[Transfer of autologous fat and plasma : The future of anti-aging medicine?]. / Autologer Fett- und Bluttransfer : Die Zukunft der Anti-aging-Medizin?

BACKGROUND: Aging is a complex process driven by endogenous and exogenous stimuli. The distinct cellular and noncellular components of skin and adjacent connective tissue are constantly and irreversibly degraded during aging. OBJECTIVES: The aim was to provide an overview of the biology of skin aging and the therapeutic options for rejuvenation. METHODS: A review of the current literature and a demonstration of autologous fat transfer and platelet-rich plasma (PRP) are presented from a clinical perspective. RESULTS: The aging process affects cellular components and the extracellular matrix (ECM); thus, the first stage is the degradation of the ECM. The loss of skin elasticity is induced by a breakdown of fibers such as collagen, elastin, or reticulin, whereas the degradation of proteoglycans results in decreased turgor and skin hydration. Synthetic filling agents primarily compensate for volume loss, but do not rejuvenate biologically. In contrast, the transfer of autologous fat and PRP is based on activating stem cell populations and growth factors, in addition to providing volume to target regions. CONCLUSIONS: A profound comprehension of the cellular and molecular mechanisms of aging is important in anti-aging medicine. The transfer of autologous fat and PRP offers interesting alternatives in the sense of more biological skin rejuvenation.

Differential role of visuospatial working memory in the propensity toward uncertainty in patients with obsessive-compulsive disorder and in healthy subjects.

BACKGROUND: Obsessive-compulsive disorder (OCD) is associated with visuospatial working memory deficits. Intolerance of uncertainty is thought to be a core component of OCD symptoms. Recent findings argue for a possible relationship between abilities in visuospatial memory and uncertainty. However, this relationship remains unclear in both OCD patients and healthy subjects. To address this issue, we measured performance in visuospatial working memory and the propensity to express uncertainty during decision making. We assessed their relationship and the temporal direction of this relationship in both OCD patients and healthy subjects. METHOD: Baseline abilities in visuospatial working memory were measured with the Corsi block-tapping test. A delayed matching-to-sample task was used to identify explicit situations of certainty, uncertainty and ignorance and to assess continuous performance in visuospatial working memory. Behavioural variables were recorded over 360 consecutive trials in both groups. RESULTS: Baseline scores of visuospatial working memory did not predict the number of uncertain situations in OCD patients whereas they did in healthy subjects. Uncertain trials led to reduced abilities in visuospatial working memory to 65% of usual performance in OCD patients whereas they remained stable in healthy subjects. CONCLUSIONS: The present findings show an opposite temporal direction in the relationship between abilities in working memory and uncertainty in OCD patients and healthy subjects. Poor working memory performance contributes to the propensity to feel uncertainty in healthy subjects whereas uncertainty contributes to decreased continuous performance in working memory in OCD patients.

Evolution of brain gray matter loss in Huntington's disease: a meta-analysis.

BACKGROUND: Huntington's disease is characterized by neuronal loss throughout the disease course. Voxel-based morphometry studies have reported reductions in gray matter concentration (GMC) in many brain regions in patients with Huntington. The description of the time course of gray matter loss may help to identify some evolution markers. Here, we conducted a meta-analysis of voxel-based morphometry studies of Huntington's disease to describe the evolution of brain gray matter loss. METHODS: A systematic search led to the inclusion of 11 articles on Huntington's disease (297 patients and 205 controls). We extracted data from patients with preclinical Huntington, patients with clinical Huntington, and controls. Finally, anatomical likelihood estimation analyses were conducted to identify GMC changes between preclinical patients and controls, between clinical patients and controls, and between preclinical and clinical patients. RESULTS: Preclinical patients exhibited gray matter loss in the left basal ganglia and the prefrontal cortex. Clinical patients had bilateral gray matter loss in the basal ganglia, the prefrontal cortex, and the insula. The left striatum was smaller in clinical patients than in preclinical patients. CONCLUSIONS: Neurodegenerative processes associated with Huntington's disease, as assessed by GMC reduction, begin in the left hemisphere and extend to the contralateral hemisphere throughout the inexorable course of the disease. Changes in gray matter, especially the volumetric side ratio of the striatum, could represent a relevant biomarker for characterizing the different progression stages of the disease.

