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Biomedical subjects

J T Henderson

Publications and source records attributed to J T Henderson.

At least 19 recordsLinked to original sources
PubMed2006

Development of a high resolution three-dimensional surgical atlas of the murine head for strains 129S1/SvImJ and C57Bl/6J using magnetic resonance imaging and micro-computed tomography.

The mouse has emerged as a major experimental model system for examining the functional properties of the mammalian CNS; both during development and following CNS injury. Histologic procedures currently used to determine the relative position of structures within the CNS are presently limited in their ability to take full advantage of this system for surgical and morphometric procedures. We present here the first three-dimensional interactive digital atlas of the murine brain and skull for two genetically important strains of mice; 129S1/SvImJ and C57Bl/6J. The final resolution of these digital atlases is 54 micro m(3). These representations of the murine brain and skull, in conjunction with our development of a new, more dynamic master coordinate system, provide improved accuracy with respect to targeting CNS structures during surgery compared with previous systems. The interactive three-dimensional nature of these atlases also provide users with stereotactic information necessary to perform accurate "off-axis" surgical procedures, as is commonly required for experiments such as in vivo micro-electroporation. In addition, three-dimensional analysis of the brain and skull shape in C57Bl, 129Sv, CD1, and additional murine strains, suggests that a stereotactic coordinate system based upon the lambda and rostral confluence of the sinuses at the sagittal midline, provides improved accuracy compared with the traditional lambda-bregma landmark system. These findings demonstrate the utility of developing highly accurate and robust three-dimensional representations of the murine brain and skull, in which experimental outputs can be directly compared using a unified coordinate system. The aim of these studies is to enhance comparative morphometric analyses and stereotactic surgical procedures in mice.

Animals↗
PubMed2004

A three-dimensional MRI atlas of the mouse brain with estimates of the average and variability.

Although there is growing interest in finding mouse models of human disease, no technique for quickly and quantitatively determining anatomical mutants currently exists. Magnetic resonance imaging (MRI) is ideally suited to probe fine structures in mice. This technology is three-dimensional, non-destructive and rapid compared to histopathology; hence MRI scientists have been able to create detailed three-dimensional images of 60 mum resolution or better. The data is digital which lends itself to sophisticated image processing algorithms. Here we show a variational MRI atlas constructed from nine excised brains of 8 week old 129S1/SvImJ male mice. This new type of atlas is comprised of an unbiased average brain--created from alignment of the individual brains--and the mathematical descriptors of anatomical variation across the individuals. We found that the majority of internal points in the individuals never varied more than 117 microm from equivalent points in the atlas. A three-dimensional annotation of the average image was performed and used to estimate the mean and standard deviation of volumes in a variety of structures across the individual brains; these volumes never differed by more than 5%. Our results indicate that variational atlases of inbred strains represent a well-defined basis against which mutant outliers can be readily compared.

Algorithms↗
PubMed2001

The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function.

Members of the Eph family of receptor tyrosine kinases control many aspects of cellular interactions during development, including axon guidance. Here, we demonstrate that EphB2 also regulates postnatal synaptic function in the mammalian CNS. Mice lacking the EphB2 intracellular kinase domain showed wild-type levels of LTP, whereas mice lacking the entire EphB2 receptor had reduced LTP at hippocampal CA1 and dentate gyrus synapses. Synaptic NMDA-mediated current was reduced in dentate granule neurons in EphB2 null mice, as was synaptically localized NR1 as revealed by immunogold localization. Finally, we show that EphB2 is upregulated in hippocampal pyramidal neurons in vitro and in vivo by stimuli known to induce changes in synaptic structure. Together, these data demonstrate that EphB2 plays an important role in regulating synaptic function.

Animals↗
PubMed2001

Physician gender effects on preventive screening and counseling: an analysis of male and female patients' health care experiences.

