Development of the cerebellum and cerebellar neural circuits

The cerebellum, a structure derived from the dorsal part of the most anterior hindbrain, is important for integrating sensory perception and motor control. While the structure and development of the cerebellum have been analyzed most extensively in mammals,recent studies have shown that the anatomy and development of the cerebellum is conserved between mammals and bony fish (teleost) species, including zebrafish. In the mammalian and teleost cerebellum,Purkinje and granule cells serve, respectively, as the major GABAergic and glutamatergic neurons. Purkinje cells originate in the ventricular zone (VZ), and receive inputs from climbing fibers. Granule cells originate in the upper rhombic lip (URL) and receive inputs from mossy fibers. Thus, the teleost cerebellum shares many features with the cerebellum of other vertebrates, and isa good model system for studying cerebellar function and development. The teleost cerebellum also has features that are specific to teleosts or have not been elucidated in mammals, including eurydendroid cells and adult neurogenesis. Furthermore, the neural circuitry in part of the optic tectum and the dorsal hindbrain closely resembles the circuitry of the teleost cerebellum; hence,these are called cerebellum-like structures. Here we describe the anatomy and development of cerebellar neurons and their circuitry, and discuss the possible roles of the cerebellum and cerebellum-like structures in behavior and higher cognitive functions. We also consider the potential use of genetics and novel techniques for studying the cerebellum in zebrafish.     

Combined Metaheuristic Algorithm and Radiomics Strategy for the Analysis of Neuroanatomical Structures in Schizophrenia and Schizoaffective Disorders

ObjectivesSchizophrenia (SZ) is the most chronic disabling psychotic brain disorder. It is characterized by delusions and auditory hallucinations, as well as impairments in memory. Schizoaffective (SA) signs are co-morbid with SZ and are characterized by symptoms of SZ and mood disorder. Various researches suggest that SZ and SA share a number of equally severe cognitive deficits, but the pathophysiology has not yet been addressed in a comprehensive way. In this work, the heterogeneity in whole brain, ventricle and cerebellum region from psychotic MR brain images is examined using Machine learning and radiomic features.Materials and methodsT1 weighted MR brain images are obtained from Schizconnect database for the analysis. The shape prior level set method is used to segment the ventricle and cerebellum structures. The radiomic features which include shape and texture are extracted from these regions to discriminate the SZ and SA subjects. The performance of these features is evaluated with Binary Particle Swarm Optimization (BPSO) based Fuzzy Support Vector Machine (FSVM) classifier.ResultsThe shape constrained Level Set method is able to better segment ventricles and cerebellum regions from the images. The significant features that are extracted from whole brain, ventricle and cerebellum are identified by the BPSO based FSVM. The combination of radiomic features extracted from cerebellum region achieved high classification accuracy (90.09%) using metaheuristic algorithm. The extracted features from cerebellum are correlated with PANSS score. The causal analysis shows that there is an association been the tissue texture variation in identifying the disease severity. The symmetry analysis shows that left brain mean area is larger than the right side area. In particular SA has low cerebellum area compared to SZ. The radiomic features such as Hermite, Laws and tensor extracted from the left cerebellum show a significant texture variation in all the considered subjects (p<0.0001).ConclusionsThe results are clinically relevant in discriminating the pattern change in the structure, hence this biomarker and frame work could be used for the severity study of psychotic disorders.     

Structural Evidence for Plastid Inclusions as a Possible 'Sealing' Mechanism in the Phloem of Monocotyledons

Sieve elements in monocotyledons possess unique plastids. Structuralevidence indicates that when mature sieve-tube members are mechanicallyperturbed the plastids release proteinaceous, quasi –crystalline inclusions. The inclusions become lodged in sieve-platepores and appear to seal portions of phloem sieve tubes.     