Oscillatory entrainment of subthalamic nucleus neurons and behavioural consequences in rodents and primates.

We investigated the functional role of oscillatory activity in the local field potential (LFP) of the subthalamic nucleus (STN) in the pathophysiology of Parkinson's disease (PD). It has been postulated that beta (15-30 Hz) oscillatory activity in the basal ganglia induces PD motor symptoms. To assess this hypothesis, an LFP showing significant power in the beta frequency range (23 Hz) was used as a stimulus both in vitro and in vivo. We first demonstrated in rat brain slices that STN neuronal activity was driven by the LFP stimulation. We then applied beta stimulation to the STN of 16 rats and two monkeys while quantifying motor behaviour. Although stimulation-induced behavioural effects were observed, stimulation of the STN at 23 Hz induced no significant decrease in motor performance in either rodents or primates. This study is the first to show LFP-induced behaviour in both rats and primates, and highlights the complex relationship between beta power and parkinsonian symptoms.

Sensory motor mismatch within the supplementary motor area in the dystonic monkey.

Dystonia, a movement disorder characterized by abnormal postures, is associated in primary forms of the disease with subtle proprioceptive troubles and aberrant somatotopic representation in the somatosensory cortex (SC). However, it is unclear whether these sensory features are a causal phenomenon or a consequence of dystonia. The supplementary motor area proper (SMAp), a premotor cortical region, receives strong inputs from both the SC and basal ganglia. We hypothesized that disruption in sensory-motor integration within the SMAp may play a part in the pathophysiology of dystonia. Using a model of secondary dystonia obtained by 3-nitropropionic acid intoxication in rhesus monkeys, we first provide evidence that the SMAp was overexcitable in dystonic animals. Second, we show that proprioceptive inputs processed by SMAp neurons were dramatically increased with wider sensory receptive fields and a mismatch between sensory inputs and motor outputs. These findings suggest that abnormal sensory inputs impinging upon SMAp neurons play a critical role in the pathophysiology of dystonia.

Differential behavioral effects of partial bilateral lesions of ventral tegmental area or substantia nigra pars compacta in rats.

Akinesia (or absence of movement) is a prominent feature of Parkinson's disease. Akinetic symptoms, however, are also observed in depression and schizophrenia, which support the hypothesis that akinesia involves more than only motor behavior. A common feature of these disorders is the disruption of dopamine homeostasis in the CNS. Here we aimed at relating the respective involvement of the nigrostriatal and mesocortical dopaminergic pathways to akinesia. We investigated in the rat the relative effects of selective bilateral partial lesions of substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) which did not affect locomotion, on fine motor, motivational and cognitive behaviors. Motor impairments were measured by the evaluation of fine motor control in the stepping test and in the paw reaching test. Cognitive functions were assessed by various paradigms: spontaneous alternation in the Y maze and object exploration task. Motivational behavior was evaluated by the 100-pellets test. The results suggested that specific behavioral impairments are obtained following selective lesions of either SNc or VTA. SNc-lesioned rats exhibited deficits in fine motor functions as previously described in animal models of Parkinson's disease, whereas VTA-lesioned rats demonstrated traits of perseveration without significant motor impairments.

A challenging task for assessment of checking behaviors in obsessive-compulsive disorder.

