PubMed Health⌕ Search

Biomedical subjects

D Yanagihara

Publications and source records attributed to D Yanagihara.

At least 19 recordsLinked to original sources

mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination.

Targeted deletion of metabotropic glutamate receptor-subtype 1 (mGluR1) gene can cause defects in development and function in the cerebellum. We introduced the mGluR1alpha transgene into mGluR1-null mutant [mGluR1 (-/-)] mice with a Purkinje cell (PC)-specific promoter. mGluR1-rescue mice showed normal cerebellar long-term depression and regression of multiple climbing fiber innervation, events significantly impaired in mGluR1 (-/-) mice. The impaired motor coordination was rescued by this transgene, in a dose-dependent manner. We propose that mGluR1 in PCs is a key molecule for normal synapse formation, synaptic plasticity, and motor control in the cerebellum.

Animals↗

A mathematical model of adaptive behavior in quadruped locomotion.

Locomotion involves repetitive movements and is often executed unconsciously and automatically. In order to achieve smooth locomotion, the coordination of the rhythms of all physical parts is important. Neurophysiological studies have related that basic rhythms are produced in the spinal network called, the central pattern generator (CPG), where some neural oscillators interact to self-organize coordinated rhythms. We present a model of the adaptation of locomotion patterns to a variable environment, and attempt to elucidate how the dynamics of locomotion pattern generation are adjusted by the environmental changes. Recent experimental results indicate that decerebrate cats have the ability to learn new gait patterns in a changed environment. In those experiments, a decerebrate cat was set on a treadmill consisting of three moving belts. This treadmill provides a periodic perturbation to each limb through variation of the speed of each belt. When the belt for the left forelimb is quickened, the decerebrate cat initially loses interlimb coordination and stability, but gradually recovers them and finally walks with a new gait. Based on the above biological facts, we propose a CPG model whose rhythmic pattern adapts to periodic perturbation from the variable environment. First, we design the oscillator interactions to generate a desired rhythmic pattern. In our model, oscillator interactions are regarded as the forces that generate the desired motion pattern. If the desired pattern has already been realized, then the interactions are equal to zero. However, this rhythmic pattern is not reproducible when there is an environmental change. Also, if we do not adjust the rhythmic dynamics, the oscillator interactions will not be zero. Therefore, in our adaptation rule, we adjust the memorized rhythmic pattern so as to minimize the oscillator interactions. This rule can describe the adaptive behavior of decerebrate cats well. Finally, we propose a mathematical framework of an adaptation in rhythmic motion. Our framework consists of three types of dynamics: environmental, rhythmic motion, and adaptation dynamics. We conclude that the time scale of adaptation dynamics should be much larger than that of rhythmic motion dynamics, and the repetition of rhythmic motions in a stable environment is important for the convergence of adaptation.

Adaptation, Physiological↗

Regulation of tie receptor expression on human endothelial cells by protein kinase C-mediated release of soluble tie.

The expression and activity of receptor tyrosine kinases (RTK) at the cell surface can be modulated by several different pathways including the proteolytic release of the extracellular domain as a soluble receptor. We investigated the regulation of tie receptor expression, an orphan RTK restricted to cells of hematopoietic and endothelial lineages, on primary human endothelial cells and a stably transfected Chinese hamster ovary (CHO) cell line. Tie was expressed in cells as a doublet of 135 and 125 kD; the 135-kD band represented mature cell surface receptor containing sialic acid and N-linked oligosaccharide residues, whereas the 125-kD band represented an intracellular pool of immature receptor. Phorbol 12-myristate 13-acetate (PMA) had dramatic effects on tie expression at the cell surface. Within 15 minutes of PMA treatment, the 135-kD band disappeared from the cell surface and was accompanied by the appearance of a 100-kD band in cell supernatants. The 100-kD band continued to accumulate in the media throughout the duration of PMA treatment during which mature tie receptor was undetectable on the cell surface by fluorescence-activated cell sorting (FACS) or in cell lysates by immunoblot analysis. Using specific antibodies, this 100-kD species was shown to be a soluble form of the tie receptor containing the extracellular domain. PMA-dependent release of soluble tie was mediated through the activation of protein kinase C (PKC); soluble tie was not released in the presence of PKC inhibitors, an inactive PMA analog, or following the downregulation of PKC through chronic PMA treatment. These results indicate that tie receptor expression on endothelial cells is regulated by the release of a soluble extracellular fragment following activation of PKC. Parallel pathways regulating c-kit, tumor necrosis factor (TNF), and colony-stimulating factor (CSF) receptor expression suggest that the release of extracellular receptor fragments represents an alternative mechanism through which cells modulate responses to growth factors and cytokines.