BACKGROUND: Studies have documented that patients of female physicians receive higher levels of preventive services. However, most studies include patients of only one gender, examine mainly gender-specific screening services, and do not examine patient education and counseling. OBJECTIVES: This study tests both physician- and patient-gender effects on screening and counseling services received in the past year and considers effects of gender-matched patient-physician pairs. RESEARCH DESIGN: Multivariate analyses are conducted to assess direct and interactive (physician x patient) gender effects and to control for important covariates. SUBJECTS: Data are from the 1998 Commonwealth Fund Survey of Women's Health, a nationally representative sample of U.S. adults. The analytic sample includes 1,661 men and 1,288 women ages 18 and over. MEASURES: Dependent variables are measures of patient-reported screening and counseling services received, including gender-specific and gender-nonspecific services and counseling on general health habits and sensitive topics. RESULTS: Female physician gender is associated with a greater likelihood of receiving preventive counseling for both male and female patients. For female patients, there is an increased likelihood of receiving more gender-specific screening (OR = 1.36, P <0.05) and counseling (OR = 1.40, P <0.05). These analyses provide no evidence that gender-matched physician-patient pairs provide an additional preventive care benefit beyond the main effect of female physician gender. CONCLUSIONS: Female physician gender influences the provision of both screening and counseling services. These influences may reflect physicians' practice and communication styles as well as patients' preferences and expectations.

Counseling↗
PubMed2000

Tumor necrosis factor receptor-associated factor 6 (TRAF6) deficiency results in exencephaly and is required for apoptosis within the developing CNS.

Tumor necrosis factor receptor-associated factors (TRAFs) are adaptor proteins important in mediating intracellular signaling. We report here that targeted deletion of traf6 greatly increases the frequency of failure of neural tube closure and exencephaly in traf6 (-/-) mice. The penetrance of this defect is influenced by genetic background. Neural tube fusion requires the coordination of several biological processes, including cell migration invoked by contact-dependent signaling, cell proliferation, and programmed cell death (PCD). To gain greater insight into the role of TRAF6 in these processes, neural development and migration within the CNS of traf6 (-/-) mice and controls were assessed through temporal examination of a number of immunohistochemical markers. In addition, relative levels of cellular proliferation and PCD were examined throughout embryonic development using bromodeoxyuridine (BrdU) and in situ terminal deoxynucleotidyl transferase-mediated dUTP biotinylated nick end labeling (TUNEL), respectively. The data suggest that loss of TRAF6 does not significantly alter the level of cellular proliferation or the pattern of neural differentiation per se, but rather regulates the level of PCD within specific regions of the developing CNS. Substantial reductions in TUNEL were observed within the ventral diencephalon and mesencephalon in exencephalic traf6 (-/-) embryos. Our results demonstrate a novel and prominent role for TRAF6 in the regional control of PCD within the developing CNS.

Animals↗
PubMed2000

The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons.

Shc proteins possess SH2 and PTB domains and serve a scaffolding function in signaling by a variety of receptor tyrosine kinases. There are three known mammalian Shc genes, of which ShcB and ShcC are primarily expressed in the nervous system. We have generated null mutations in ShcB and ShcC and have obtained mice lacking either ShcB or ShcC or both gene products. ShcB-deficient animals exhibit a loss of peptidergic and nonpeptidergic nociceptive sensory neurons, which is not enhanced by additional loss of ShcC. Mice lacking both ShcB and ShcC exhibit a significant loss of neurons within the superior cervical ganglia, which is not observed in either mutant alone. The results indicate that these Shc family members possess both unique and overlapping functions in regulating neural development and suggest physiological roles for ShcB/ShcC in TrkA signaling.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Neuronal defects and posterior pituitary hypoplasia in mice lacking the receptor tyrosine phosphatase PTPsigma.

The LAR-family protein tyrosine phosphatase sigma (PTPsigma, encoded by the gene Ptprs) consists of a cell adhesion-like extracellular domain composed of immunoglobulin and fibronectin type-III repeats, a single transmembrane domain and two intracellular catalytic domains. It was previously shown to be expressed in neuronal and lung epithelial tissues in a developmentally regulated manner. To study the role of PTPsigma in mouse development, we inactivated Ptprs by gene targeting. All Ptprs+/- mice developed normally, whereas 60% of Ptprs-/- mice died within 48 hours after birth. The surviving Ptprs-/- mice demonstrated stunted growth, developmental delays and severe neurological defects including spastic movements, tremor, ataxic gait, abnormal limb flexion and defective proprioception. Histopathology of brain sections revealed reduction and hypocellularity of the posterior pituitary of Ptprs-/- mice, as well as a reduction of approximately 50-75% in the number of choline acetyl transferase-positive cells in the forebrain. Moreover, peripheral nerve electrophysiological analysis revealed slower conduction velocity in Ptprs-/- mice relative to wild-type or heterozygous animals, associated with an increased proportion of slowly conducting, small-diameter myelinated fibres and relative hypomyelination. By approximately three weeks of age, most remaining Ptprs-/- mice died from a wasting syndrome with atrophic intestinal villi. These results suggest that PTPsigma has a role in neuronal and epithelial development in mice.

Age Factors↗
PubMed1998

Differential requirement for caspase 9 in apoptotic pathways in vivo.

Mutation of Caspase 9 (Casp9) results in embryonic lethality and defective brain development associated with decreased apoptosis. Casp9-/- embryonic stem cells and embryonic fibroblasts are resistant to several apoptotic stimuli, including UV and gamma irradiation. Casp9-/- thymocytes are also resistant to dexamethasone- and gamma irradiation-induced apoptosis, but are surprisingly sensitive to apoptosis induced by UV irradiation or anti-CD95. Resistance to apoptosis is accompanied by retention of the mitochondrial membrane potential in mutant cells. In addition, cytochrome c is translocated to the cytosol of Casp9-/- ES cells upon UV stimulation, suggesting that Casp9 acts downstream of cytochrome c. Caspase processing is inhibited in Casp9-/- ES cells but not in thymocytes or splenocytes. Comparison of the requirement for Casp9 and Casp3 in different apoptotic settings indicates the existence of at least four different apoptotic pathways in mammalian cells.

Animals↗
PubMed1998

Glial overexpression of NGF enhances neuropathic pain and adrenergic sprouting into DRG following chronic sciatic constriction in mice.

Adrenergic sprouts within axotomized dorsal root ganglia (DRG) may contribute to neuropathic pain, and may arise under the influence of nerve growth factor (NGF). We investigated effects of chronic constriction injury (CCI) on behavior and sprouting in mice in which NGF overexpression is driven by a glial protein (GFAP) promotor. GFAP-NGF mice were naturally hyperresponsive to radiant heat, and had enhanced ipsilateral responses to thermal and mechanical stimulation following CCI compared to wild-type mice. Sympathetic axons were already present in intact DRG of GFAP-NGF mice. Following CCI, sprouting in ipsilateral and to a lesser extent contralateral DRG occurred in both genotypes, but the sprout density 2 weeks post-lesion was much greater in GFAP-NGF mice. These results demonstrate a connection between the endogenous ectopic overexpression of NGF and (1) neuropathic pain behaviour and (2) sympathetic sprouting in the DRG.

Animals↗
PubMed1998

Multiple behavioral anomalies in GluR2 mutant mice exhibiting enhanced LTP.

We have previously disrupted the ionotropic glutamate receptor type 2 gene (GluR2) using gene targeting in embryonic stem cells and generated mice which lacked the GluR2 gene product. Neurophysiological analyses of these mice showed a markedly enhanced long-term potentiation (LTP) and a 9-fold increase in kainate induced Ca2+ permeability in the hippocampus. Here, we analyze the behavioral and neuroanatomical consequences of GluR2 deficiency in homozygous null mutant and age-matched littermate control mice. We show that despite unaltered gross brain morphology, several aspects of behavior were abnormal in the mutants. Object exploration, rearing, grooming and locomotion were altered in the novel arena. Eye-closure reflex, motor performance on the rotating rod and spatial and non-spatial learning performance in the water maze were also abnormal in the mutants. These abnormalities together with the widespread expression pattern of GluR2 in most excitatory CNS pathways suggest that the absence of GluR2 leads to neurological phenotypes associated with not only the hippocampus but several other brain regions potentially including the cortex and cerebellum. We speculate that GluR2 mutant mice suffer from an overall non-specifically increased excitability that may alter cognitive functions ranging from stimulus processing to motivation and learning.

Animals↗
PubMed1997

Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP.

Class I metabotropic glutamate receptors (mGluRs) have been postulated to play a role in synaptic plasticity. To test the involvement of one member of this class, we have recently generated mutant mice that express no mGluR5 but normal levels of other glutamate receptors. The CNS revealed normal development of gross anatomical features. To examine synaptic functions we measured evoked field EPSPs in the hippocampal slice. Measures of presynaptic function, such as paired pulse facilitation in mutant CA1 neurons, were normal. The response of mutant CA1 neurons to low concentrations of (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) was missing, which suggests that mGluR5 may be the primary high affinity ACPD receptor in these neurons. Long-term potentiation (LTP) in mGluR5 mutants was significantly reduced in the NMDA receptor (NMDAR)-dependent pathways such as the CA1 region and dentate gyrus of the hippocampus, whereas LTP remained intact in the mossy fiber synapses on the CA3 region, an NMDAR-independent pathway. Some of the difference in CA1 LTP could lie at the level of expression, because the reduction of LTP in the mutants was no longer observed 20 min after tetanus in the presence of 2-amino-5-phosphonopentanoate. We propose that mGluR5 plays a key regulatory role in NMDAR-dependent LTP. These mutant mice were also impaired in the acquisition and use of spatial information in both the Morris water maze and contextual information in the fear-conditioning test. This is consistent with the hypothesis that LTP in the CA1 region may underlie spatial learning and memory.

Animals↗
PubMed1996

Reduction of lower motor neuron degeneration in wobbler mice by N-acetyl-L-cysteine.

The murine mutant wobbler is a model of lower motoneuron degeneration with associated skeletal muscle atrophy. This mutation most closely resembles Werdnig-Hofmann disease in humans and shares some of the clinical features of amyotrophic lateral sclerosis (ALS). It has been suggested that reactive oxygen species (ROS) may play a role in the pathogenesis of disorders such as ALS. To examine the relationship between ROS and neural degeneration, we have studied the effects of agents such as N-acetyl-L-cysteine (NAC), which reduce free radical damage. Litters of wobbler mice were given a 1% solution of the glutathione precursor NAC in their drinking water for a period of 9 weeks. Functional and neuroanatomical examination of these animals revealed that wobbler mice treated with NAC exhibited (1) a significant reduction in motor neuron loss and elevated glutathione peroxidase levels within the cervical spinal cord, (2) increased axon caliber in the medial facial nerve, (3) increased muscle mass and muscle fiber area in the triceps and flexor carpi ulnaris muscles, and (4) increased functional efficiency of the forelimbs, as compared with untreated wobbler littermates. These data suggest that reactive oxygen species may be involved in the degeneration of motor neurons in wobbler mice and demonstrate that oral administration of NAC effectively reduces the degree of motor degeneration in wobbler mice. This treatment thus may be applicable in the treatment of other lower motor neuropathies.

Acetylcysteine↗
PubMed1996

Nuk controls pathfinding of commissural axons in the mammalian central nervous system.

Eph family receptor tyrosine kinases have been proposed to control axon guidance and fasciculation. To address the biological functions of the Eph family member Nuk, two mutations in the mouse germline have been generated: a protein null allele (Nuk1) and an allele that encodes a Nuk-beta gal fusion receptor lacking the tyrosine kinase and C-terminal domains (Nuk(lacZ)). In Nuk1 homozygous brains, the majority of axons forming the posterior tract of the anterior commissure migrate aberrantly to the floor of the brain, resulting in a failure of cortical neurons to link the two temporal lobes. These results indicate that Nuk, a receptor that binds transmembrane ligands, plays a critical and unique role in the pathfinding of specific axons in the mammalian central nervous system.

Alleles↗
PubMed1996

Physiological effects of CNTF-induced wasting.

The authors have shown previously that in addition to its survival effects on neurons and glia, ciliary neurotrophic factor (CNTF) induced potent cachectic effects and acute phase proteins when present in the peripheral circulation at concentrations of < or = 10 ng/ml. These effects did not depend upon the induction of other cytokine family members. Described here are the specific physiological effects which systemic administration of CNTF can induce in somatic tissue. Mice implanted with C6 glioma cells, genetically modified to secrete CNTF, exhibited rapid catabolism of adipose tissue and skeletal muscle, depressed steady-state levels of glucose and triglycerides, elevations in red blood cell content, gall bladder hypertrophy and thymic atrophy, with a disproportionate loss of CD4+/CD8+ T cells. This cachectic wasting resulted in death over a period of 7-10 days. Implantation of the parental C6 line, or C6 cells which express a non-secreted form of CNTF, did not result in overt effects over this time period. These findings have implications both for the biology of CNTF family members, and the therapeutic use of factors such as CNTF in vivo.