OBJECTIVE: The present study concerns the objective and quantitative measurement of checking activity, which represents the most frequently observed compulsions in obsessive-compulsive disorder (OCD). To address this issue, we developed an instrumental task producing repetitive checking in OCD subjects. METHOD: Fifty OCD subjects and 50 normal volunteers (NV) were administered a delayed matching-to-sample task that offered the unrestricted opportunity to verify the choice made. Response accuracy, number of verifications, and response time for choice taken to reflect the degree of uncertainty and doubt were recorded over 50 consecutive trials. RESULTS: Despite similar levels of performance, patients with OCD demonstrated a greater number of verifications and a longer response time for choice before checking than NV. Such behavioral patterns were more pronounced in OCD subjects currently experiencing checking compulsions. CONCLUSION: The present task might be of special relevance for the quantitative assessment of checking behaviors and for determining relationships with cognitive processes.

The restless legs syndrome.

The restless legs syndrome (RLS) is one of the commonest neurological sensorimotor disorders at least in the Western countries and is often associated with periodic limb movements (PLM) during sleep leading to severe insomnia. However, it remains largely underdiagnosed and its underlying pathogenesis is presently unknown. Women are more affected than men and early-onset disease is associated with familial cases. A genetic origin has been suggested but the mode of inheritance is unknown. Secondary causes of RLS may share a common underlying pathophysiology implicating iron deficiency or misuse. The excellent response to dopaminegic drugs points to a central role of dopamine in the pathophysiology of RLS. Iron may also represent a primary factor in the development of RLS, as suggested by recent pathological and brain imaging studies. However, the way dopamine and iron, and probably other compounds, interact to generate the circadian pattern in the occurrence of RLS and PLM symptoms remains unknown. The same is also the case for the level of interaction of the two compounds within the central nervous system (CNS). Recent electrophysiological and animals studies suggest that complex spinal mechanisms are involved in the generation of RLS and PLM symptomatology. Dopamine modulation of spinal reflexes through dopamine D3 receptors was recently highlighted in animal models. The present review suggests that RLS is a complex disorder that may result from a complex dysfunction of interacting neuronal networks at one or several levels of the CNS and involving numerous neurotransmitter systems.

[Present contribution of neurosciences to a new clinical reading of obsessive-compulsive disorder]. / Apport actuel des neurosciences à travers une nouvelle lecture clinique du trouble obsessionnel compulsif.

Obsessive-compulsive disorder (OCD), that affects 2 to 3% of the general population, is characterized by recurrent intrusive thoughts and repetitive, time-consuming behaviors. It is a severely incapacitating mental illness that causes profound impairment in psychosocial functioning and quality of life. Although the physiopathology of OCD is still far from resolved, the existence of a biological basis for OCD is now clearly established and should be interpreted from phenomenological considerations, on the one hand, and in the light of our increasing knowledge of the physiology of cortico-subcortical functional loops, on the other. In a phenomenological view, the heart of the obsessional process is the subject's underlying impression that "something is wrong". In other words, obsessions may be thought of as the permanent perception of a mistake and/or error in certain behavioral situations. Compulsions occur as behavioral responses aimed at relieving the tensions or anxiety generated by the situation. If obtained, this relief may be felt to be a form of reward. Nevertheless, it is only transient, thereby creating a feeling of considerable anxiety. This contributes to immediately reproducing the behavior in a cyclic manner, on the basis of an internal motivational state through an expectation of the reward. Therefore, it can be assumed that several malfunctioning processes are altered within the OCD: 1) error recognition; and, 2) emotion and motivation. This suggests that there is a dysfunction of the brain regions mediating these cognitive and emotional functions. Experimental neurophysiology in laboratory animals indicates the central role of the fronto-subcortical circuits originating in the orbitofrontal and anterior cingulate cortices, respectively. The orbitofrontal cortex (OFC) and ventromedial areas are involved in appraisal of the emotional and motivational values of environmental information, and in integrating the subject's prior experience, which is crucial in decision-making. The OFC also contributes to the selection, comparison and judgment of stimuli and error detection. The anterior cingulate cortex (ACC) is comprised of 1) a ventral or affective region that could keep attention on the internal emotional and motivational status and regulation of autonomic responses, and 2) a dorsal and cognitive region that serves a wide range of functions including attention, working memory, error detection, conflict monitoring, response selection, and anticipation of incoming information. Ventral striatum, that is intimately connected to the OFC and ACC, participates in the preparation, initiation and execution of behavioral responses oriented toward reward delivery following the cognitive and emotional integration of behaviorally relevant information at the cortical level. Functional imaging research in humans has shown an increased functional activity in the OFC, ACC, head of the caudate nucleus and thalamus in OCD patients. These functional abnormalities have been found in basal conditions and during provocation tests. Moreover, the therapeutic efficacy of antidepressants with preponderant serotonin-reuptake inhibiting properties and cognitive-behavioral therapies seems to be associated with a progressive reduction in activity of the OFC, ACC and the caudate nucleus. Therefore, these observations are suggestive of the responsibility of 5HT neurotransmission in the dysfunction of the frontal-subcortical loops that emanate from the OFC and ACC. However, several lines of research suggest that the dopamine system, with which 5HT interacts, may play a major role in the expression of OC symptoms. In conclusion, it seems that in OCD there is a dysfunction of the brain regions that belong to the orbitofrontal and anterior cingulate loops in view of evidence obtained from separate and complementary approaches.