Animals↗

Nitric oxide plays a key role in adaptive control of locomotion in cat.

Diverse roles in cellular functions have been ascribed to nitric oxide (NO), and its involvement in induction of long-term depression in cerebellar Purkinje cells has been demonstrated. Manipulations of NO concentration or its synthesis in cerebellar tissues therefore provide a means for investigating roles of NO in cerebellar functions at both cellular and behavioral levels. We tested adaptive control of locomotion to perturbation in cats, and found that this form of motor learning was abolished by application of either an inhibitor of NO synthase or a scavenger of NO to the cerebellar cortical locomotion area. This finding supports the view that NO in the cerebellum plays a key role in motor learning.

Acclimatization↗

Activation of the erythropoietin (EPO) receptor by bivalent anti-EPO receptor antibodies.

Oligomerization of cytokine receptors including the erythropoietin (EPO) receptor has been advanced as a model for activation. If homodimerization of the EPO receptor activates it, then bivalent antibodies raised to the extracellular domain of the EPO receptor should also homodimerize and activate. Mouse monoclonal antibodies (IgG) raised to the soluble, extracellular domain of the human EPO receptor (EPOR) were found that would stimulate thymidine uptake of an human EPO-dependent cell line, UT-7/EPO. Dose response curves showed bell shapes where activity was low at low and high concentrations. Monovalent (Fab) fragments bound to the receptor but did not stimulate thymidine uptake, which indicates that two antibody binding sites are required for activation. The anti-EPOR antibodies stimulated the formation of burst forming unit erythroid colonies from human CD34(+) cells purified from peripheral blood. This indicates that homodimerization of the EPO receptor by anti-EPOR antibodies is sufficient for both proliferation and differentiation of erythroid progenitor cells and that the constraints on dimerization necessary for activation are rather loose.

Animals↗

Studies on the structure and function of glycosylated and nonglycosylated neu differentiation factors. Similarities and differences of the alpha and beta isoforms.

Comparative analyses of both glycosylated and nonglycosylated neu differentiation factor (NDF) isoforms revealed significant similarities and differences of their overall structures and functions. Biophysical analyses confirmed that all NDF isoforms are monomeric, but have an extended ellipsoidal shape in solution. All full-length NDFs are similar in secondary and tertiary structures and they contain no alpha-helix but are abundant in beta-strand structures. A small NDF fragment containing only the epidermal growth factor domain is also rich in beta-strand structures, but exhibits tertiary structure different from the long NDF forms. Monoclonal antibodies that selectively recognize epidermal growth factor domains of human NDF-alpha and -beta can specifically bind the respective NDF-alpha and -beta isoforms independent of NDF origins. Western blot analysis and quantitative binding assays further identify that an NDF preparation produced naturally from Rat1-EJ cells contains both alpha and beta isoforms in a 3 to 2 ratio. In receptor-binding competition experiments, human and rat NDF-beta isoforms have higher affinity than NDF-alpha isoforms. NDF-beta isoforms can dramatically enhance the stimulation of DNA synthesis for transfected NIH3T3 cells that overexpress HER-3 and HER-4 receptors, while NDF-alpha isoforms can only stimulate proliferation of HER-4-transfected cells with lower activity. Taken together, NDF-alpha and -beta isoforms share similar gross protein conformations but are biologically distinct.

3T3 Cells↗

Keratinocyte growth factor is an important endogenous mediator of hair follicle growth, development, and differentiation. Normalization of the nu/nu follicular differentiation defect and amelioration of chemotherapy-induced alopecia.

