Localization of immunoreactivity for deleted in colorectal cancer (DCC), the receptor for the guidance factor netrin-1, in ventral tier dopamine projection pathways in adult rodents

DCC (deleted in colorectal cancer)-the receptor of the netrin-1 neuronal guidance factor-is expressed and is active in the central nervous system (CNS) during development, but is down-regulated during maturation. The substantia nigra contains the highest level of netrin-1 mRNA in the adult rodent brain, and corresponding mRNA for DCC has also been detected in this region but has not been localized to any particular neuron type. In this study, an antibody raised against DCC was used to determine if the protein was expressed by adult dopamine neurons, and identify their distribution and projections. Significant DCC-immunoreactivity was detected in midbrain, where it was localized to ventrally displaced A9 dopamine neurons in the substantia nigra, and ventromedial A10 dopamine neurons predominantly situated in and around the interfascicular nucleus. Strong immunoreactivity was not detected in dopamine neurons found elsewhere, or in non-dopamine-containing neurons in the midbrain. Terminal fields selectively labeled with DCC antibody corresponded to known nigrostriatal projections to the dorsolateral striatal patches and dorsomedial shell of the accumbens, and were also detected in prefrontal cortex, septum, lateral habenular and ventral pallidum. The unique distribution of DCC-immunoreactivity in adult ventral midbrain dopamine neurons suggests that netrin-1/DCC signaling could function in plasticity and remodeling previously identified in dopamine projection pathways. In particular, a recent report that DCC is regulated through the ubiquitin-proteosome system via Siah/Sina proteins, is consistent with a potential involvement in genetic and sporadic forms of Parkinson's disease. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.

The physical and chemical properties of eumelanin

In this article, we review the current state of knowledge concerning the physical and chemical properties of the eumelanin pigment. We examine properties related to its photoprotective functionality, and draw the crucial link between fundamental molecular structure and observable macroscopic behaviour. Where necessary, we also briefly review certain aspects of the pheomelanin literature to draw relevant comparison. A full understanding of melanin function, and indeed its role in retarding or promoting the disease state, can only be obtained through a full mapping of key structure-property relationships in the main pigment types. We are engaged in such an endeavor for the case of eumelanin.

Progressive supranuclear palsy (PSP):A quantitative study of the pathological changes in cortical and subcortical regions of eight cases

In eight cases of progressive supranuclear palsy (PSP), neurofibrillary tangles (NFT) were numerous in the substantia nigra (SN), red nucleus (RN), locus caeruleus (LC), pontine nuclei (PN), and inferior olivary nucleus (ION) and abnormally enlarged neurons (EN) in the ION, LC and PN. Loss of Purkinje cells was evident in the cerebellum. Tufted astrocytes (TA) were abundant in the striatum, SN and RN and glial inclusions ('coiled bodies') (GI) in the midbrain (SN, RN) and pons (LC). Neuritic plaques were frequent in one case. NFT, GI, and TA densities were uncorrelated in most areas. NFT and EN densities were positively correlated in the midbrain and surviving neurons and disease duration in several areas. These results suggest: 1) predominantly subcortical pathology in PSP with widespread NFT while TA and GI have a more localized distribution, 2) little correlation between neuronal and glial pathologies, and 3) shorter duration cases may be more likely to develop cortical pathology. © 2007 Springer-Verlag.

A quantitative study of the pathological changes in ten patients with multiple system atrophy (MSA)

The densities of the glial cytoplasmic inclusions (GCI), neuronal inclusions (NI), and abnormal neurons were studied in the frontal cortex, hippocampus, cerebellum, basal ganglia and areas of the pons and medulla in 10 cases of multiple system atrophy (MSA). GCI density was greater in the substantia nigra and globus pallidus compared with the frontal cortex and hippocampus. Abnormal neurons were most abundant in the frontal cortex, substantia nigra, and inferior olivary nucleus. NI and abnormal neuron densities were positively correlated in the globus pallidus but negatively correlated in the hippocampus. The NI and GCI were only positively correlated in the pons. GCI in the pons and inferior olivary nucleus, NI in the substantia nigra, and abnormal neurons in the frontal cortex varied significantly between cases. The MSA cases did not cluster according to disease subtype. The data suggest that: 1) the greatest densities of pathological changes occur in the substantia nigra and globus pallidus, 2) density of the GCI is unrelated to that of the NI, and 3) there is overlapping pathology between the various subtypes of MSA.

Subthalamic nucleus neurones in slices from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity

The loss of dopamine in idiopathic or animal models of Parkinson's disease induces synchronized low-frequency oscillatory burst-firing in subthalamic nucleus neurones. We sought to establish whether these firing patterns observed in vivo were preserved in slices taken from dopamine-depleted animals, thus establishing a role for the isolated subthalamic-globus pallidus complex in generating the pathological activity. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed significant reductions of over 90% in levels of dopamine as measured in striatum by high pressure liquid chromatography. Likewise, significant reductions in tyrosine hydroxylase immunostaining within the striatum (>90%) and tyrosine hydroxylase positive cell numbers (65%) in substantia nigra were observed. Compared with slices from intact mice, neurones in slices from MPTP-lesioned mice fired significantly more slowly (mean rate of 4.2 Hz, cf. 7.2 Hz in control) and more irregularly (mean coefficient of variation of inter-spike interval of 94.4%, cf. 37.9% in control). Application of ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonopentanoic acid (AP5) and the GABAA receptor antagonist picrotoxin caused no change in firing pattern. Bath application of dopamine significantly increased cell firing rate and regularized the pattern of activity in cells from slices from both MPTP-treated and control animals. Although the absolute change was more modest in control slices, the maximum dopamine effect in the two groups was comparable. Indeed, when taking into account the basal firing rate, no differences in the sensitivity to dopamine were observed between these two cohorts. Furthermore, pairs of subthalamic nucleus cells showed no correlated activity in slices from either control (21 pairs) or MPTP-treated animals (20 pairs). These results indicate that the isolated but interconnected subthalamic-globus pallidus network is not itself sufficient to generate the aberrant firing patterns in dopamine-depleted animals. More likely, inputs from other regions, such as the cortex, are needed to generate pathological oscillatory activity. © 2006 IBRO.

Is neuropathological heterogeneity in Alzheimer’s disease related to apolipoprotein genotype?

The abundance of senile plaques (SP) and neurofibrillary tangles (NFT) was studied in cortical and subcortical regions from 30 patients with Alzheimer’s disease (AD) expressing different apolipoprotein E (apoE) genotypes. Principal components analysis (PCA) was used to identify the most important neuropathological variations between individual patients and to determine whether these variations were related to apoE genotype. The first two principal components (PC) accounted for 60% and 40% of the total variance of the SP and NFT data respectively. The abundance of SP in the frontal and occipital cortex and NFT in the frontal cortex, amygdala and substantia nigra were positively correlated with the first principal component (PC1). Analysis of the SP data revealed that the apoE score of the patient (the sum of the two alleles) was positively correlated with PC1 while analysis of the NFT data revealed no significant correlations between apoE score and the PC. The data suggest that apoE genotype was more closely related to variations in the distribution and abundance of SP than of NFT. In addition, a more rapid spread of SP into the frontal and occipital cortex may occur in patients with a high apoE score.

Dissociable brain structural changes associated with predisposition, resilience, and disease expression in bipolar disorder

Genetic factors are important in the etiology of bipolar disorder (BD). However, first-degree relatives of BD patients are at risk for a number of psychiatric conditions, most commonly major depressive disorder (MDD), although the majority remain well. The purpose of the present study was to identify potential brain structural correlates for risk and resilience to mood disorders in patients with BD, type I (BD-I) and their relatives. Structural magnetic resonance imaging scans were acquired from 30 patients with BD-I, 50 of their firstdegree relatives (28 had no Axis I disorder, while 14 had MDD) and 52 controls. We used voxel-based morphometry, implemented in SPM5 to identify group differences in regional gray matter volume. From the identified clusters, potential differences were further examined based on diagnostic status (BD-I patients, MDD relatives, healthy relatives, controls). Whole-brain voxel-based analysis identified group differences in the left hemisphere in the insula, cerebellum, and substantia nigra. Increased left insula volume was associated with genetic preposition to BD-I independent of clinical phenotype. In contrast, increased left substantia nigra volume was observed in those with the clinical phenotype of BD-I. Changes uniquely associated with the absence of a clinical diagnosis in BD relatives were observed in the left cerebellum. Our data suggest that in BD, genetic and phenotype-related influences on brain structure are dissociable; if replicated, these findings may help with early identification of high-risk individuals who are more likely to transition to syndromal states. Copyright © 2009 Society for Neuroscience.

Neuropathology of Basal Ganglia and its role in the Parkinsonian syndromes with special reference to the Globus pallidus

The globus pallidus, together with the striatum (caudate nucleus and putamen), substantia nigra, nucleus accumbens, and subthalamic nucleus constitute the basal ganglia, a group of nuclei which act as a single functional unit. The basal ganglia have extensive connections to the cerebral cortex and thalamus and exert control over a variety of functions including voluntary motor control, procedural learning, and motivation. The action of the globus pallidus is primarily inhibitory and balances the excitatory influence of other areas of the brain such as the cerebral cortex and cerebellum. Neuropathological changes affecting the basal ganglia play a significant role in the clinical signs and symptoms observed in the ‘parkinsonian syndromes’ viz., Parkinson’s disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD). There is increasing evidence that different regions of the basal ganglia are differentially affected in these disorders. Hence, in all parkinsonian disorders and especially PD, there is significant pathology affecting the substantia nigra and its dopamine projection to the striatum. However, in PSP and MSA, the globus pallidus is also frequently affected while in DLB and CBD, whereas the caudate nucleus and/or putamen are affected, the globus pallidus is often spared. This chapter reviews the functional pathways of the basal ganglia, with special reference to the globus pallidus, and the role that differential pathology in these regions may play in the movement disorders characteristic of the parkinsonian syndromes.

Dementia with Lewy bodies

Dementia with Lewy bodies (‘Lewy body dementia' or ‘diffuse Lewy body disease') (DLB) is the second commonest form of dementia after Alzheimer’s disease (AD). Characteristic of DLB are: (1) fluctuating cognitive ability with variations in attention and alertness, (2) recurrent visual hallucinations, and (3) motor features including akinesia, rigidity, and tremor. Various brain regions are affected in DLD including cortical and limbic regions. Histopathologically, alpha-synuclein-immunoreactive Lewy bodies (LB) are observed in the substantia nigra and in the cerebral cortex. DLB has affinities both with the parkinsonian syndromes including Parkinson’s disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA), and with AD, which can make differential diagnosis difficult. The presence of visual hallucinations may aid differential diagnosis of the parkinsononian syndromes and occipital hypometabolism may be a useful potential method of distinguishing DLB from AD. Treatment of CBD involves managing and reducing the effect of symptoms.

A quantitative study of tau pathology in eleven cases of chronic traumatic encephalopathy

AIMS: To quantify tau pathology of chronic traumatic encephalopathy (CTE) and investigate influence of dot-like lesions (DL), brain region, co-morbidity, and sporting career length. METHODS: Densities of neurofibrillary tangles (NFT), astrocytic tangles (AT), DL, oligodendroglial inclusions (GI), neuropil threads (NT), vacuoles, neurons, and enlarged neurons (EN) were measured in tau-immunoreactive sections of upper cortical laminae of frontal and temporal lobe, hippocampus (HC), amygdala, and substantia nigra (SN) of eleven cases of CTE. RESULTS: DL were a consistent finding in CTE. Densities of NFT, NT and DL were greatest in sectors CA1 and CA2 of the HC. Densities of AT were lower than NFT, small numbers of GI were recorded in temporal lobe, and low densities of vacuoles and EN were consistently present. β-amyloid containing neuritic plaques (NP) also occurred at low density. Densities of NFT, NT, DL, and AT were greater in sulci than gyri while vacuole density was greater in gyri. Principal components analysis (PCA) suggested that sporting career length and densities of NFT in entorhinal cortex, NT in CA2 and SN, and vacuolation in the DG were significant sources of variation among cases. CONCLUSION: DL are frequent in CTE suggesting affinity with argyrophilic grain disease (AGD) and Parkinson's disease dementia (PD-Dem). Densities of AT in all regions and NT/DL in sectors CA2/4 were consistent features of CTE. The eleven cases are neuropathologically heterogeneous which may result from genetic diversity, and variation in anatomical pathways subjected to trauma. This article is protected by copyright. All rights reserved.