Dopamine receptors set the pattern of activity generated in subthalamic neurons.

Information processing in the brain requires adequate background neuronal activity. As Parkinson's disease progresses, patients typically become akinetic; the death of dopaminergic neurons leads to a dopamine-depleted state, which disrupts information processing related to movement in a brain area called the basal ganglia. Using agonists of dopamine receptors in the D1 and D2 families on rat brain slices, we show that dopamine receptors in these two families govern the firing pattern of neurons in the subthalamic nucleus, a crucial part of the basal ganglia. We propose a conceptual frame, based on specific properties of dopamine receptors, to account for the dominance of different background firing patterns in normal and dopamine-depleted states.

Side-effects of subthalamic stimulation in Parkinson's disease: clinical evolution and predictive factors.

Chronic bilateral high-frequency stimulation of the subthalamic nucleus (STN) is an alternative treatment for disabling forms of Parkinson's disease when on-off fluctuations and levodopa-induced dyskinesias compromise patients' quality of life. The aim of this study was to assess the evolution of side-effects during the first year of follow-up and search for clinical predictive factors accounting for their occurrence. We compared the frequency of side-effects at 3 and 12 months after surgery in a cohort of 44 patients. The off-medication scores of Unified Parkinson's Disease Rating Scale (UPDRS) II, III, axial symptoms, disease duration and age at surgery were retained for correlation analysis. Dysarthria/hypophonia, weight gain and postural instability were the most frequent chronic side-effects. Whereas dysarthria/hypophonia remained stable over time, weight gain and postural instability increased during the first year post-op. High axial and UPDRS II scores at surgery were predictive of dysarthria/hypophonia. Age and axial score at surgery were positively correlated with postural instability. Despite the occurrence of side-effects, the benefit/side-effects ratio of STN stimulation was largely positive during the first year of follow-up. Age, intensity of axial symptoms and UDPRS II off-medication score before surgery are predictive factors of dysarthria/hypophonia and postural instability after surgery.

From experimentation to the surgical treatment of Parkinson's disease: prelude or suite in basal ganglia research?

