Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

Pharmacological studies of antidepressants and atypical antipsychotics have suggested a role of dopamine and serotonin signaling in depression. However, depressive symptoms and treatment effects are difficult to explain based simply on brain‐wide decrease or increase in the concentrations of these molecules. Recent animal studies using advanced neuronal manipulation and observation techniques have revealed detailed dopamine and serotonin dynamics that regulate diverse aspects of motivation‐related behavior. Dopamine and serotonin transiently modulate moment‐to‐moment behavior at timescales ranging from sub‐second to minutes and also produce persistent effects, such as reward‐related learning and stress responses that last longer than several days. Transient and sustained effects often exhibit specific roles depending on the projection sites, where distinct synaptic and cellular mechanisms are required to process the neurotransmitters for each transient and sustained timescale. Therefore, it appears that specific aspects of motivation‐related behavior are regulated by distinct synaptic and cellular mechanisms in specific brain regions that underlie the transient and sustained effects of dopamine and serotonin signaling. Recent clinical studies have implied that subjects with depressive symptoms show impaired transient and sustained signaling functions; moreover, they exhibit heterogeneity in depressive symptoms and neuronal dysfunction. Depressive symptoms may be explained by the dysfunction of each transient and sustained signaling mechanism, and distinct patterns of impairment in the relevant mechanisms may explain the heterogeneity of symptoms. Thus, detailed understanding of dopamine and serotonin signaling may provide new insight into depressive symptoms.     

Polyglucosan bodies in the central nervous system of a fox.

Polyglucosan bodies (PGB) in the central nervous system of an old male fox, Vulpes vulpes japonica, without neurological signs were examined by light and electron microscopy, lectin histochemistry and immunohistochemistry. Fox PGB were round, slightly-basophilic and PAS-positive structures. Most of the bodies were situated free in the neuropil. Electron microscopically, fox PGB were composed mainly of branching filaments and electron-dense material. Lectin histochemistry revealed that fox PGB contained mannose and galactose in addition to glucose. Fox PGB were immunoreactive for monoclonal antibodies raised against human polyglucosan. These findings indicate that fox PGB are similar to feline ones.     

Gerstmann-Sträussler syndrome — A variant type: amyloid plaques and Alzheimer's neurofibrillary tangles in cerebral cortex

Summary This report presents a variant of Gerstmann-Sträussler syndrome (GSS). A 53-year-old female had developed slowly progressive dementia and atactic gait since the age of 45. No myoclonic jerks and periodic synchronous discharges were observed throughout the illness. The neuropathological study revealed that many amyloid plaques and widespread Alzheimer's neurofibrillary tangles (NFTs) appeared in the cerebral cortex. Characteristically, the plaques reacted with anti-prion protein and none of them reacted with anti- protein, and they were made of many components, including amyloid cores, macrophages laden with lipid granules and/or degenerated neurites. Neuropil threads were seen mainly in amyloid plaques. Moreover, plaques appeared which were confluent and laminar in arrangement in the fifth and sixth cortical layers and had a close relationship to the neuronal loss. There was no spongiform change in the cerebral cortex or cerebellum. The cerebellum was almost intact except for a few amyloid plaques. Ultrastructurally, some of the plaques simulated kuru plaques and others had many degenerated neurites possessing paired helical filaments and other accumulated organelles. GSS has been proposed to include cases with progressive ataxia, dementia and massive multifocal plaques in the brain with or without cerebral spongiform changes. The case presented here is a very peculiar case of GSS. Recently, similar cases have been reported in some large families, diagnosed as familial Alzheimer's disease. These cases may be a telencephalic form with numerous NFTs of GSS.     

Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia

We report here that loss of the Sprouty2 gene (also known as Spry2) in mice resulted in enteric nerve hyperplasia, which led to esophageal achalasia and intestinal pseudo-obstruction. Glial cell line-derived neurotrophic factor (GDNF) induced hyperactivation of ERK and Akt in enteric nerve cells. Anti-GDNF antibody administration corrected nerve hyperplasia in Sprouty2-deficient mice. We show Sprouty2 to be a negative regulator of GDNF for the neonatal development or survival of enteric nerve cells.     

Molecular mechanism for connective tissue destruction by dipeptidyl aminopeptidase IV produced by the periodontal pathogen Porphyromonas gingivalis

Porphyromonas gingivalis is a pathogen associated with adult periodontitis. It produces dipeptidyl aminopeptidase IV (DPPIV), which may act as a virulence factor by contributing to the degradation of connective tissue. We investigated the molecular mechanism by which DPPIV contributes to the destruction of connective tissue. DPPIV itself did not show gelatinase or collagenase activity toward human type I collagen, but it promoted the activity of the host-derived matrix metalloproteinase 2 (MMP-2) (gelatinase) and MMP-1 (collagenase). DPPIV bound to fibronectin and mediated the adhesion of P. gingivalis to fibronectin. Mutant DPPIV with catalytic Ser mutagenized to Ala (DPPSA) did not accelerate the degradation of collagen and gelatin by MMPs but retained fibronectin-binding activity. The adhesion of human gingival fibroblasts and NIH 3T3 cells to fibronectin was inhibited by DPPIV. Strain 4351ADPPSA exhibited an intermediate level of virulence in mice, between that of the strain expressing wild-type DPPIV (4351ADPP) and that of the strain harboring only the plasmid vector (4351AVEC). It is suggested that both activity promoting the degradation of collagen and gelatin and binding to fibronectin are required for full virulence. These results reveal novel biological functions of DPPIV and suggest a pathological role in the progression of periodontitis.     

Histopathological studies on virulence of dipeptidyl aminopeptidase IV (DPPIV) of Porphyromonas gingivalis in a mouse abscess model: use of a DPPIV-deficient mutant

To elucidate the role of dipeptidyl aminopeptidase IV (DPPIV) in the virulence of Porphyromonas gingivalis, mice were infected with either a wild-type strain or a DPPIV-deficient mutant using an abscess model. Histopathological analysis of the resulting lesions indicated that DPPIV participates in virulence through the destruction of connective tissue and the less effective mobilization of inflammatory cells.     

Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839)

Gefitinib (Iressa, ZD1839), an inhibitor of epidermal growth factor receptor-tyrosine kinase, has shown potent anti-tumor effects and improved symptoms and quality-of-life of a subset of patients with advanced non-small cell lung cancer (NSCLC). However, a large portion of the patients showed no effect to this agent. To establish a method to predict the response of NSCLC patients to gefitinib, we used a genome-wide cDNA microarray to analyze 33 biopsy samples of advanced NSCLC from patients who had been treated with an identical protocol of second to seventh line gefitinib monotherapy. We identified 51 genes whose expression differed significantly between seven responders and 10 non-responders to the drug. We selected the 12 genes that showed the most significant differences to establish a numerical scoring system (GRS, gefitinib response score), for predicting response to gefitinib treatment. The GRS system clearly separated the two groups without any overlap, and accurately predicted responses to the drug in 16 additional NSCLC cases. The system was further validated by the semi-quantitative RT-PCR, immunohistochemistry and ELISA for serological test. Moreover, we proved that the anti-apoptotic activity of amphiregulin, a protein that was significantly over-expressed in non-responders but undetectable in responders, leads to resistance of NSCLC cells to gefitinib in vitro. Our results suggested that sensitivity of a given NSCLC to gefitinib can be predicted according to expression levels of a defined set of genes that may biologically affect drug sensitivity and survival of lung cancer cells. Our scoring system might eventually lead to achievement of personalized therapy for NSCLC patients.     

Morphological investigations on axonal swellings and spheroids in various human diseases

Summary Axonal swellings and spheroids in various human diseases were studied by light and electron microscopy. 4 cases of infantile neuroaxonal dystrophy, 2 of degenerative diseases, 2 brain tumors and 3 of cerebrovascular disease were examined.Ultrastructurally most spheroids in infantile neuroaxonal dystrophy consisted of interconnected tubules, stacked membranotubular profiles, alternating layered membranes and accumulations of neurofilaments. Combinations of these four constituents were seen only in infantile neuroaxonal dystrophy. Torpedos (fusiform swelling of the axon of a Purkinje cell) consisted exclusively of neurofilaments. Spheroids in case 6 (mental retardation) and 7 (atypical teratoma) consisted of interwoven skeins of neurofilaments and grouped mitochondria. Spheroids in case 8 (demyelination) and 9 (cerebrovascular disease) consisted of packed complex bodies and mitochondria. Spheroids in cases 10 and 11 (cerebrovascular disease) consisted of degenerating organelles only. The morphological differences between cases 9, 10 and 11 probably depends on the severity and timing of the cerebral injury.Most spheroids show similar histological and histochemical properties, but ultrastructural study may give some clue to the origin of the bodies.     

Enamel mineralization and an initial crystalline phase

In this communication, we summarized our recent experimental approaches to an unsettled issue, i.e., the nature and role of an acidic precursor in enamel mineralization. The objectives we specially focused our attention on are: the composition, structure and high resolution images of enamel crystals at various developmental stages, thermodynamic and kinetic consideration of octacalcium phosphate (OCP) vs hydroxyapatite (HA) precipitation in physiological media simulating the enamel fluid, reversible changes in the composition and structure of OCP, effects of fluoride at low concentrations and enamel proteins on OCP hydrolysis, and adsorption of enamel proteins onto OCP and fluoridated hydrolysates at neutral pH and room temperature. On the basis of all experimental evidence, we propose that enamel crystal growth comprises two events: the two-dimensional growth of an OCP-like precursor in a narrow outermost zone adjacent to the ameloblasts and the subsequent overgrowth of apatite units on the template under discrete fluid environment in the underlying region distant from the cell layer. The experimental data also support the concept that the whole process of enamel mineralization is modulated substantially through interaction between enamel proteins and crystals including the acidic precursor.