Organization of ventral tegmental area projections to the ventral tegmental area-nigral complex in the rat

The ventral tegmental area (VTA) is a nodal link in reward circuitry. Based on its striatal output, it has been subdivided in a caudomedial part which targets the ventromedial striatum, and a lateral part which targets the ventrolateral striatum [Ikemoto S (2007) Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev 56:27-78]. Whether these two VTA parts are interconnected and to what extent the VTA innervates the substantia nigra compacta (SNc) and retrorubral nucleus (RR) are critical issues for understanding information processing in the basal ganglia. Here, VTA projections to the VTA-nigral complex were examined in rats, using Phaseolus vulgaris leucoagglutinin (PHA-L) as anterograde tracer. The results show that the dorsolateral VTA projects to itself, as well as to the dorsal tier of the SNc and RR, largely avoiding the caudomedial VTA. The ventrolateral VTA innervates mainly the interfascicular nucleus. The components of the caudomedial VTA (the interfascicular, paranigral and caudal linear nuclei) are connected with each other. In addition, the caudomedial VTA (especially the paranigral and caudal linear nuclei) innervates the lateral VTA, and, to a lesser degree, the SNc and RR. The caudal pole of the VTA sends robust, bilateral projections to virtually all the VTA-nigral complex, which terminate in the dorsal and ventral tiers. Modest inputs from the medial supramammillary nucleus to ventromedial parts of the VTA-nigral complex were also identified. In double-immunostained sections, PHA-L-labeled varicosities were sometimes found apposed to tyrosine hydroxylase-positive neurons in the ventral mesencephalon. Overall, the results underscore that VTA projections to the VTA-nigral complex are substantial and topically organized. In general, these projections, like the spiralated striato-nigro-striatal loops, display a medial-to-lateral organization. This anatomical arrangement conceivably permits the ventromedial striatum to influence the activity of the lateral striatum. The caudal pole of the VTA appears to be a critical site for a global recruitment of the mesotelencephalic system. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.

Mitochondrial energy metabolism in neurodegeneration associated with methylmalonic acidemia

Methylmalonic acidemia is one of the most prevalent inherited metabolic disorders involving neurological deficits. In vitro experiments, animal model studies and tissue analyses from human patients suggest extensive impairment of mitochondrial energy metabolism in this disease. This review summarizes changes in mitochondrial energy metabolism occurring in methylmalonic acidemia, focusing mainly on the effects of accumulated methylmalonic acid, and gives an overview of the results found in different experimental models. Overall, experiments to date suggest that mitochondrial impairment in this disease occurs through a combination of the inhibition of specific enzymes and transporters, limitation in the availability of substrates for mitochondrial metabolic pathways and oxidative damage.

Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knock-out mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.

Subtle Cognitive Deficits in Adults With a Previous History of Sydenham's Chorea During Childhood

Objective. To evaluate the neuropsychological profile and health-related quality of life (HRQOL) of adults who had rheumatic fever (RF) during childhood with and without Sydenham's chorea (SC).Methods. Three groups of patients were assessed: adults who had RF with SC during childhood (SC group), adults who had RF without SC during childhood (RF group), and controls (CT group). A range of neuropsychological tests looked at several cognitive domains. HRQOL was measured through a Brazilian version of the Short Form 36 (SF-36) health survey.Results. Twenty patients were included in the SC group, 23 patients in the RF group, and 19 patients in the CT group. The 3 groups were homogeneous regarding sex (P = 0.078), age (P = 0.799), schooling (P = 0.600), socioeconomic status (P = 0.138), intelligence quotient (P = 0.329), and scores for anxiety (P = 0.156) and depression (P = 0.076). The SC group demonstrated inferior performance in tests that assessed attention (Digit Span Forward [ P = 0.005], Corsi Block Forward [ P = 0.014]), speeded information processing (Trail Making A [ P = 0.009], Symbol Search [ P = 0.042]), and executive functions and working memory (Corsi Block Backward [ P = 0.028]), and higher scores for attention deficit scale (P = 0.030) when compared with the RF and CT groups. They also showed a tendency toward lower scores in the physical aspects, vitality, emotional aspects, and mental health domains of the SF-36. The RF group had a lower score for the general health domain than the CT group (P = 0.030).Conclusion. Patients who had SC during childhood can exhibit inferior performance in tasks that evaluate attention, speeded information processing, executive functions, and working memory in adult life. Therefore, there is indirect evidence of the persistence of dysfunction in cerebral circuits involved with the basal ganglia. They also presented a worse self-evaluation in HRQOL that was not related to cognitive impairments.

Estudo dos efeitos comportamentais do neuropeptídeos em camundongos submetidos a modelos animais de Parkinson

Neuropeptide S (NPS) is the endogenous ligand of a G-protein coupled receptor. Preclinical studies have shown that NPSR receptor activation can promote arousal, anxiolytic-like behavioral, decrease in food intake, besides hyperlocomotion, which is a robust but not well understood phenomenon. Previous findings suggest that dopamine transmission plays a crucial role in NPS hyperactivity. Considering the close relationship between dopamine and Parkinson Disease (PD), and also that NPSR receptors are expressed on dopaminergic nuclei in the brain, the current study attempted to investigate the effects of NPS in motor deficits induced by intracerebroventricular (icv) administration of 6-OHDA and systemic administration of haloperidol. Motor deficits induced by 6-OHDA and haloperidol were evaluated on Swiss mice in the rota-rod and catalepsy test. Time on the rotating rod and time spent immobile in the elevated bar were measured respectively in each test. L-Dopa, a classic antiparkinsonian drug, and NPS were administrated in mice submitted to one of the animal models of PD related above. 6-OHDA injection evoked severe motor impairments in rota-rod test, while the cataleptic behavior of 6-OHDA injected mice was largely variable. The administration of L-Dopa (25 mg/kg) and NPS (0,1 and 1 nmol) reversed motor impairments induced by 6-OHDA in the rota-rod. Haloperidolinduced motor deficits on rota-rod and catalepsy tests which were reversed by L-Dopa (100 e 400 mg/kg), but not by NPS (0,1 and 1 nmol) administration. The association of L-Dopa 10 mg/kg and NPS 1 nmol was also unable to counteract haloperidol-induced motor deficits. To summarize, 6-OHDA-, but not haloperidol-, induced motor deficits were reversed by the central administration of NPS. These data suggest that NPS possibly facilitates dopamine release in basal ganglia, what would explain the overcome of motor performance promoted by NPS administration in animals pretreated with 6-OHDA, but not haloperidol. Finally, the presented findings point, for the first time, to the potential of NPSR agonist as an innovative treatment for PD.

Alternative pathways for catecholamine action in oral motor control

Orofacial movement is a complex function performed by facial and jaw muscles. Jaw movement is enacted through the triggering of motoneurons located primarily in the trigeminal motor nucleus (Mo5). The Mo5 is located in the pontine reticular formation, which is encircled by premotor neurons. Previous studies using retrograde tracers have demonstrated that premotor neurons innervating the Mo5 are distributed in brainstem areas, and electrophysiological studies have suggested the existence of a subcortical relay in the corticofugal-Mo5 pathway. Various neurotransmitters have been implicated in oral movement. Dopamine is of special interest since its imbalance may produce changes in basal ganglia activity, which generates abnormal movements, including jaw motor dysfunction, as in oral dyskinesia and possibly in bruxism. However, the anatomical pathways connecting the dopaminergic systems with Mo5 motoneurons have not been studied systematically. After injecting retrograde tracer fluorogold into the Mo5, we observed retrograde-labeled neurons in brainstem areas and in a few forebrain nuclei, such as the central nucleus of the amygdala, and the parasubthalamic nucleus. By using dual-labeled immunohistochemistry, we found tyrosine hydroxylase (a catecholamine-processing enzyme) immunoreactive fibers in close apposition to retrograde-labeled neurons in brainstem nuclei, in the central nucleus of the amygdala and the parasubthalamic nucleus, suggesting the occurrence of synaptic contacts. Therefore, we suggested that catecholamines may regulate oralfacial movements through the premotor brainstem nuclei, which are related to masticatory control, and forebrain areas related to autonomic and stress responses. (C) 2005 Elsevier B.V.. All rights reserved.

Cognitive Deficits in Machado-Joseph Disease Correlate with Hypoperfusion of Visual System Areas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Hallazgos de neuroimagen y desempeño ortográfi co de estudiantes con trastorno por défi cit de atención con hiperactividad según la semiología de los errores

Aim: To characterize, compare and classify the performance of students with attention deficit-hyperactivity disorder (ADHD) according to the semiology of errors and to describe the neuroimaging findings in these students. Methods: We evaluated 36 primary school boys and girls aged between 8 and 11 years old in the 3 rd to 5 th grades. The children were divided in two groups. Group I consisted of 18 students with an interdisciplinary diagnosis of ADHD (60% boys and 40% girls). Group II consisted of 18 children with good academic performance, paired by gender, age and grade with children in group I. The collective and individual versions of the Pro-ortografia spelling tests were applied. Results: Statistically significant differences were found in almost all the tests of the individual and collective versions of the spelling evaluation, with children with ADHD showing a higher average number of errors. Neuroimaging examinations indicated that 81% of the students in GI showed hypoperfusion in the frontal lobe, 7% had hypoperfusion of the thalamus and basal ganglia, 6% showed hypoperfusion in the basal ganglia only and 6% showed hypoperfusion in the left and right frontal lobes. Conclusions: Children with ADHD demonstrated poorer knowledge of the use of spelling rules in Brazilian Portuguese, which could be related to changes in blood flow in the frontal lobe, parietal lobe, thalamus and basal ganglia. These changes could cause a lack of attention, affecting phonological working memory and the planning of writing. © 2011 AELFA.

