multimodality microimaging techniques and spectroscopic approaches, is mainly based on small animal studies. Monitoring such models requires an efficient treatment and use of electrophysiological signals which may be spoiled by environmental effects especially when working with nuclear magnetic resonance (NMR) since radiofrequency (RF) pulses and magnetic field gradient commutations may create spurious supplementary signals. In this work, a method is given for EEG and EMG denoising of signals acquired during phosphorous magnetic resonance (MR) brain spectroscopy data acquisition on a rat model developed for sleep/awake studies. The proposed approach is based on wavelet decomposition and the key method is to turn into profit the shape variations of EMG during the time course of sleep/awake cycles. Statistical properties of the noise are studied using EMG recorded during paradoxical sleep as noise model. A specific estimation of noise level using EMG recorded during slow sleep leads to an optimal wavelet coefficients thresholding. This approach is well suited to improve signal to noise ratio of EEG and EMG and to preserve small amplitude electro physiological signals.

Effects of chloramphenicol on brain energy metabolism using 31P spectroscopy: influences on sleep‐wake states in rat

Effects of chloramphenicol (antibiotic inhibiting complex‐1 of respiratory chain) and thioamphenicol (TAP, a structural analog of CAP inactive on complex‐1) were examined on cerebral energy metabolites and sleep‐wake cycle architecture in rat. In the first group, animals were chronically equipped with a cranial surface resonator and 31P spectroscopic measurements were performed using a 2 T magnetic resonance spectrometer (operating frequency 34.46 MHz). CAP administration (400 mg/kg, tail vein, light period) induced deficits in phosphocreatine (−30%, p < 0.01) and ATP (−40%, p < 0.01), whereas TAP (400 mg/kg) had no effect. In the second group, animals were chronically implanted with polygraphic electrodes for EEG and electromyogram recordings. CAP administered intraperitoneally at light‐onset reduced rapid‐eye movement (REM) sleep (−60% in the first 6 h of light period, p < 0.01), increased waking state (+65% in the first 6 h of light period, p < 0.01), and slightly affected slow‐wave sleep (SWS). During waking state, θ and σ power bands of the EEG were, respectively, increased and decreased (p < 0.05). During SWS, delta power band was reinforced (p < 0.05), while θ, α, and σ bands were decreased (p < 0.05). No changes occurred during REM sleep. TAP had no effect on sleep‐wake states and spectral components of the EEG. Overall, these data indicate that REM sleep occurrence is linked to an aerobic production of ATP.