The intrapopulation structure of the northern fur seal (<Emphasis Type="Italic">Callorhinus ursinus</Emphasis> L.) on Tyuleniy Island during the post-depression years (1993–2009)

The dynamics of the intrapopulation parameters of the northern fur seal on Tyuleniy Island are considered for the period when their population was recovering after a depression. Almost all its characteristics, except for those dependent on density, showed a positive tendency. Dynamic processes in the northern fur seal populations in the post-depression years are found to be based on the demographic transformation of the community, which closely correlates with its qualitative changes, predetermined by the dynamics of its age structure. The process of complete reversal in the state of the fur seal population, which is distinguished by peak values at the depression and in the years of prosperity, is approximately equal to the life span of one generation of these animals.     

Amino acid sequence of the triple-helical domain of human collagen type VI

The complete amino acid sequence of the triple-helical domain of human collagen VI was deduced from sequences of appropriate cDNA clones and confirmed to about 50% by Edman degradation of tryptic peptides. This domain consists of three different peptide segments containing some 335-336 amino acid residues originating from central portions of the alpha 1 (VI), alpha 2(VI), and alpha 3(VI) chains, respectively. Sequence identity in the X/Y positions of the Gly-X-Y repeats is rather low (10-15%) between the chains. Peculiar features of these sequences include 3 cysteine residues about 50 (alpha 3(VI)) and 89 (alpha 1(VI), alpha 2(VI)) residues away from the N-terminus and several Gly-X-Y interruptions clustered in the C-terminal two-thirds of the triple helix. These structures are presumably required for cross-linking collagen VI oligomers and for super-coiling of triple helices in the dimers. Other features include 11 Arg-Gly-Asp sequences, some of which are likely to be used as cell-binding sites, and four Asn-X-Thr sequences, allowing N-linked glycosylation along the triple helix. Junctional areas close to the helix contain short, cysteine-rich segments which may seal the triple-helical domain through disulfide bond formation, endowing it with high stability. These features, together with a low sequence homology to fiber-forming and basement-membrane collagens, document the unique character of collagen VI, whose triple helix is specifically adjusted for forming microfibrils in tissues.     

Phospholipids and thromboplastins in various sections of the brain normally and in excitation states]

The level of the neutral and acid phospholipids and thromboplastic activity of various portions of the rabbit brain were studied under normal conditions and following adrenaline stimulation. The level of total phospholipids, neutral phospholipids, and the ratio of neutral to acid phospholipids, thromboplastic activity and its increase following incubation of homogenates of the brain tissue of normal and adrenaline-treated animals were found to be distributed in the following descending order: the medulla oblongata, cerebellum, cerebral hemispheres. Adrenaline decreased the thromboplastic activity and induced changes in the neutral and acid phospholipid levels. The role of phospholipids in the biosynthesis of various components of the blood clotting and anticoagulant systems are discussed.     

Structure of the neocortex of the Baikal ringed seal (Pusa sibirica Gm.)]

The sulci and gyri of the neocortex, as well as cyto-, synaptoarchitectonics and neuronal composition of the sensomotor (brain area) have been studied in the Baikal ringed seal. The structure of the sulci and gyri have been found to be similar to that in carnivores. The following specific features have been revealed in the brain of this endemic species: a thick layer I, presence of giant pyramidal cells in the layer III, large mitochondria in the presynaptic parts and dendrites. The results obtained are discussed concerning adaptation to semiaqueous way of life and to diving.     

Does the common topknot Zeugopterus punctatus (Teleosteii: Pleuronectiformes: Scophthalmidae) use a novel Venturi-effect attachment mechanism? A testable hypothesis

Common topknots (Zeugopterus punctatus) attach to vertical rock surfaces and overhangs. It has been speculated that attachment is by a suction cup, with the median (anal, dorsal) fins providing a peripheral seal. Here the authors propose that the attachment is actually based on a Venturi effect. The rear portions of the median fins continually move in a fan-like fashion (at c. 4 cycles per second). This movement produces a tailward fluid flow that ventilates the shallow underbody space between the fish and its rocky substratum. The anterior portions of the median fins seal the space laterally, but the space is open anterior (beneath the raised head) and posterior to the sea. The mid-underbody space likely has a lower cross-sectional area than does the front intake or rear exit, so flow should be faster (and pressure lower) within it than outside, thus providing pressure gradient suction. Topknots attach to rough and heavily biofouled surfaces, presumably because the high numbers of fin rays and their associated membranes plus fine muscle control allow effective sealing. The attachment ability is shared by all members of the flatfish tribe Phrynorhombini; it can be related to anatomical peculiarities and constitutes a probable synapomorphy for this clade.     