Alterações oxidativas em portadores de doença de Parkinson: correlação com critérios clínicos e estágios da doença

A doença de Parkinson (DP) constitui uma das mais prevalentes doenças neurológicas. Nesta doença, ocorre a neurodegeneração do sistema nigroestriatal com alteração da circuitaria neuronal dos núcleos da base levando ao comprometimento motor característico da doença. Os sintomas clássicos são o tremor de repouso, rigidez, acinesia ou bradicinesia e instabilidade postural. A patogênese da DP ainda permanece obscura. No entanto, estima-se que a disfunção mitocondrial e o desenvolvimento de estresse oxidativo na substância negra tenham papel relevante neste processo. O diagnóstico da DP é clinico e normalmente acontece tardiamente, quando a maioria dos neurônios nigrais está degenerada. Alguns trabalhos mostram o efeito neuroprotetor de medicações antiparkinsonianas e isto demonstra que quanto mais precoce a introdução do tratamento melhor o prognóstico à longo prazo da doença. Portanto o desenvolvimento de marcadores periféricos que ajudem no diagnóstico precoce da doença é importante para que se inicie o tratamento a tempo de retardar o avanço da morte neuronal. O objetivo deste trabalho foi verificar a existência de alterações em parâmetros oxidantes e antioxidantes no sangue de pacientes parkinsonianos e sua relação com o estágio da doença e critérios clínicos. Foram avaliados 30 portadores de DP e 30 indivíduos sem a doença. Para avaliar o estágio da doença e caracteres clínicos foram aplicadas as escalas de Hoehn & Yahr e a UPDRS (escala unificada para doença de Parkinson) nos pacientes parkinsonianos. Para avaliar a atividade oxidativa no plasma dos individuos, foi analisada a peroxidação lipídica através da mensuração de produtos da ação de Espécies Reativas de Oxigênio e Nitrogênio (ERON; TBARS) e para avaliar a resposta antioxidante foi feita a avaliação da Capacidade Antioxidante Total (TEAC). Nos grupos DP leve e DP moderado foi encontrado maior valor do TBARS e menor valor do TEAC em relação aos controles e DP grave (p<0,05), confirmando a presença de estresse oxidativo nas fases precoces da DP. Nesta pesquisa esses parâmetros demonstraram serem bons marcadores periféricos do estresse oxidativo, colaborando para um diagnóstico precoce da DP.

Neurocriptococose pediátrica no Estado do Pará: espectro de achados tomográficos na infecção por Cryptococcus neoformans var. gattii

Este estudo mostra o espectro de lesões cerebrais, através de tomografia computadorizada, na neurocriptococose da infância, por Cryptococcus neoformans var. gattii, no Estado do Pará. Analisamos os achados tomográficos de onze crianças (menores de 13 anos de idade), com infecção comprovada do sistema nervoso central por Cryptococcus neoformans var. gattii, internados no Hospital Universitário João de Barros Barreto, Belém PA, entre janeiro de 1992 a dezembro de 2000. A neurocriptococose foi definida pela identificação de leveduras encapsuladas ao exame microscópico, isolamento de Cryptococcus neoformans do líquor e identificação positiva da variedade gattii, através do meio composto de canavanina, glicina e azul-de-bromotimol com, pelo menos, o estudo tomográfico no momento do diagnóstico. A idade das crianças estudadas variou entre 6 a 12 anos, com média de 8,8 anos. Cincos eram meninos e seis meninas. Os principais achados clínicos foram cefaléia, febre e rigidez de nuca (n=11), náuseas e vômitos (n=10). O tempo médio entre o início dos sintomas e o diagnóstico foi de 4,2 semanas (variando de 2 a 8 semanas). Todas as tomografias de crânio foram anormais. Em todos os pacientes foram observados nódulos hipodensos. As demais anormalidades tomográficas observadas foram: 6 pacientes com hidrocefalia, 9 com atrofia difusa e 5 com associação de hidrocefalia e atrofia difusa. Descreve-se, pela primeira vez, achados tomográficos em série de casos de neurocriptococose por Cryptococcus neoformans var. gattii em crianças imunocompetentes. Este estudo mostra que esta infecção desenvolve múltiplos nódulos hipodensos, especialmente na região dos gânglios da base e na substância branca cerebral. As lesões, aparentemente progridem para importante atrofia da substância branca, com dilatação ventricular e proeminência de sulcos cerebrais, provavelmente, conseqüência de hidrocefalia compensatória. Em geral, estes pacientes apresentaram alterações leves do córtex cerebral.