The growth and development of hair follicles is influenced by a number of different growth factors and cytokines, particularly members of the fibroblast growth factor (FGF) family. Keratinocyte growth factor (KGF or FGF-7) is a recently identified 28-kd member of the FGF family that induces proliferation of a wide variety of epithelial cells, including keratinocytes within the epidermis and dermal adnexa. Because KGF induces marked proliferation of keratinocytes, and both KGF and KGF receptor (KGFR) mRNA are expressed at high levels in skin, we sought to localize KGF and KGFR in skin by in situ hybridization. KGFR mRNA was relatively strongly expressed by keratinocytes in the basilar epidermis as well as throughout developing hair follicles of rat embryos and neonates. KGF mRNA was expressed at lower levels than was KGFR but could be localized to follicular dermal papillae in rat embryos and neonates. These results prompted us to investigate the effects of KGF on hair follicles in two distinct murine models of alopecia. In the first model, recombinant KGF (rKGF) induced dose-dependent hair growth over most of the body in nu/nu athymic nude mice when administered intraperitoneally or subcutaneously over 17 to 18 days. When administered subcutaneously, rKGF induced the most extensive hair growth at the sites of injection. Histologically, rKGF induced marked follicular and sebaceous gland hypertrophy, a normalization of the nu/nu follicular keratinization defect, and an increase in follicular keratinocyte proliferation as assessed by bromodeoxyuridine labeling. In the second model, a neonatal rat model of cytosine arabinoside chemotherapy-induced alopecia in which interleukin-1, epidermal growth factor, and acidic FGF have all demonstrated some degree of alopecia cytoprotection, rKGF induced a dose-dependent cytoprotective effect, abrogating as much as 50% of the alopecia in this model when administered beginning 1 day before the onset of chemotherapy. Taken together, these data suggest that KGF is an important endogenous mediator of normal hair follicle growth, development, and differentiation.

Alopecia↗

Stimulation of all epithelial elements during skin regeneration by keratinocyte growth factor.

Keratinocyte growth factor (KGF), a recently discovered 18.9 kD member of the fibroblast growth factor family has been shown to selectively induce keratinocyte proliferation and differentiation in tissue culture. To explore its potential stimulating keratinocyte growth and differentiation in vivo, we analyzed for the influence of KGF on epithelial derived elements within a wound created through the cartilage on the rabbit ear. KGF accelerated reepithelialization (p = 0.004) and increased the thickness of the epithelium (p = 0.0005) when 4-40 micrograms/cm2 recombinant KGF was added at the time of wounding. The regenerating epidermis showed normal differentiation as detected by cytokeratin immunostaining. Remarkably, however, KGF stimulated proliferation and differentiation of early progenitor cells within hair follicles and sebaceous glands in the wound bed and adjacent dermis. There was a transient but highly significant increase in specific labeling of cycling cells in both basal and suprabasal layers that extended into the spinous layer of the regenerating epidermis. As an indication of specificity, the inflammatory cells and fibroblasts within the wound were not influenced by KGF. The results indicate that KGF is unique in its ability to accelerate reepithelialization and dermal regeneration by targeting multiple epithelial elements within the skin. These results suggest that KGF may induce specific epithelial progenitor cell lineages within the skin to proliferate and differentiate, and thus may be a critical determinant of regeneration of skin. Furthermore, these findings illustrate the potential capacity of this system to analyze epithelial differentiation programs and disorders of epidermis, dermal glandular elements, and hair follicles.

Animals↗

Climbing fiber responses in cerebellar vermal Purkinje cells during perturbed locomotion in decerebrate cats.

We recorded spike potentials from Purkinje cells in the lateral vermis of lobule V in cat cerebellum, and found significant enhancement in climbing fiber discharges during perturbed locomotion. Five adult cats were decerebrated at a precollicular level, and 4-5 days thereafter, they were mounted on a treadmill. During stable locomotion at 36 cm/s belt velocity, climbing fiber responses were slightly modulated with a weak increment at the swing phase of the ipsilateral forelimb. When the left contralateral forelimb alone was suddenly imposed with a faster belt velocity of 61 cm/s, the occurrence of the climbing fiber discharges was significantly enhanced during the late swing phase of the ipsilateral forelimb. This observation is in accordance with the general notion that climbing fiber responses represent error signals in control of movements.

Animals↗

Neuroanatomical substrate for the dorsal light response. I. Differential afferent connections of the lateral lobe of the valvula cerebelli in goldfish (Carassius auratus).

The afferent connections of the lateral lobe of the valvula cerebelli in goldfish were investigated by retrograde labeling with horseradish peroxidase (HRP). Retrogradely labeled neurons were observed ipsilaterally in the lateral nucleus of the valvula and contralaterally in the inferior olivary nucleus after HRP injection into all parts of the lateral valvula. The valvulopetal projections from these nuclei were topographically arranged. After HRP injection confined to the rostral half of the lateral valvula, labeled neurons were also found ipsilaterally in the octavolateral and trigeminal cell groups: the eminentia granularis, the medial nucleus of the octavolateralis column, and the isthmic primary sensory trigeminal nucleus. HRP injection confined to the caudal half of the lateral valvula resulted in retrograde labeling of the following vision-related cell groups; the central pretectal nucleus, nucleus paracommissuralis, and the nucleus isthmi. However, the octavolateral and trigeminal cell groups did not project to the caudal half of the lateral valvula. These data provide insight into central nervous integration of visual and vestibular information, and help reveal the mechanism of the dorsal light response (DLR). Bilateral lesions of either the valvula cerebelli or pretectal area completely abolish this visually-guided response, but lesions of the optic tectum have no such effect. The pretectal nuclei (central pretectal nucleus, nucleus paracommissuralis) project to the lateral valvula directly, not via the optic tectum. These direct projections from the pretectal accessory optic nuclei to the lateral valvula may control the DLR. On the other hand, the lateral valvula receives vestibular and lateral line inputs indirectly, via the eminentia granularis and the medial nucleus of the octavolateralis column, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗

Neuroanatomical substrate for the dorsal light response. II. Effects of kainic acid-induced lesions of the valvula cerebelli on the goldfish dorsal light response.

The dorsal light response (DLR) to the continuously rotating light source was investigated in goldfish that had lesioned the valvula cerebelli. The body inclination was observed and analyzed for every 10 degrees of light rotation. The effects of selective lesions of the medial and lateral valvula cerebelli on the DLR were compared. After the lesion of the medial valvula cerebelli, the fish responded to the rotating light in the similar pattern to that seen preoperatively. However, after the unilateral lesion of the lateral valvula cerebelli, the fish did not respond to light from the side contralateral to the lesion, as if the fish had been unilaterally blindfolded. The lesion induced by kainic acid of the rostral and caudal part of the lateral valvula cerebelli differently influenced on the DLR. The DLR was impaired only after the caudal part of the lateral valvula cerebelli was lesioned by kainic acid. These findings suggest that the lateral valvula cerebelli in goldfish mediate the induction of the visually guided aspects of the DLR.

Animals↗

A new learning paradigm: adaptive changes in interlimb coordination during perturbed locomotion in decerebrate cats.

Adaptive interlimb coordination was studied during perturbed locomotion in experimental chronically decerebrate cats. Perturbations were applied to the stance phases of the left forelimb using a newly developed treadmill which consisted of three compartments, one each for the left forelimb, the left hindlimb and both right limbs. During the perturbed locomotion, the treadmill belt for the left forelimb was driven at about twice the speed for the other limbs. During the first 1-50 perturbed steps, the step cycles of both forelimbs showed marked fluctuations; thereafter, the animals achieved stable locomotion by slightly shortening step cycle durations, and also by adjusting durations of bisupport phases asymmetrically in the left and right forelimbs. The present method provides a new test paradigm for adaptive interlimb coordination in locomotion, which will be useful in studying neural mechanisms of motor learning involving cerebellar synaptic plasticity.

Adaptation, Psychological↗

Muscle sympathetic nerve responses to graded leg cycling.

The aim of this study was to clarify the relationship between sympathetic outflow to skeletal muscle and oxygen uptake during dynamic exercise. Muscle sympathetic nerve activity (MSNA) was recorded from the right median nerve microneurographically in eight healthy volunteers during leg cycling at four different intensities in a seated position for a 16-min bout. Work loads selected were 20, 40, 60, and 75% of maximal oxygen uptake (VO2max). Heart rate and blood pressure were measured during each exercise test. MSNA burst frequency was suppressed by 28% during cycling at 20% VO2max (23 vs. 33 bursts/min for control). Thereafter, it increased in a linear fashion with increasing work rate, with a significantly higher burst frequency during 60% VO2max than the control value. Both heart rate and mean blood pressure rose significantly during 20% VO2max from the control value and increased linearly with increased exercise intensity. During light exercise, MSNA was suppressed by arterial and cardiopulmonary baroreceptors as a result of the hemodynamic changes associated with leg muscle pumping. The baroreflex inhibition may overcome the muscle metaboreflex excitation to induce MSNA suppression during light exercise. These results suggest that during light exercise MSNA is inhibited, perhaps due to loading of the cardiopulmonary and arterial baroreflexes, and that during heavier exercise the increase in MSNA occurs as muscle metaboreflexes are activated.

Adult↗

Functional participation of the valvula cerebelli on the goldfish dorsal light response.

Most fish swim freely in three dimensions. The vestibular organs of fish are well developed and play an important role in maintaining postural equilibrium. Postural equilibrium in teleost fish also depend on visual information. Dorsal light response (DLR) of fish has been well-known as representative visually guided behavioral response since von Holst's description in 1935. The DLR, an innate behavior of teleost fish, whereby the back is oriented toward a given light source, represents a simple interaction between the visual and vestibular sensory inputs. In order to identify the neural center of the DLR in goldfish, lesion studies of the goldfish brain were conducted in our laboratory. The DLR was not affected by the extirpation of the corpus cerebelli, but was entirely abolished after bilateral lesions of the valvula cerebelli. The valvula cerebelli in goldfish was separated into the medial and lateral lobes by a longitudinal fissure. As to the afferent connections of the corpus cerebelli, many findings have been reported. However, the function and the fiber connections of the valvula cerebelli, especially its lateral lobe, are still unknown. Therefore, we examined the afferent connections of the lateral lobe of the valvula cerebelli by means of tracing technique with horseradish peroxidase. Furthermore, we investigated the effects of selective lesions of the medial and lateral valvula cerebelli on the DLR.

Afferent Pathways↗

Telescience testbed: operational support functions for biomedical experiments.

A telescience testbed was conducted to study the methodology of space biomedicine with simulated constraints imposed on space experiments. An experimental subject selected for this testbedding was an elaborate surgery of animals and electrophysiological measurements conducted by an operator onboard. The standing potential in the ampulla of the pigeon's semicircular canal was measured during gravitational and caloric stimulation. A principal investigator, isolated from the operation site, participated in the experiment interactively by telecommunication links. Reliability analysis was applied to the whole layers of experimentation, including design of experimental objectives and operational procedures. Engineering and technological aspects of telescience are discussed in terms of reliability to assure quality of science. Feasibility of robotics was examined for supportive functions to reduce the workload of the onboard operator.

Aerospace Medicine↗

Telescience testbed for biomedical experiments in space morphological and physiological experiments of rat musculoskeletal system.

As the second telescience testbed experiment we were examined sophisticated processes of biomedical experiment, such as an implantation of a transmitter into the hamster's abdominal cavity, non-stressful blood sampling, large amount of blood collection, muscle extirpation and biopsy from the hamsters on February 6-8, 1990. To make clear the differences between successful results obtained by an experienced hand and by a non-experienced one, three operators were selected for three successive experimental days; an engineer who had never experienced any biological experiment, a non-biology student, who experienced on biological experiments, and a veterinary surgeon. Surgical procedures need much experiences on maneuvering and understanding of theory to shorten the elapse time. Especially for a non-experienced hand, graphic instructions were much helpful to understand and to maneuver the procedures. Continuous recordings of ECG from a operator and PIs were of an advantage to grasp an extent of the mental strain, which was compared with their reports requested after end of each experimental day. The mental strain was not related to degrees of scientific achievement, but showed faithfully difficulty of each experimental procedure. Training effects on PIs in successive experimental days were found in their instructions for the operator to let understand the procedures.

Animals↗

Platelet-derived growth factor (BB homodimer), transforming growth factor-beta 1, and basic fibroblast growth factor in dermal wound healing. Neovessel and matrix formation and cessation of repair.

Recombinant platelet-derived growth factor (BB homodimer, rPDGF-BB), transforming growth factor beta 1 (rTGF-beta 1), and basic fibroblast growth factor (rbFGF) can accelerate healing of soft tissues. However, little information is available characterizing the components of wound matrix induced by these growth factors and the molecular mechanisms underlying accelerated repair and wound maturation. In this study, the composition, quantity, and rate of extracellular matrix deposition within growth factor-treated lapine ear excisional wounds were analyzed at different stages of healing using specific histochemical and immunohistochemical stains, coupled with image analysis techniques. Single application of optimal concentrations of each growth factor accelerated normal healing by 30% (P less than 0.0003); rPDGF-BB markedly augmented early glycosaminoglycan (GAG) and fibronectin deposition, but induced significantly greater levels of collagen later in the repair process, compared with untreated wounds rTGF-beta 1 treatment led to rapidly enhanced collagen synthesis and maturation, without increased GAG deposition. In contrast, rbFGF treatment induced a predominantly angiogenic response in wounds, with a marked increase in endothelia and neovessels (P less than 0.0001), and increased wound collagenolytic activity (P less than 0.03). rbFGF-treated wounds did not evolve into collagen-containing scars and continued to accumulate only provisional matrix well past wound closure. These results provide new evidence that growth factors influence wound repair via different mechanisms: 1) rPDGF-BB accelerates deposition of provisional wound matrix; 2) rTGF-beta 1 accelerates deposition and maturation of collagen; and 3) rbFGF induces a profound monocellular angiogenic response which may lead to a marked delay in wound maturation, and the possible loss of the normal signal(s) required to stop repair. These results suggest that specific growth factors may selectively regulate components of the repair response by differing mechanisms, offering the potential for targeted therapeutic intervention.

Animals↗