Adipose Tissue↗
PubMed1995

Ciliary neurotrophic factor promotes the terminal differentiation of v-myc immortalized sympathoadrenal progenitor cells in vivo.

Survival and differentiation of a sympathoadrenal progenitor cell line (termed MAH), transduced with a v-myc oncogene, was studied subsequent to transplantation in the peripheral and central nervous system of adult rats. In the brain, MAH cell survival depended on the secretion of ciliary neurotrophic factor (CNTF) by co-grafts of genetically modified glioma cells. No trophic factor supplement was required for development of the MAH cells in the peripheral nerve environment. Transplanted progenitor cells withdrew from the cell cycle within 48 h and differentiated into a prominent population of large sympathetic-like neurons. The neurons expressed the alpha subunit of the CNTF receptor and appropriate spatial distributions of cytoskeletal proteins and catecholamine related enzymes. The results identify a role for CNTF in the development of the sympathoadrenal cell lineage and support the concept of immortalized progenitor cells as alternatives to primary cells for cell replacement strategies in the nervous system.

Adrenal Medulla↗
PubMed1995

Neurons express ciliary neurotrophic factor mRNA in the early postnatal and adult rat brain.

The regional and subcellular localization in the central nervous system (CNS) of postnatal day 5, day 15, and adult rats of ciliary neurotrophic factor (CNTF) mRNA was examined by in situ hybridization with biotinylated riboprobes. Probe specificity was determined by Northern blot analysis of poly(A)+ RNA extracted from adult rat brain using digoxigenin labeled riboprobes and chemiluminescent detection. Both a 4 kb and a 1.2 kb transcript were detected in the cortex and brainstem. In situ hybridization revealed that CNTF mRNA was widely distributed in neurons and glia throughout the CNS at each of the developmental time points. The density of the neuronal hybridization signal was found to be greater in neuronal nuclei than in their cytoplasm. In the nucleus of most neurons, CNTF mRNA distribution was concentrated in a perinucleolar fashion. Alternate sections from the same animals, which were incubated with a specific polyclonal antibody against a CNTF peptide fragment, revealed that both neurons and glia in postnatal day 5, day 15, and adult rat brain were immunoreactive for CNTF.

Aging↗
PubMed1994

Increased CNTF gene expression in process-bearing astrocytes following injury is augmented by R(-)-deprenyl.

R(-)-deprenyl has been shown to rescue axotomized immature facial motoneurons with an efficacy comparable to that of the neurotrophic factors CNTF and BDNF (Salo and Tatton, J Neurosci Res 31:394-400, 1992; Ansari et al., J Neurosci 13:4042-4053, 1993). Recent work has suggested that some of the actions of (-)-deprenyl may be mediated through reactive astrocytes (Biagini et al., NeuroReport 4:955-958, 1993). To test this proposal we have developed an in vitro model of reactive gliosis consisting of a mixed astrocyte population of flat and process-bearing (PB) astroglia taken from postnatal day (PD) 2 or PD5 rat cerebral cortex. After mechanical wounding, PB astrocytes preferentially migrate into the wound zone while flat astrocytes maintain their position at the wound edge. CNTF mRNA was localized to PB astrocytes, but not flat astrocytes, as determined by in situ hybridization using biotin-labelled riboprobes. Following "wounding," there was an increase in CNTF mRNA in PB astrocytes only, which could be further enhanced by a single pulse of (-)-deprenyl (10(-8)-10(-11) M) 48 hr after injury. (-)-Deprenyl also increased the total process length of PB astrocytes after wounding by an average of 50%. The stereoisomer (+)-deprenyl (10(-9) M) had no effect on either astrocyte process length or CNTF mRNA content. This is the first report to our knowledge of an agent which can upregulate CNTF gene expression in astroglial cell culture as well as influence glial cell process length.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