Modelo animal da Doença de Parkinson baseado na expressão de alfa - sinucleína: caracterização comportamental, eletrofisiológica e avaliação dos efei tos da estimulação da medula espinhal

Parkinson disease (PD) is associated with motor symptoms and dopaminergic cell loss in the nigrostriatal pathway. Alpha-synuclein is the major component of the Lewy bodies, the biological hallmarks of disease, and has been associated with familial cases of PD. Recently, the spinal cord stimulation (SCS) showed to be effective to alleviate the Parkinson symptoms in animal models and human patients. In this project, we characterized the motor and electrophysiological effects of alpha-synuclein overexpression in the substantia nigra of rats. We further investigated the effects of spinal electrical stimulation, AMPT and L-dopa administration in this model. Method: Sprague-Dawley rats were injected with empty viral vector or the vector carrying the gene for alpha-synuclein in the substantia nigra, and were tested weekly for 10 weeks in the open field and cylinder tests. A separated group of animals implanted with bilateral electrode arrays in the motor cortex and the striatum were recorded in the open field, during the SCS sessions and the pharmacological experiments. Results: Alpha-synuclein expression resulted in motor asymmetry, observed as the reduction in use of contralateral forepaw in the cylinder test. Animals showed an increase of local field potential activity in beta band three and four weeks after the virus injection, that was not evident after the 5th week. AMPT resulted in a sever parkinsonian state, with reduction in the locomotor activity and significant peak of oscillatory activity in cortex and striatum. SCS was effective to alleviate the motor asymmetry at long term, but did not reduce the corticostriatal low frequency oscillations observed 24 hs after the AMPT administration. These oscillations were attenuated by L-dopa that, even as SCS, was not effective to restore the locomotor activity during the severe dopaminergic depletion period. Discussion: The alpha-synuclein model reproduces the motor impairment and the progressive neurodegenerative process of PD. We demonstrated, by the first time, that this model also presents the increase in low frequency oscillatory activity in the corticostriatal circuit, compatible with parkinsonian condition; and that SCS has a therapeutic effect on motor symptom of this model.

Caracterização citoarquitetônica e por imunoistoquímica para tirosina-hidroxilase da substância negra, área tegmentar ventral e zona retrorubral do Sagui (Callithrix jacchus)

It is known that the catecholamine group is constituted by dopamine, noradrenaline and adrenaline, in which the synthesis is regulated by an enzyme named tyrosine hydroxylase. Thus, 3-hydroxytyramine/dopamine (DA) is a precursor of the noradrenaline and adrenaline synthesis and acts as a neurotransmitter in the central nervous system. The three main nuclei, named the retrorubral field (A8 group), the substantia nigra pars compacta (A9 group) and the ventral tegmental area (A10 group), are arranged in the die-mesencephalic portion and are involved in three complexes circuitries - the mesostriatal, mesolimbic and mesocortical pathways. These pathways are related to behavioral manifestations, motricity, learning, reward and pathologies such as Parkinson’s Disease and Schizophrenia. Thus, the aim of this study was to perform de morphological analysis of the A8, A9 and A10 nuclei of the common marmoset (Callithrix jacchus). The marmoset is a neotropical primate, whose morphological and functional characteristics supports the suitability of use of this animal in biomedical research. Coronal sections of the marmoset brain were submitted to cytoarchitectonic characterization and TH-immunohistochemistry. Based on the morphology of the neurons, it was possible to subdivide the A10 group in seven regions: interfascicular nucleus, raphe rostral linear nucleus and raphe caudal linear nucleus, in the middle line; paranigral and parainterfascicular nucleus, in the middle zone; rostral portion of the ventral tegmental area nucleus and parabrachial pigmented nucleus, located in the dorsolateral portion of the mesencephalic tegmentum. A9 group was divided into four regions: substantia nigra compacta dorsal and ventral tiers; substantia nigra compacta lateral and medial clusters. No subdivisions were founded into A8 group. These results revealed that A8, A9 and A10 are phylogenetically conserved between species, but it’s necessary to expand the studies about this compartmentalization, investigating its occurrence in other primate species or investigating its functional relevance.

Citoarquitetura e imunoistoquímica para tirosinahidroxilase dos núcleos dopaminérgicos mesencefálicos do morcego (Artibeus planirostris)

The 3-Hidroxytyramine/dopamine (DA) is a monoamine of catecholamine family and isthe precursor substance synthesis of noradrenaline and adrenaline, having the enzymeTyrosine Hydroxylase (TH) as this regulatory process. In addition, the DA has theability to act as a neurotransmitter in the Central Nervous System - SNC, being themain neurotransmitter of brain nuclei, namely of A8 to A16. The nuclei of the midbrainthat express DA are the Retrorubral Field (RRF, A8), the Substantia Nigra parsCompacta (SNc, A9) and the Ventral Tegmental Area (VTA, A10). Such nuclei areinvolved in complex three circuitry that are the mesostriatal, mesolimbic andmesocotical and are directly related with several behavioral manifestations as motricitycontrol, reward signaling in behavioral learning, motivation and pathologicalconditions, such as Parkinson's Disease and schizophrenia. Interestingly, many of themorphological bases of these neural disturbance remain unknown. Considering therelevance of mesencephalic dopaminergic nuclei, the aim of this research is tocharacterize morphologically the dopaminergic nuclei (clusters A8, A9 and A10) of themidbrain of the bat (Artibeus planirostris). The Artibeus planirostris is a common bat inRio Grande do Norte. Ten animals were used in this research. The animals wereanesthetized, perfused, and the brain was removed from the skull. After dehydration insucrose, the brain was underwent microtomy. Saggital and coronal sections wereobtained and collected in six separate series. The series were Nissl-stained to identifythe cytoarchitectonic boundaries and the other series were subjected toimmunohistochemistry for TH. After cytoarchitectonic analysis and TH+ cellsidentification was possible to establish the anatomical boundaries of the nuclei, as wellas the subdivisions of three of the midbrain dopaminergic nuclei. The SNc is the mostrostral nucleus observed in the midbrain and is identified throughout the rostrocaudalextension of the midbrain. The VTA neurons were seen immediately caudal to the SNcappearance. The RRF neurons were observed just in the caudal levels of the midbrain.The SNc in Artibeus planirostris shows a particular feature, the tail of the SNc. The tailhave been described just in two other studied species. The present work shows aparticular variation in the organizational morphology of the SNc in the artibeus andcontribute to understand the phylogenetic routes by which the dopaminergic system hasevolved.

Simulazione della bradicinesia in soggetti parkinsoniani attraverso modello neurale

I Gangli della Base svolgono un ruolo molto importante nel movimento volontario, ovvero nel meccanismo di azione-selezione, e la loro influenza è evidente soprattutto in alcune patologie che ancora ad oggi sono in fase di studio: una di queste è il Morbo di Parkinson. I Gangli della Base comprendono quattro formazioni nervose: lo striato, il globus pallidus, la substantia nigra e il nucleo subtalamico: essi ricevono le principali afferenze dalla corteccia cerebrale ed inviano le principali efferenze al tronco dell’encefalo, e, per mezzo del talamo, alle corteccia prefrontale, premotoria e motrice. A differenza della maggior parte delle altre componenti dei sistemi motori, i Gangli della Base non stabiliscono direttamente né connessioni afferenti, né efferenti con il midollo spinale. Il compito principale svolto dai Gangli dDella Base è la selezione di un’azione: esso permette ad un’azione di essere selezionata rispetto ad un’altra, che in questo modo viene inibita. La descrizione dell’anatomia, dei meccanismi fisiologici e del Morbo di Parkinson è trattata nel Capitolo 1. In questo elaborato è utilizzato il modello computazionale di Mauro Ursino e Chiara Baston, che sarà illustrato dettagliatamente nel Capitolo 2, riguardante il meccanismo di azione-selezione svolto dai Gangli della Base. E’ descritto un sistema di valutazione di un paziente parkinsoniano, il tapping test: esso consiste in un movimento alternato del dito e ad oggi risulta essere uno dei metodi più semplici per ottenere informazioni sulla gravità della bradicinesia. L’obiettivo di questo lavoro è quello di comprendere, tramite l’analisi di simulazioni effettuate per mezzo del modello computazionale di Mauro Ursino e Chiara Baston, come la frequenza di tapping dipenda dal variare di alcuni parametri delle equazioni del modello: gli effetti dovuti alla variazione di un singolo parametro o più di uno, saranno mostrati nel Capitolo 3.

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.