Analysis of generalized interictal discharges using quantitative EEG

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Glioma misto em um cão: relato de caso

Intracranial neoplasms are common causes of neurological disorders in middle-aged and elderly dogs. With the feasibility of computed tomography, it is now possible to determine the extent and exact location of brain tumors, identifying them ante mortem in dogs and cats. This paper aims to report the occurrence of a mixed glioma in a Boxer dog examined at the Veterinary Hospital of Unesp, Botucatu Campus. The animal presented with a brain syndrome of acute onset and progressive course. CT scan showed the presence of a mass in the right cerebral hemisphere extending from the frontal to the parietal region and involving the basal ganglia. Given the gravity of the neurological disorder, the owner chose to perform euthanasia. Microscopic analysis of the mass allowed the diagnosis of mixed glioma.

Análise quantitativa das descargas epileptiformes generalizadas e da neuroimagem de pacientes com epilepsia generalizada idiopática

Pós-graduação em Fisiopatologia em Clínica Médica - FMB

Near-Term Fetal Hypoxia-Ischemia in Rabbits MRI Can Predict Muscle Tone Abnormalities and Deep Brain Injury

Background and Purpose-The pattern of antenatal brain injury varies with gestational age at the time of insult. Deep brain nuclei are often injured at older gestational ages. Having previously shown postnatal hypertonia after preterm fetal rabbit hypoxia-ischemia, the objective of this study was to investigate the causal relationship between the dynamic regional pattern of brain injury on MRI and the evolution of muscle tone in the near-term rabbit fetus. Methods-Serial MRI was performed on New Zealand white rabbit fetuses to determine equipotency of fetal hypoxia-ischemia during uterine ischemia comparing 29 days gestation (E29, 92% gestation) with E22 and E25. E29 postnatal kits at 4, 24, and 72 hours after hypoxia-ischemia underwent T2- and diffusion-weighted imaging. Quantitative assessments of tone were made serially using a torque apparatus in addition to clinical assessments. Results-Based on the brain apparent diffusion coefficient, 32 minutes of uterine ischemia was selected for E29 fetuses. At E30, 58% of the survivors manifested hind limb hypotonia. By E32, 71% of the hypotonic kits developed dystonic hypertonia. Marked and persistent apparent diffusion coefficient reduction in the basal ganglia, thalamus, and brain stem was predictive of these motor deficits. Conclusions-MRI observation of deep brain injury 6 to 24 hours after near-term hypoxia-ischemia predicts dystonic hypertonia postnatally. Torque-displacement measurements indicate that motor deficits in rabbits progressed from initial hypotonia to hypertonia, similar to human cerebral palsy, but in a compressed timeframe. The presence of deep brain injury and quantitative shift from hypo-to hypertonia may identify patients at risk for developing cerebral palsy. (Stroke. 2012;43:2757-2763.)

Behavioral and EEG effects of GABAergic manipulation of the nigro-tectal pathway in the Wistar audiogenic rat (WAR) strain II: An EEG wavelet analysis and retrograde neuronal tracer approach

The role of the substantia nigra pars reticulata (SNPr) and superior colliculus (SC) network in rat strains susceptible to audiogenic seizures still remain underexplored in epileptology. In a previous study from our laboratory, the GABAergic drugs bicuculline (BIC) and muscimol (MUS) were microinjected into the deep layers of either the anterior SC (aSC) or the posterior SC (pSC) in animals of the Wistar audiogenic rat (WAR) strain submitted to acoustic stimulation, in which simultaneous electroencephalographic (EEG) recording of the aSC, pSC, SNPr and striatum was performed. Only MUS microinjected into the pSC blocked audiogenic seizures. In the present study, we expanded upon these previous results using the retrograde tracer Fluorogold (FG) microinjected into the aSC and pSC in conjunction with quantitative EEG analysis (wavelet transform), in the search for mechanisms associated with the susceptibility of this inbred strain to acoustic stimulation. Our hypothesis was that the WAR strain would have different connectivity between specific subareas of the superior colliculus and the SNPr when compared with resistant Wistar animals and that these connections would lead to altered behavior of this network during audiogenic seizures. Wavelet analysis showed that the only treatment with an anticonvulsant effect was MUS microinjected into the pSC region, and this treatment induced a sustained oscillation in the theta band only in the SNPr and in the pSC. These data suggest that in WAR animals, there are at least two subcortical loops and that the one involved in audiogenic seizure susceptibility appears to be the pSC-SNPr circuit. We also found that WARs presented an increase in the number of FG + projections from the posterior SNPr to both the aSC and pSC (primarily to the pSC), with both acting as proconvulsant nuclei when compared with Wistar rats. We concluded that these two different subcortical loops within the basal ganglia are probably a consequence of the WAR genetic background. (C) 2012 Elsevier Inc. All rights reserved.