Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology.
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The data we report in this study concern the types, location, numbers, forms, and composition of microscopic huntingtin aggregates in brain tissues from humans with different grades of Huntington's disease (HD). We have developed a fusion protein antibody against the first 256 amino acids that preferentially recognizes aggregated huntingtin and labels many more aggregates in neuronal nuclei, perikarya, and processes in human brain than have been described previously. Using this antibody and human brain tissue ranging from presymptomatic to grade 4, we have compared the numbers and locations of nuclear and neuropil aggregates with the known patterns of neuronal death in HD. We show that neuropil aggregates are much more common than nuclear aggregates and can be present in large numbers before the onset of clinical symptoms. There are also many more aggregates in cortex than in striatum, where they are actually uncommon. Although the striatum is the most affected region in HD, only 1-4% of striatal neurons in all grades of HD have nuclear aggregates. Neuropil aggregates, which we have identified by electron microscopy to occur in dendrites and dendritic spines, could play a role in the known dendritic pathology that occurs in HD. Aggregates increase in size in advanced grades, suggesting that they may persist in neurons that are more likely to survive. Ubiquitination is apparent in only a subset of aggregates, suggesting that ubiquitin-mediated proteolysis of aggregates may be late or variable. (+info)
Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice.
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How aggregates of polyglutamine proteins are involved in the neurological symptoms of glutamine repeat diseases is unknown. We show that huntingtin aggregates are present in the neuronal processes of transgenic mice that express exon 1 of the Huntington's disease (HD) gene. Unlike aggregates in the nucleus, these neuropil aggregates are usually smaller and are not ubiquitinated. Electron microscopy reveals many neuropil aggregates in axons and axon terminals. Huntingtin aggregates in the axon terminal are co-localized with some synaptic vesicles, implying that they may affect synaptic transmission and neuronal communication. The formation of neuropil aggregates is highly correlated with the development of neurological symptoms. The present study raises the possibility that neuropil aggregates may cause a dysfunction in neuronal communication and con-tribute to the neurological symptoms of HD. (+info)
Nitric oxide in the retinotectal system: a signal but not a retrograde messenger during map refinement and segregation.
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The role of nitric oxide (NO) as a mediator of synaptic plasticity is controversial in both the adult and developing brain. NO generation appears to be necessary for some types of NMDA receptor-dependent synaptic plasticity during development but not for others. Our previous work using several NO donors revealed that Xenopus laevis retinal ganglion cell axons stop growing in response to NO exposure. We demonstrate here that the same response occurs in tectal neuron processes bathed in the NO donor S-nitrosocysteine (SNOC) and in RGC growth cones to which SNOC is very locally applied. We show that NO synthase (NOS) activity is present in the Rana pipiens optic tectum throughout development in a dispersed subpopulation of tectal neurons, although effects of NO on synaptic function in a Rana pipiens tectal slice were varied. We chronically inhibited NOS in doubly innervated Rana tadpole optic tecta using L-N(G)-nitroarginine methyl ester in Elvax. Despite significant NOS inhibition as measured biochemically, eye-specific stripes remained normally segregated. This suggests that NOS activity is not downstream of NMDA receptor activation during retinotectal synaptic competition because NMDA receptor activation is necessary for segregation of retinal afferents into ocular dominance stripes in the doubly innervated tadpole optic tectum. We conclude that NO has some signaling function in the retinotectal pathway, but this function is not critical to the mechanism that refines the projection and causes eye-specific stripes. (+info)
Evolution, discovery, and interpretations of arthropod mushroom bodies.
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Mushroom bodies are prominent neuropils found in annelids and in all arthropod groups except crustaceans. First explicitly identified in 1850, the mushroom bodies differ in size and complexity between taxa, as well as between different castes of a single species of social insect. These differences led some early biologists to suggest that the mushroom bodies endow an arthropod with intelligence or the ability to execute voluntary actions, as opposed to innate behaviors. Recent physiological studies and mutant analyses have led to divergent interpretations. One interpretation is that the mushroom bodies conditionally relay to higher protocerebral centers information about sensory stimuli and the context in which they occur. Another interpretation is that they play a central role in learning and memory. Anatomical studies suggest that arthropod mushroom bodies are predominately associated with olfactory pathways except in phylogenetically basal insects. The prominent olfactory input to the mushroom body calyces in more recent insect orders is an acquired character. An overview of the history of research on the mushroom bodies, as well as comparative and evolutionary considerations, provides a conceptual framework for discussing the roles of these neuropils. (+info)
Tripartite mushroom body architecture revealed by antigenic markers.
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We have explored the organization of the axonal lobes in Drosophila mushroom bodies by using a panel of immunohistochemical markers. These markers consist of antibodies to eight proteins expressed preferentially in the mushroom bodies: DAMB, DCO, DRK, FASII, LEO, OAMB, PKA RII, and RUT. Previous to this work, four axonal lobes, two projecting dorsally (alpha and alpha') and two medially (beta and gamma), had been described in Drosophila mushroom bodies. However, our analysis of immunohistochemically stained frontal and sagittal sections of the brain revealed three medially projecting lobes. The newly distinguished lobe, which we term beta', lies along the dorsal surface of beta, just posterior to gamma. In addition to resolving a fifth lobe, our studies revealed that there are specific lobe sets defined by equivalent marker expression levels. These sets are (1) the alpha and beta lobes, (2) the alpha' and beta' lobes, and (3) the gamma lobe and heel (a lateral projection formed by a hairpin turn of some of the peduncle fibers). All of the markers we have examined are consistent with these three sets. Previous Golgi studies demonstrate that each mushroom body cell projects one axon that branches into a dorsal lobe and a medial lobe, or one unbranched axon that projects medially. Taken together with the lobe sets listed above, we propose that there are three major projection configurations of mushroom body cell axons: (1) one branch in the alpha and one in the beta lobe, (2) one branch in the alpha' and one in the beta' lobe, and (3) one unbranched axon projecting to the heel and the gamma lobe. The fact that these neuron types exhibit differential expression levels of a number of mushroom body genes suggests that they may have corresponding functional differences. These functions may be conserved in the larvae, as several of these genes were expressed in larval and embryonic mushroom bodies as well. The basic mushroom body structure, including the denritic calyx, peduncle, and lobes, was already visible by the late stages of embryogenesis. With new insights into mushroom body organization, and the characterization of markers for developing mushroom bodies, we are beginning to understand how these structures form and function. (+info)
The organization of extrinsic neurons and their implications in the functional roles of the mushroom bodies in Drosophila melanogaster Meigen.
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Although the importance of the Drosophila mushroom body in olfactory learning and memory has been stressed, virtually nothing is known about the brain regions to which it is connected. Using Golgi and GAL4-UAS techniques, we performed the first systematic attempt to reveal the anatomy of its extrinsic neurons. A novel presynaptic reporter construct, UAS-neuronal synaptobrevin-green fluorescent protein (n-syb-GFP), was used to reveal the direction of information in the GAL4-labeled neurons. Our results showed that the main target of the output neurons from the mushroom body lobes is the anterior part of the inferior medial, superior medial, and superior lateral protocerebrum. The lobes also receive afferents from these neuropils. The lack of major output projections directly to the deutocerebrum's premotor pathways discourages the view that the role of the mushroom body may be that of an immediate modifier of behavior. Our data, as well as a critical evaluation of the literature, suggest that the mushroom body may not by itself be a "center" for learning and memory, but that it can equally be considered as a preprocessor of olfactory signals en route to "higher" protocerebral regions. (+info)
Immunocytochemical mapping of an RDL-like GABA receptor subunit and of GABA in brain structures related to learning and memory in the cricket Acheta domesticus.
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The distribution of putative RDL-like GABA receptors and of gamma-aminobutyric acid (GABA) in the brain of the adult house cricket Acheta domesticus was studied using specific antisera. Special attention was given to brain structures known to be related to learning and memory. The main immunostaining for the RDL-like GABA receptor was observed in mushroom bodies, in particular the upper part of mushroom body peduncle and the two arms of the posterior calyx. Weaker immunostaining was detected in the distal part of the peduncle and in the alpha and beta lobes. The dorso- and ventrolateral protocerebrum neuropils appeared rich in RDL-like GABA receptors. Staining was also detected in the glomeruli of the antennal lobe, as well as in the ellipsoid body of the central complex. Many neurons clustered in groups exhibit GABA-like immunoreactivity. Tracts that were strongly immunostained innervated both the calyces and the lobes of mushroom bodies. The glomeruli of the antennal lobe, the ellipsoid body, as well as neuropils of the dorso- and ventrolateral protocerebrum were also rich in GABA-like immunoreactivity. The data demonstrated a good correlation between the distribution of the GABA-like and of the RDL-like GABA receptor immunoreactivity. The prominent distribution of RDL-like GABA receptor subunits, in particular areas of mushroom bodies and antennal lobes, underlines the importance of inhibitory signals in information processing in these major integrative centers of the insect brain. (+info)
Early development of mushroom bodies in the brain of the honeybee Apis mellifera as revealed by BrdU incorporation and ablation experiments.
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In the honeybee the mushroom bodies are prominent neuropil structures arranged as pairs in the dorsal protocerebrum of the brain. Each mushroom body is composed of a medial and a lateral subunit. To understand their development, the proliferation pattern of mushroom body intrinsic cells, the Kenyon cells, were examined during larval and pupal stages using the bromodeoxyuridine (BrdU) technique and chemical ablation with hydroxyurea. By larval stage 1, approximately 40 neuroblasts are located in the periphery of the protocerebrum. Many of these stem cells divide asymmetrically to produce a chain of ganglion mother cells. Kenyon cell precursors underly a different proliferation pattern. With the beginning of larval stage 3, they are arranged in two large distinct cell clusters in each side of the brain. BrdU incorporation into newly synthesized DNA and its immunohistochemical detection show high mitotic activity in these cell clusters that lasts until mid-pupal stages. The uniform diameter of cells, the homogeneous distribution of BrdU-labeled nuclei, and the presence of equally dividing cells in these clusters indicate symmetrical cell divisions of Kenyon cell precursors. Hydroxyurea applied to stage 1 larvae caused the selective ablation of mushroom bodies. Within these animals a variety of defects were observed. In the majority of brains exhibiting mushroom body defects, either one mushroom body subunit on one or on both sides, or three or four subunits (e.g., complete mushroom body ablation) were missing. In contrast, partial ablation of mushroom body subunits resulting in small Kenyon cell clusters and peduncles was observed very rarely. These findings indicate that hydroxyurea applied during larval stage 1 selectively deletes Kenyon stem cells. The results also show that each mushroom body subunit originates from a very small number of stem cells and develops independently of its neighboring subunit. (+info)