The metamorphosis of the developing cerebellar microcircuit

The cerebellar cortical circuit with its organized and repetitive structure provides an excellent model system for studying how brain circuits are formed during development. The emergence of the mature brain requires that appropriate synaptic connections are formed and refined, which in the rodent cerebellum occurs primarily during the first three postnatal weeks. Developing circuits typically differ substantially from their mature counterparts, which suggests that development may not simply involve synaptic refinement, but rather involves restructuring of key synaptic components and network connections, in a manner reminiscent of metamorphosis. Here, we discuss recent evidence that, taken together, suggests that transient features of developing cerebellar synapses may act to coordinate network activity, and thereby shape the development of the cerebellar microcircuit.     

Domains in the fibrinogen molecule

Intramolecular melting of fibrinogen and its degradation products has been studied by a scanning microcalorimetric method in various solution environments (especially variations in pH), and inferences are made about the features that seemed to be independently folding segments (“domains”), as evidenced by their independent resistance to thermal denaturation. It was shown that there are 12 more or less independent co-operative regions of ordered compact structure in fibrinogen, which can be considered as structural domains of this macromolecule. Of these 12 domains, two are in the central part of the molecule, corresponding to the E fragment, four are in each terminal part, corresponding to the D fragments, and two are formed by the carboxy-terminal portions of the α-chains. All fibrinogen domains can be divided into two groups according to their thermodynamic properties: (1) thermolabile domains, to which belong three domains from each terminal part of the molecule and the domains formed by the carboxy-terminal portions of the α-chains; (2) thermostable domains, to which belong both domains from the central part and one domain from each terminal part of the molecule. This division seems to reflect the structural differences between the domains.     

Histology and histochemistry of the seal ovaries and the age-related changes in the ovaries of the Greenland seal]

Histological and histochemical methods were used to study the ovaries of Greenland seal (Pagophoca groenlandica) from birth-time up to 30 years of age and mature females of Phoca vitulina and Erignathus barbatus. The ovary of the new-born Greenland seal has fetal medullary substance which is a provisory endocrinous gland producing not only sex hormones but also corticosteron. In other species of seals the intestinal cells of the medullary substance are the equivalent of this gland. Within 3-4 weeks after birth the reduction of the fetal medullary substance is completed, it is substituted by the connective tissue and the ovary acquires its typical structure. The rest of the fetal medullary substance is in the depth of the cortex and near the infundibulum of the ovary as lipofuscincontaining cells. When the maturation period approaches, the process of the follicle atresia regularly changes: the epithelium dies quicker, and the multiplication of intestinal cells increases. The ovaries of seals are rich in interstitial cells. Their amount cyclically changes. The cells producing steroid hormones always well hydrolize AS naphthyl-phosphates, the reaction with glycerophosphate is more variable. The connective tissue is poor in acid mucopolysaccharides, its amorphous substance in the ovary cortex is rich in protein. Senile changes of the ovary are noticed in the seal beginning from 20 years of age.     

Drainage of the prelymphatics of the brain via the adventitia of the vertebral artery

Carbon particles injected into the cortex of the cerebellum of the rat were found in the Virchow-Robin spaces of the adjacent capillaries, and in the adventitia of the cerebellar artery, basilar artery and vertebral artery--both inside and outside the skull. They were also found in some portions of the deeper cervical lymph nodes. However, while tracers injected into the cerebral hemispheres are drained via the tissue channels in the adventitia of the internal carotid arteries, tracers injected into the cerebellar hemispheres are drained via those of the vertebral arteries.     