Parkinson's disease remains one of the greatest challenges facing those who work in the field of neurological research. Although the development of levodopa treatment revolutionised management of this debilitating diseases, no effective long-term therapy has yet been found. With recent advances in the understanding of basal ganglia physiopathology and the experimental demonstration of the efficacy of certain surgical procedures, there is a renewed interest in the surgical approach. This paper provides a chronological overview of the history of parkinsonian surgery and discusses the principal surgical options at our disposal today. These take three main forms: ablation (thalamotomy, pallidotomy and subthalamotomy); cell graft and gene therapy (mainly in the striatum); and deep brain stimulation (of the thalamus, globus pallidus pars internalis and the subthalamic nucleus). Our knowledge of basal ganglia function and our conception of how motor information is processed by this network have evolved parallel to the development of surgical techniques. Recent results from both clinical and experimental studies underline the complexity of the physiopathological mechanisms which generate parkinsonian symptomatology and lead us to question our assumption that each class of clinical signs (tremor, akinesia, rigidity, levodopa-induced dyskinesias...) is produced by a specific and separate mechanism. In the same way, comparison of the electrophysiological and biochemical effects of the different techniques induced in brain function vary considerably. This complex world of interaction and interconnection is a labyrinth that we are still far from comprehending in its entirety. All the more reason, in consequence, for extending experimental investigation into the impact of any new therapy before proposing its clinical application.

Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.

The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease symptoms, although widely accepted, has, to date, not been determined experimentally in nonhuman primates in which a more rigorous definition of the mechanisms responsible for the threshold effect might be obtained. The present study was thus designed to determine (1) the relationship between Parkinsonian symptom appearance and level of degeneration of the nigrostriatal pathway and (2) the concomitant presynaptic and postsynaptic striatal response to the denervation, in monkeys treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that produces a progressive Parkinsonian state. The kinetics of the nigrostriatal degeneration described allow the determination of the critical thresholds associated to symptom appearance, these were a loss of 43.2% of tyrosine hydroxylase-immunopositive neurons at the nigral level and losses of 80.3 and 81.6% DA transporter binding and DA content, respectively, at the striatal level. Our data argue against the concept that an increase in DA metabolism could act as an efficient adaptive mechanism early in the disease progress. Surprisingly, the D(2)-like DA receptor binding showed a biphasic regulation in relation to the level of striatal dopaminergic denervation, i.e., an initial decrease in the presymptomatic period was followed by an upregulation of postsynaptic receptors commencing when striatal dopaminergic homeostasis is broken. Further in vivo follow-up of the kinetics of striatal denervation in this, and similar, experimental models is now needed with a view to developing early diagnosis tools and symptomatic therapies that might enhance endogenous compensatory mechanisms.

[Animal models of parkinsonism]. / Modèles animaux des syndromes parkinsoniens.

Research into the pathophysiology of Parkinson's disease has been rapidly advanced by the development of animal models. Initial models were developed by using toxins that specifically targeted dopamine neurons, the most successful of which used 6-hydroxydopamine in rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice and primates. Their combination with specific striatal toxins, such as quinolinic acid or 3-nitropropionic acid, has led to the development of experimental models replicating the salient pathological and clinical features of multiple system atrophy of the striatonigral degeneration subtype both in rodents and primates. More recently, the identification of alpha-synuclein gene mutations in rare familial cases of Parkinson's disease has led to the development of alpha-synuclein knock-out and transgenic animals. We conclude that the use and improvement of both phenotypic and genetic models can significantly speed progress toward understanding the pathophysiology of these devastating diseases and finding innovative cures.

Is self-reported morbidity related to the circadian clock?

