Effects of caffeine or RX821002 in rats with a neonatal ventral hippocampal lesion.

Rats with a neonatal ventral hippocampal lesion (NVHL) are used to model schizophrenia. They show enhanced locomotion and difficulties in learning after puberty. Such behavioral modifications are strengthened by dopaminergic psychostimulant drugs, which is also relevant for schizophrenia because illustrating its dopaminergic facet. But it remains questionable that only dopaminergic drugs elicit such effects. The behavioral effects could simply represent a non specific arousal, in which case NVHL rats should also be hyper-responsive to other vigilance enhancing drugs. We administered an adenosine (caffeine) or an adrenaline receptor antagonist, (RX821002) at doses documented to modify alertness of rats, respectively 5 mg/kg and 1 mg/kg. Rats were selected prior to the experiments using magnetic resonance imaging (MRI). Each group contained typical and similar NVHL lesions. They were compared to sham lesioned rats. We evaluated locomotion in a new environment and the capacity to remember a visual or acoustic cue that announced the occurrence of food. Both caffeine and RX82100 enhanced locomotion in the novel environment, particularly in NVHL rats. But, RX82100 had a biphasic effect on locomotion, consisting of an initial reduction preceding the enhancement. It was independent of the lesion. Caffeine did not modify the learning performance of NVHL rats. But, RX821002 was found to facilitate learning. Patients tend to intake much more caffeine than healthy people, which has been interpreted as a means to counter some cognitive deficits. This idea was not validated with the present results. But adrenergic drugs could be helpful for attenuating some of their cognitive deficits.

Neonatal ventral hippocampal lesions modify pain perception and evoked potentials in rats.

This work concerns the debate surrounding the modified pain reactivity of patients with schizophrenia and other possible perceptive distortions. Rats with a neonatal ventral hippocampal lesion (NVHL) were used to model the neuro-developmental aspect of schizophrenia, and their reactivity to various stimuli was evaluated. The results could also help understand sensory deficits in other neuro-developmental disorders. Behavioural reactions to graduated painful thermal and mechanical stimuli were observed, and evoked potential responsiveness to tactile, visual and acoustic non-painful stimuli was recorded and compared to non-operated and sham lesioned controls. A higher threshold was observed with painful mechanical stimuli and shorter paw withdrawal latency with thermal stimuli. This was particularly relevant as there was no change in the evoked potentials triggered by non-nociceptive tactile stimulation of the same part of the body. There was a 10 dB(A) increase in the auditory threshold and a suppression of auditory sensory motor gating. Visually evoked potentials did not appear to be affected. Taken together, the results showed that NVHL-evoked alteration of brain development induces mechanical hypoalgesia, thermal hyperalgesia and auditory sensory changes. The data also contribute towards elucidating mechanisms underlying sensory deficits in neurodevelopmental diseases, including schizophrenia.

Prefrontal dopamine release and sensory-specific satiety altered in rats with neonatal ventral hippocampal lesions.

Rats with a neonatal ventral hippocampal lesion (NVHL) have been used to model certain features of schizophrenia because they display dopaminergic activity and behavioral alterations consistent with a dysfunctional prefrontal cortex after puberty. Microdialysis studies in normal rats demonstrated increased prefrontal dopamine release during the incentive phase of behavior in an experimental situation specifically designed to evidence this behavioral aspect: the so called "sensory-specific satiety" procedure. Our hypothesis is that if dopaminergic activity in the prefrontal cortex of NVHL rats differs from sham lesioned rats, the responsiveness to the aforementioned experimental situation should also be different. Extracellular medial prefrontal dopamine outflow increased in hungry control rats when they had access to food and decreased across satiety. It increased again when a new food was presented, even when the rats were satiated. NVHL rats also had increased dopamine prefrontal outflow in these conditions, but it remained high after the end of the consumption period. The food consumption behavior declined less rapidly and the reinstatement of food consumption, usually produced by new food, did not occur in NVHL rats, provided the lesions were large. These data were discussed in relation to several theoretical backgrounds developed about the incentive aspect of behavior and for understanding the pathophysiology of schizophrenia.

The HDAC Inhibitor Phenylbutyrate Reverses Effects of Neonatal Ventral Hippocampal Lesion in Rats.

Recent evidence suggests that epigenetic mechanisms play a role in psychiatric diseases. In this study, we considered rats with neonatal ventral hippocampal lesions (NVHL) that are currently used for modeling neurodevelopmental aspects of schizophrenia. Contribution of epigenetic regulation to the effects of the lesion was investigated, using a histone deacetylase (HDAC) inhibitor. Lesioned or sham-operated rats were treated with the general HDAC inhibitor phenylbutyrate, which was injected daily from the day after surgery until adulthood. Changes in the volume of the lesion were monitored by magnetic resonance imaging (MRI). Anxiety was analyzed in the Plus Maze Test. Hypersensitivity of the dopaminergic system was evaluated by measuring the locomotor response to apomorphine. An associative conditioning test rewarded with food was used to evaluate learning abilities. The volume of the lesions expanded long after surgery, independently of the treatment, as assessed by MRI. Removal of the ventral hippocampus reduced anxiety, and this remained unchanged when animals were treated with phenylbutyrate. In contrast, NVHL rats' hypersensitivity to apomorphine and deterioration of the associative learning were reduced by the treatment. Global HDAC activity, which was increased in the prefrontal cortex of lesioned non-treated rats, was found to be reversed by HDAC inhibition. The study provides evidence that chromatin remodeling may be useful for limiting behavioral consequences due to lesioning of the ventral hippocampus at an early age. This represents a novel approach for treating disorders resulting from insults occurring during brain development.

MRI and X-ray scanning images of the brain of 3-, 6- and 9-month-old rats with bilateral neonatal ventral hippocampus lesions.

Rats with bilateral neonatal ventral hippocampus lesions (NVHL) are commonly used for modeling developmental aspects of the pathophysiology of schizophrenia. Given that functional changes become significant only after puberty, NVHL as well as sham-operated rats were analyzed at the ages of 21, 42 and 63days (i.e. as pups, adolescents and adults), using MRI to examine the damage caused by surgery over time. Morphometric evaluations were considered and lesions were classified as small, medium and large. The volume of lesions increased regularly with age, to a greater extent than increases in overall brain size. This was relatively linear, corresponding to a gradually shrinking forebrain, and these observations held true for each class of lesions considered. Following the observation that the lesion procedure elicited calcifications in the brain, the same rats were subjected to 3D X-ray scanning the day after each MRI session, allowing precise measurements of skull size to be carried out. The NVHL rats had smaller skulls; however, the dimensions of the calcifications did not grow more than the skull size over time. The mechanisms underlying the progressive anatomical changes following surgery are discussed, and we propose this in vivo follow-up method to investigate therapeutic strategies aimed at countering or limiting the post-lesion consequences of a neonatal brain damage.

Recovery from chronic demyelination by thyroid hormone therapy: myelinogenesis induction and assessment by diffusion tensor magnetic resonance imaging.

The failure of the remyelination processes in multiple sclerosis contributes to the formation of chronic demyelinated plaques that lead to severe neurological deficits. Long-term cuprizone treatment of C57BL/6 mice resulted in pronounced white matter pathology characterized by oligodendrocyte depletion, irreversible demyelination and persistent functional deficits after cuprizone withdrawal. The use of a combination of in vivo diffusion tensor magnetic resonance imaging (DT-MRI) and histological analyses allowed for an accurate longitudinal assessment of demyelination. Injection of triiodothyronine (T(3)) hormone over a 3 week interval after cuprizone withdrawal progressively restored the normal DT-MRI phenotype accompanied by an improvement of clinical signs and remyelination. The effects of T(3) were not restricted to the later stages of remyelination but increased the expression of sonic hedgehog and the numbers of Olig2(+) and PSA-NCAM(+) precursors and proliferative cells. Our findings establish a role for T(3) as an inducer of oligodendrocyte progenitor cells in adult mouse brain following chronic demyelination.

Astrocytic hypertrophy in dysmyelination influences the diffusion anisotropy of white matter.

The effect of a proteolipid protein (PLP) mutation on the developing white matter anisotropy was examined by diffusion tensor magnetic resonance imaging (DT-MRI) in a noninvasive study of a mouse model of Pelizaeus-Merzbacher disease (PMD). The jimpy PLP mutation in mice produces an irreversible dysmyelination in jimpy males, whereas heterozygous females exhibit a transient hypomyelination, as assessed by a longitudinal study of the same mice during development. Modifications of the different individual DT-MRI parameters were highlighted by specific changes in tissue structures caused by the mutation that includes the hypomyelination, axonal abnormalities, and recovery. Astrocytic hypertrophy is a striking cellular event in dysmyelinated jimpy brain, where most axons or bundles of fibers are entirely wrapped by astrocyte cytoplasmic processes, so its influences on DT-MRI parameters in dysmyelination were examined for the first time. DT-MRI data of the jimpy brain were compared with those obtained from dysmyelination of (oligo-TTK) transgenic mice, induced by oligodendrocyte killing, which have a mild astrocyte hypertrophy (Jalabi et al., 2005), and from recovering jimpy females, which have reduced astrocyte hypertrophy. The unique morphological feature of astrocytes in jimpy males coupled with an increase in the water channel protein aquaporin 4 (AQP4) was found to facilitate the directional water diffusion in the white matter. In addition to the major changes of DT-MRI parameters in the two dysmyelinated mice caused by the myelin loss and axonal modifications, the amplified magnitude of radial and axial diffusions in jimpy males was attributed principally to the strongly pronounced astrocyte hypertrophy.

Texture analysis of brain MRI evidences the amygdala activation by nociceptive stimuli under deep anesthesia in the propofol-formalin rat model.

Magnetic resonance images of rat brain were analyzed by texture analysis in order to study the effects of a nociceptive stimulation (formalin test) under propofol deep anesthesia. Changes of the texture in different cerebral brain areas acquired before and after stimulation were checked. Our statistical analysis of texture shows that these changes were present only in the amygdala, in agreement with the facts already known about the unconscious memorization of nociceptive stimuli.

Brain dysmyelination and recovery assessment by noninvasive in vivo diffusion tensor magnetic resonance imaging.

Diffusion tensor magnetic resonance imaging (DT-MRI) was applied for in vivo quantification of myelin loss and regeneration. A transgenic mouse line (Oligo-TTK) expressing a truncated form of the herpes simplex virus 1 thymidine kinase gene (hsv1-tk) in oligodendrocytes was studied along with two induced phenotypes of myelin pathology. Myelin loss and axonal abnormalities differentially affect values of DT-MRI parameters in the brain of transgenic mice. Changes in the anisotropy of the white matter were assessed by calculating and mapping the radial (D perpendicular) and axial (D parallel) water diffusion to axonal tracts and fractional anisotropy (FA). A significant increase in D perpendicular attributed to the lack of myelin was observed in all selected brain white matter tracts in dysmyelinated mice. Lower D parallel values were consistent with the histological observation of axonal modifications, including reduced axonal caliber and overexpression of neurofilaments and III beta-tubulin. We show clearly that myelination and axonal changes play a role in the degree of diffusion anisotropy, because FA was significantly decreased in dysmyelinated brain. Importantly, myelin reparation during brain postnatal development induced a decrease in the magnitude of D( perpendicular) and an increase in FA compared with the same brain before recovery. The progressive increase in D parallel values was attributed to the gain in normal axonal morphology. This regeneration was confirmed by the detection of enlarged oligodendrocyte population, newly formed myelin sheaths around additional axons, and a gradual increase in axonal caliber.

Remyelination assessment by MRI texture analysis in a cuprizone mouse model.

The purpose of this study was to perform serial texture analysis of brain MRI of cuprizone-treated mice for the assessment of regional demyelination and remyelination. Cuprizone-fed mice undergo a brain demyelination process. This process was followed over 56 days by MRI in the olfactory bulbs, cerebellum, putamen and brain stem. The texture of T2-weighted images has been analyzed at two levels: (1) with the average intensity as first order parameter and (2) with several higher order parameters for the best differentiation between myelinated (controls) and demyelinated brains. The most pertinent of these parameters, called horizontal gray level nonuniformity (HGLNU), has been selected by stepwise discriminant analysis. The time evolution of the average value of HGLNU not only confirmed the overall demyelination tendency followed by the average intensity, but also more precisely characterized a transitory remyelination on day 41 in the olfactory bulbs and cerebellum, in agreement with already published immunohistochemical destructive studies.