Zonal distribution of Purkinje cells in the zebrafish cerebellum: analysis by means of a specific monoclonal antibody

We have isolated a monoclonal antibody that recognizes a 42-kDa protein from adult zebrafish brain. The antibody stains the typical drop-shaped perikaryon of Purkinje cells and their dendrites. The cerebellum of teleosts has complex features. It is composed of three parts; the valvula cerebelli (Va), the corpus cerebelli (CCe), and the crista cerebellaris (CC). In higher vertebrates, the molecular layer is always found as the most outer layer of the cerebellum, but in teleosts, some of the granular cells are located on the surface of the Va. In higher vertebrates, the boundary between the granular and molecular layers always contains Purkinje cells, but this does not occur in teleosts. The Purkinje cells are found only in a part of the boundary in Va. We have found that the layer containing Purkinje cells forms a continuous zone in the cerebellum in the zebrafish. The complex structure of the cerebellum is more easily understood with the aid of the concept of a "Purkinje zone". The Purkinje zone starts at the caudal end of Val (lateral division of Va), turns at the edge of Va toward Vam (medial division of Va), connects to CCe, and ends at the bottom of CCe. The dendrites are found only on one side of the zone. The dendrites of the Purkinje cells in Vam are planar and are packed regularly, similar to those of higher vertebrates. However, the dendrites in Val and the posterior part of CCe are not planar and are irregularly packed.     

A Histochemical Study of the Distribution of β-Hydroxybutyrate Dehydrogenase in Developing Rat Cerebellum

The distribution of beta-hydroxybutyrate dehydrogenase (3-hydroxybutyrate dehydrogenase, EC 1.1.1.30) in the developing rat cerebellum has been determined using a histochemical method. Staining of Purkinje cells, particularly the soma, was seen at all ages examined. Intense staining of the proximal portions of Purkinje dendrites was noted at 8-11 days postnatally, with less prominent staining of Purkinje dendrites and surrounding structures of the molecular layer seen at later times. Development of glomeruli in the granule cell layer could also be observed due to the intense staining of these structures. (Although noncerebellar structures were not the focus of this study, intense staining of the choroid plexus of the fourth ventricle was also noted.) the transient external germinal layer of the cerebellum did not show appreciable staining. Since beta-hydroxybutyrate dehydrogenase is required for ketone body metabolism, the apparent low level of this enzyme in the external germinal layer suggests that the cells of this layer are not particularly well adapted for utilization of ketone bodies. Thus these results do not provide support for the suggestion that ketone bodies may serve as major substrates for energy metabolism in the external germinal layer of the developing cerebellum. Indeed, the rather restricted distribution of this enzyme in both developing and mature cerebellum (and presumably elsewhere in brain) suggests that ketone body metabolism may be largely confined to relatively few specific cellular compartments.     

Structure of the radially asymmetrical uncalcified region of the teeth of the red-backed salamander,Plethodon cinereus (Amphibia,Plethodontidae)

The teeth of the adult plethodontid salamander, Plethodon cinereus, were examined by light and electron microscopy with emphasis on the ringlike zone of uncalcified dentin that divides the calcified portion of each tooth into a proximal pedestal and a distal apex. The uncalcified region displays radial asymmetry, forming an integral part of the posterior wall of the tooth but bulging into the pulp cavity anteriorly, thus forming a hingelike structure. All portions of the dentin, including the uncalcified region, are composed predominantly of collagenous fibers but lack elastin. In scanning electron micrographs of teeth from which the oral mucosa has been removed, the location of the anterior uncalcified hinge is marked externally by a notch-like articulation of the apex and pedestal. Sites of transition between calcified and uncalcified areas of the dentin show no special modifications in transmission electron micrographs, but collagenous fibers in calcified portions are associated with more electron-dense amorphous material than are those in the uncalcified region. Odontoblasts associated with the uncalcified region possess ultrastructural features closely resembling those of odontoblasts found in calcified areas. The uncalcified region seems to afford the teeth a certain degree of flexibility, and the asymmetry of the region appears to allow the teeth to flex only in a posterior direction, thus facilitating the entry of living prey but hindering its escape. The uncalcified region also seems to permit the apex of a tooth to break away from its pedestal without damage to underlying bone.     