Morningness and eveningness preference, an endogenous component of the circadian clock, is characterized by an interindividual difference in circadian phase and requires of humans a specific timing of behavior. The biological rhythms of morning and evening types are consequently phase shifted with fixed socioeconomic constraints. The impact of this phase shift on health is widely debated. The purpose of the authors' study was to determine the influence of morningness/eveningness preference on self-reported morbidity and health in an active population. A total of 1165 nonshift workers of the French national electrical and gas company, enrolled in the GAZEL cohort and aged 51.3+/-3.3 years, were included in this study. They replied by mail with a completed questionnaire, including morningness/eveningness preference, self-reported morbidity, subjective sleep patterns, and daytime somnolence and sleeping schedules for 3 weeks, during the spring of 1997. Annual self-reported health impairments were assessed with the annual general questionnaire of the GAZEL cohort for 1997. After adjustment for age, sex, and occupational status, morningness-like and eveningness-like participants reported a specific worse self-reported morbidity. Whereas morningness was associated with worse sleep (p = 0.0001), eveningness was associated with feeling less energetic (p = 0.04) and physical mobility (p = 0.02). These relationships were observed even in good sleepers, except for physical mobility. After adjustment for confounding variables, eveningness-like participants reported more sleep (p = 0.0004) and mood (p = 0.00018) disorders than morningness-like participants. Morningness/eveningness preference was related to specific chronic complaints of insomnia: morningness was related with difficulty in maintaining sleep (p = 0.0005) and the impossibility to return to sleep in the early morning (p = 0.0001) (sleep phase-advance syndrome); eveningness was related to difficulty in initiating sleep (p = 0.0001) and morning sleepiness (p = 0.0001). In good sleepers, morningness was related with sleep phase-advance syndrome (p = 0.0001) and eveningness with morning sleepiness (p = 0.0001). In conclusion, the expression (phase advance or delay) of the circadian clock could be related to worse self-reported morbidity and health. These findings must be verified by further epidemiological studies, but they suggest that the impossibility to return to sleep in the early morning is not only associated with age.

Serotoninergic dysfunction in the 47, XYY syndrome.

In six XYY patients suffering from aggressiveness and admitted by order of law into a security setting for acts of violence, the estimation of cerebrospinal fluid amine metabolites before and after a probenecid test revealed a clear decrease in the turnover of central serotonin (5-HT) while that of dopamine (DA) was unchanged. The treatment with the 5-HT precursor, L-5-hydroxytryptophan (L-5-HTP), in five of the XYYs resulted in a clinical status equivalent to that observed when the patients were previously treated by conventional neuroleptics.

Minimal tissue damage after stimulation of the motor thalamus in a case of chorea-acanthocytosis.

Autopsy findings are reported from a patient with chorea-acanthocytosis treated for 2 years by deep brain stimulation (DBS) of the motor thalamus. Postoperative testing showed a progressive improvement in axial truncal spasms. Although relatively high currents were used for 2 years in this patient, postmortem analysis showed minimal tissue damage in the vicinity of the electrode tip. It is concluded that DBS has little impact on the surrounding tissues.

Compensatory effects of glutamatergic inputs to the substantia nigra pars compacta in experimental parkinsonism.

The effect of transitory blockage of substantia nigra pars compacta glutamatergic inputs by intracranial injections of kynurenic acid were evaluated in two monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The MPTP protocol was designed to mimic the gradual evolution of human Parkinson's disease. No effects were observed before MPTP treatment or in the first stage of treatment. Once clinical signs appeared, however, motor abnormalities were significantly aggravated by blockage of these inputs (P < 0.001). Conversely, after full Parkinsonism was established, blockage no longer had any behavioural effect. These results confirm the postulated compensatory role of the glutamatergic pathways feeding the substantia nigra pars compacta. This added insight into the physiopathology of the basal ganglia, when compared with previous data on the presymptomatic revelation of experimental Parkinsonism, should help elucidation of the time pattern of evolution of Parkinson's disease.

A 'single toxin-double lesion' rat model of striatonigral degeneration by intrastriatal 1-methyl-4-phenylpyridinium ion injection: a motor behavioural analysis.

Previous attempts to reproduce striatonigral degeneration, the core pathology underlying Parkinsonism in multiple system atrophy, have been impeded by interactions in the neurotoxins used to replicate striatal and nigral degeneration in rodents. To overcome these interactions, we have developed a new model of striatonigral degeneration which uses a single unilateral administration of 1-methyl-4-phenylpyridinium ion (MPP(+)) into the rat striatum. Spontaneous and drug-induced rotational behaviour, thigmotactic scanning, stepping adjusting steps and paw reaching deficits were compared in four groups of animals: group 1 (control), group 2 (20 microg quinolinic acid), group 3 (20 microg 6-hydroxydopamine), and group 4 (90 nmol MPP(+)). MPP(+) administration resulted in the absence of the amphetamine-induced ipsilateral bias observed in the 6-hydroxydopamine group and of the apomorphine-induced ipsilateral bias observed in the quinolinic acid group. There was no thigmotactic scanning asymmetry in the MPP(+)-injected rats compared to the quinolinic acid- and the 6-hydroxydopamine-injected rats. MPP(+) elicited a bilateral stepping adjustment deficit similar to that found in the quinolinic acid group when compared to controls. MPP(+) also elicited a more severe and significant contralateral deficit in paw reaching compared to controls, 6-hydroxydopamine and quinolinic acid groups. Histopathology revealed a significant reduction of the lesioned striatal surface (-47.53%) with neuronal loss and increased astrogliosis in the MPP(+) group grossly similar to that found in the quinolinic acid group. Contrary to the latter group, however, loss of intrastriatal and striatal-crossing fibre bundles was observed in the MPP(+) group as there was also some retrograde degeneration in the ipsilateral thalamic parafascicular nucleus. The mean loss of dopaminergic cells in the ipsilateral substantia nigra pars compacta in MPP(+) rats was less marked (-48.8%) than in the 6-hydroxydopamine rats (-63.6%) and was not significant in quinolinic acid rats (-5.2%). This study shows that a single unilateral intrastriatal administration of MPP(+) induces a unique motor behaviour resulting from both nigral and striatal degeneration, but also from possible extrastriatal damage. This 'single toxin-double lesion' paradigm may thus serve as a rat model of striatonigral degeneration.

Subacute systemic 3-nitropropionic acid intoxication induces a distinct motor disorder in adult C57Bl/6 mice: behavioural and histopathological characterisation.

Data on motor behavioural disorders induced by systemic 3-nitropropionic acid, an irreversible inhibitor of mitochondrial succinate dehydrogenase and their histopathological correlates in mice, are sparse. We thus further characterised the subacute 3-nitropropionic-acid-induced motor disorder and its time course in C57Bl/6 mice using standard behavioural tests, histopathological correlates and in vivo magnetic resonance imaging. Firstly, we studied two intoxication paradigms (340 and 560 mg 3-nitropropionic acid/kg, 7 days) compared to controls. The low-dose regimen induced only slight motor changes (reduced hindlimb stride length and rearing). The high-dose regimen induced significant (P<0.05) behavioural and sensorimotor integration deficits (pole test, rotarod, stride length, open-field spontaneous activity) but with 37.5% lethality at week one. The clinical motor disorder consisted of hindlimb clasping and dystonia, truncal dystonia, bradykinesia and impaired postural control. Histopathologically, there were discrete lesions of the dorsolateral striatum in 62.5% of mice together with a 32% reduction (P<0.0001) of the striatal volume, reduced caldbindin-D28K immunoreactivity in the lateral striatum, and met-enkephalin and substance P in the striatal output pathways. There was also a significant (P<0.05) 30-40% dopaminergic cell loss within the substantia nigra pars compacta. Secondly, we validated a semi-quantitative behavioural scale to describe the time course of the motor deficits and to predict the occurrence of striatal damage. We sought to determine whether it could also be disclosed in vivo by magnetic resonance imaging. The scale correlated with the striatal volume reduction (r(2)=0.57) and striatal cell loss (r(2)=0.87) but not with the loss of striatal dopaminergic terminals (dopamine transporter binding). Increased T2-signal intensity within the striatal lesion correlated with the cell loss (r(2)=0.66). We conclude that systemic administration of 3-nitropropionic acid in C57Bl/6 mice induces a distinct motor disorder and dose-dependent striatonigral damage, which are potentially useful to model human diseases of the basal ganglia.