Inshore associations of the spotted seal (<Emphasis Type="Italic">Phoca largha</Emphasis> Pallas, 1811)

Spotted seal Phoca largha is considered typically pagophilic species, but in the Peter the Great Bay of the Sea of Japan it is closely associated with specific coastal sites all the year round. Four types of largha inshore associations (preliminary, breeding, molting, and rehabilitative) invariably connected with certain types of haulout sites are cyclically formed on the islands of the bay. Principles of formation and features of functioning, as well as structure, specificity of dynamics, the degree of aggregation and behavior features of each type of inshore associations are considered.     

Architecture of a gamma retroviral genomic RNA dimer

Retroviral genomes contain two sense-strand RNAs that are noncovalently linked at their 5' ends, forming a dimer. Establishing a structure for this dimer is an obligatory first step toward understanding the fundamental role of the dimeric RNA in retroviral biology. We developed a secondary structure model for the minimal dimerization active sequence (MiDAS) for the Moloney murine sarcoma virus in the final dimer state using selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE). In this model, two self-complementary, or palindromic, sequences (PAL1 and PAL2) form extended intermolecular duplexes of 10 and 16 base pairs, respectively. The monomeric starting state was shown previously to contain a flexible domain in which nucleotides do not form stable interactions with other parts of the RNA. In the final dimer state, portions of this initial flexible domain form stable base pairs, while previously base-paired elements lie in a new flexible domain. Thus, partially overlapping and structurally well-defined flexible domains are prominent features of both monomer and dimer states. We then used hydroxyl radical cleavage experiments to characterize the global architecture of the dimer state. Extensive regions, including portions of both PAL1 and PAL2, are occluded from solvent-based cleavage indicating that the MiDAS domain does not function simply as a collection of autonomous secondary structure elements. Instead, the retroviral dimerization domain adopts a compact architecture characterized by close packing of its constituent helices.     

Electron microscopy of the secondary structure in partially denatured rRNAs of Escherichia coli and Bacillus stearothermophilus.

Partially denatured 16S and 23S rRNAs from the thermophile Bacillus stearothermophilus show characteristic loop patterns when observed by electron microscopy. The patterns are very similar to those seen in rRNAs from Escherichia coli. At least 2 of 4 most stable interactions in 16S rRNA and 8 of 12 interactions in 23S rRNA are in common for the two species. These interactions correspond well to features of secondary structure in models inferred for rRNA from phylogenetic sequence comparisons and chemical modification studies. However, two additional large loops, enclosing large portions of the 23S rRNA, have been detected in B. stearothermophilus for the first time, and even though other loops are similar, their relative frequencies vary in the two species. Much of the variation is consistent with relative delta G degree values for putative base-paired stems at the base of different loops; but the 5'-terminal loops in 23S rRNA, for example, are unaccountably far less stable in B. stearothermophilus. Also, in general, structural features are not differentially stabilized in B. stearothermophilus; the relative stability of secondary structure in its ribosomes at elevated growth temperatures must involve interactions with ribosomal proteins or other cellular components.     

Population structure of ice-breeding seals

The development of population genetic structure in ice-breeding seal species is likely to be shaped by a combination of breeding habitat and life-history characteristics. Species that return to breed on predictable fast-ice locations are more likely to exhibit natal fidelity than pack-ice-breeding species, which in turn facilitates the development of genetic differentiation between subpopulations. Other aspects of life history such as geographically distinct vocalizations, female gregariousness, and the potential for polygynous breeding may also facilitate population structure. Based on these factors, we predicted that fast-ice-breeding seal species (the Weddell and ringed seal) would show elevated genetic differentiation compared to pack-ice-breeding species (the leopard, Ross, crabeater and bearded seals). We tested this prediction using microsatellite analysis to examine population structure of these six ice-breeding species. Our results did not support this prediction. While none of the Antarctic pack-ice species showed statistically significant population structure, the bearded seal of the Arctic pack ice showed strong differentiation between subpopulations. Again in contrast, the fast-ice-breeding Weddell seal of the Antarctic showed clear evidence for genetic differentiation while the ringed seal, breeding in similar habitat in the Arctic, did not. These results suggest that the development of population structure in ice-breeding phocid seals is a more complex outcome of the interplay of phylogenetic and ecological factors than can be predicted on the basis of breeding substrate and life-history characteristics.     

Cerebellar Integrity in the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia Continuum

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology.