2023 |
Marsland M, Dowdell A, Faulkner S, Jobling P, Rush RA, Gedye C, et al., 'ProNGF Expression and Targeting in Glioblastoma Multiforme.', Int J Mol Sci, 24 (2023) [C1]
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Nova |
2022 |
Astono IP, Welsh JS, Rowe CW, Jobling P, 'Objective quantification of nerves in immunohistochemistry specimens of thyroid cancer utilising deep learning.', PLoS Comput Biol, 18 e1009912 (2022) [C1]
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Nova |
2022 |
Jiang CC, Marsland M, Wang Y, Dowdell A, Eden E, Gao F, et al., 'Tumor innervation is triggered by endoplasmic reticulum stress', ONCOGENE, 41 586-599 (2022) [C1]
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Nova |
2022 |
Stitt IM, Wellings TP, Drury HR, Jobling P, Callister RJ, Brichta AM, Lim R, 'Properties of Deiters? neurons and inhibitory synaptic transmission in the mouse lateral vestibular nucleus', JOURNAL OF NEUROPHYSIOLOGY, 128 131-147 (2022) [C1]
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Nova |
2021 |
Ferdoushi A, Griffin N, Marsland M, Xu X, Faulkner S, Gao F, et al., 'Tumor innervation and clinical outcome in pancreatic cancer', SCIENTIFIC REPORTS, 11 (2021) [C1]
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Nova |
2021 |
Griffin N, Gao F, Jobling P, Oldmeadow C, Wills V, Walker MM, et al., 'The neurotrophic tyrosine kinase receptor 1 (TrkA) is overexpressed in oesophageal squamous cell carcinoma', Pathology, 53 470-477 (2021) [C1]
Nerve growth factor (NGF) and its receptors, the neurotrophic receptor tyrosine kinase 1 (NTRK1/TrkA) and the common neurotrophin receptor (NGFR/p75NTR), are increasingly implicat... [more]
Nerve growth factor (NGF) and its receptors, the neurotrophic receptor tyrosine kinase 1 (NTRK1/TrkA) and the common neurotrophin receptor (NGFR/p75NTR), are increasingly implicated in cancer progression, but their clinicopathological significance in oesophageal cancer is unclear. In this study, the expression of NGF, NTRK1 and NGFR were analysed by immunohistochemistry in a cohort of 303 oesophageal cancers versus 137 normal adjacent oesophageal tissues. Immunostaining was digitally quantified and compared to clinicopathological parameters. NGF and NGFR staining were found in epithelial cells and at similar levels between oesophageal cancers and normal oesophageal tissue. NGFR staining was slightly increased with grade (p=0.0389). Interestingly, NTRK1 staining was markedly higher in oesophageal squamous cell carcinoma (OR 2.31, 95%CI 1.13¿4.38, p<0.0001) and significantly lower in adenocarcinoma (OR 0.50, 95%CI 0.44¿0.63, p<0.0001) compared to normal oesophageal tissue. In addition, NTRK1 staining was decreased in grade 2 and grade 3 (OR 0.51, 95%CI 0.21¿1.40, p<0.0001) compared to grade 1, suggesting a preferential involvement of this receptor in the more differentiated forms of oesophageal carcinomas. Together, these data point to NTRK1 as a biomarker and a candidate therapeutic target in oesophageal squamous cell carcinoma.
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Nova |
2020 |
Madden JF, Davis OC, Boyle KA, Iredale JA, Browne TJ, Callister RJ, et al., 'Functional and Molecular Analysis of Proprioceptive Sensory Neuron Excitability in Mice', Frontiers in Molecular Neuroscience, 13 1-13 (2020) [C1]
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Nova |
2020 |
Griffin N, Rowe CW, Gao F, Jobling P, Wills V, Walker MM, et al., 'Clinicopathological Significance of Nerves in Esophageal Cancer', American Journal of Pathology, 190 1921-1930 (2020) [C1]
Nerves are emerging promoters of cancer progression, but the innervation of esophageal cancer and its clinicopathologic significance remain unclear. In this study, nerves were ana... [more]
Nerves are emerging promoters of cancer progression, but the innervation of esophageal cancer and its clinicopathologic significance remain unclear. In this study, nerves were analyzed by immunohistochemistry in a cohort of 260 esophageal cancers, including 40 matched lymph node metastases and 137 normal adjacent esophageal tissues. Nerves were detected in 38% of esophageal cancers and were more associated with squamous cell carcinomas (P = 0.04). The surrounding or invasion of nerves by cancer cells (perineural invasion) was detected in 12% of esophageal cancers and was associated with reduced survival (P = 0.04). Nerves were found to express the following receptors for nerve growth factor (NGF): neurotrophic receptor tyrosine kinase 1 and nerve growth factor receptor. An association was suggested between high production of NGF by cancer cells and the presence of nerves (P = 0.02). In vitro, NGF production in esophageal cancer cells was shown by Western blot, and esophageal cancer cells were able to induce neurite outgrowth in the PC12 neuronal cells. The neurotrophic activity of esophageal cancer cells was inhibited by anti-NGF blocking antibodies. Together, these data suggest that innervation is a feature in esophageal cancers that may be driven by cancer cell¿released NGF.
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Nova |
2020 |
Faulkner S, Griffin N, Rowe CW, Jobling P, Lombard JM, Oliveira SM, et al., 'Nerve growth factor and its receptor tyrosine kinase TrkA are overexpressed in cervical squamous cell carcinoma.', FASEB bioAdvances, 2 398-408 (2020) [C1]
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Nova |
2020 |
Peneaux C, Hansbro PM, Jobling P, Holdsworth JL, Griffin AS, 'Tissue structure contributes to the production of a coloured skin display in the Common Myna', Avian Biology Research, 13 100-107 (2020) [C1]
Conspicuous coloured displays from ultraviolet to bright red have been documented in many species throughout the animal kingdom. These colours often occur as sexual signals and ca... [more]
Conspicuous coloured displays from ultraviolet to bright red have been documented in many species throughout the animal kingdom. These colours often occur as sexual signals and can be incorporated into different types of integuments (e.g. scales, feathers, skin). Two main mechanisms are known to produce coloured integuments: pigmentation and tissue structure. Although pigmental and structural coloration are separate mechanisms and can occur independently, some coloured displays might emerge from a combination of both. Here, we demonstrate, using biochemical, optical and morphological methodologies, that the yellow coloration of the skin located around the eye of Common (Indian) Mynas (Acridotheres tristis) is produced by both light-reflecting nanostructures and light-absorbing carotenoid pigments. Our analysis confirms that nanostructured collagen in the avian dermis work in combination with carotenoid pigments to produce vivid integumentary colours. Identifying the mechanisms behind the production of a coloured signal provides a basis for predicting how a signal¿s function might be influenced by environmental factors such as fledgling nutrition.
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Nova |
2020 |
Ferdoushi A, Li X, Griffin N, Faulkner S, Jamaluddin MFB, Gao F, et al., 'Schwann Cell Stimulation of Pancreatic Cancer Cells: A Proteomic Analysis', Frontiers in Oncology, 10 (2020) [C1]
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Nova |
2020 |
Gao F, Griffin N, Faulkner S, Li X, King SJ, Jobling P, et al., 'The Membrane Protein Sortilin Can Be Targeted to Inhibit Pancreatic Cancer Cell Invasion.', The American journal of pathology, 190 (2020) [C1]
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Nova |
2020 |
Lee JM, Mayall JR, Chevalier A, McCarthy H, Van Helden D, Hansbro PM, et al., 'Chlamydia muridarum infection differentially alters smooth muscle function in mouse uterine horn and cervix', American Journal of Physiology - Endocrinology and Metabolism, 318 E981-E994 (2020) [C1]
Lee JM, Mayall JR, Chevalier A, McCarthy H, Van Helden D, Hansbro PM, Horvat JC, Jobling P. Chlamydia muridarum infection differentially alters smooth muscle function in mouse ute... [more]
Lee JM, Mayall JR, Chevalier A, McCarthy H, Van Helden D, Hansbro PM, Horvat JC, Jobling P. Chlamydia muridarum infection differentially alters smooth muscle function in mouse uterine horn and cervix. Am J Physiol Endocrinol Metab 318: E981 E994, 2020. First published April 21, 2020; doi:10.1152/ajpendo.00513. 2019. Chlamydia trachomatis infection is a primary cause of reproductive tract diseases including infertility. Previous studies showed that this infection alters physiological activities in mouse oviducts. Whether this occurs in the uterus and cervix has never been investigated. This study characterized the physiological activities of the uterine horn and the cervix in a Chlamydia muridarum (Cmu)-infected mouse model at three infection time points of 7, 14, and 21 days postinfection (dpi). Cmu infection significantly decreased contractile force of spontaneous contraction in the cervix (7 and 14 dpi; P < 0.001 and P < 0.05, respectively), but this effect was not observed in the uterine horn. The responses of the uterine horn and cervix to oxytocin were significantly altered by Cmu infection at 7 dpi (P < 0.0001), but such responses were attenuated at 14 and 21 dpi. Cmu infection increased contractile force to prostaglandin (PGF2_) by 53 83% in the uterine horn. This corresponded with the increased messenger ribonucleic acid (mRNA) expression of Ptgfr that encodes for its receptor. However, Cmu infection did not affect contractions of the uterine horn and cervix to PGE2 and histamine. The mRNA expression of Otr and Ptger4 was inversely correlated with the mRNA expression of Il1b, Il6 in the uterine horn of Cmu-inoculated mice (P < 0.01 to P < 0.001), suggesting that the changes in the Otr and Ptger4 mRNA expression might be linked to the changes in inflammatory cytokines. Lastly, this study also showed a novel physiological finding of the differential response to PGE2 in mouse uterine horn and cervix.
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Nova |
2020 |
Astono I, Rowe CW, Welsh J, Jobling P, 'MON-535 Deep-Machine Learning for Objective Quantification of Nerves in Immunohistochemistry Specimens of Thyroid Cancer', Journal of the Endocrine Society, 4 (2020) [C1]
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2020 |
Rowe CW, Dill T, Griffin N, Jobling P, Faulkner S, Paul JW, et al., 'Innervation of papillary thyroid cancer and its association with extra-thyroidal invasion', Scientific Reports, 10 (2020) [C1]
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Nova |
2020 |
March B, Faulkner S, Jobling P, Steigler A, Blatt A, Denham J, Hondermarck H, 'Tumour innervation and neurosignalling in prostate cancer', Nature Reviews Urology, 17 119-130 (2020) [C1]
Prostate cancer progression has been shown to be dependent on the development of autonomic nerves into the tumour microenvironment. Sympathetic nerves activate adrenergic neurosig... [more]
Prostate cancer progression has been shown to be dependent on the development of autonomic nerves into the tumour microenvironment. Sympathetic nerves activate adrenergic neurosignalling that is necessary in early stages of tumour progression and for initiating an angiogenic switch, whereas parasympathetic nerves activate cholinergic neurosignalling resulting in tumour dissemination and metastasis. The innervation of prostate cancer seems to be initiated by neurotrophic growth factors, such as the precursor to nerve growth factor secreted by tumour cells, and the contribution of brain-derived neural progenitor cells has also been reported. Current experimental, epidemiological and clinical evidence shows the stimulatory effect of tumour innervation and neurosignalling in prostate cancer. Using nerves and neurosignalling could have value in the management of prostate cancer by predicting aggressive disease, treating localized disease through denervation and relieving cancer-associated pain in bone metastases.
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Nova |
2019 |
Duchatel RJ, Harms LR, Meehan CL, Michie PT, Bigland MJ, Smith DW, et al., 'Reduced cortical somatostatin gene expression in a rat model of maternal immune activation', PSYCHIATRY RESEARCH, 282 (2019) [C1]
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Nova |
2019 |
Faulkner S, Jobling P, March B, Jiang CC, Hondermarck H, 'Tumor neurobiology and the war of nerves in cancer', Cancer Discovery, 9 702-710 (2019) [C1]
Nerves are emerging regulators of cancer progression. Cancer cells induce the outgrowth of nerves in the tumor microenvironment through the release of neu-rotrophic factors, and i... [more]
Nerves are emerging regulators of cancer progression. Cancer cells induce the outgrowth of nerves in the tumor microenvironment through the release of neu-rotrophic factors, and in return nerves liberate neurotransmitters that activate cancer growth and dissemination. Although sympathetic nerves drive tumor angiogenesis via the liberation of noradrena-line, sensory and parasympathetic nerves stimulate cancer stem cells. Interestingly, recent evidence indicates that parasympathetic nerves can eventually inhibit tumor progression, suggesting a yin¿yang type of regulation of cancer by nerves. From a broader perspective, the question of a higher level of control of cancer development by the central nervous system should be raised. Significance: Nerves are emerging regulators of cancer initiation, progression, and metastasis. Here, we review the evidence to date and explore the basic and clinical ramifications of these findings.
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Nova |
2019 |
Smith KM, Browne TJ, Davis OC, Coyle A, Boyle KA, Watanabe M, et al., 'Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn', ELIFE, 8 (2019) [C1]
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Nova |
2018 |
Gao F, Griffin N, Faulkner S, Rowe CW, Williams L, Roselli S, et al., 'The neurotrophic tyrosine kinase receptor TrkA and its ligand NGF are increased in squamous cell carcinomas of the lung', SCIENTIFIC REPORTS, 8 (2018) [C1]
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Nova |
2018 |
Hondermarck H, Jobling P, 'The Sympathetic Nervous System Drives Tumor Angiogenesis', TRENDS IN CANCER, 4 93-94 (2018)
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2018 |
Griffin N, Faulkner S, Jobling P, Hondermarck H, 'Targeting neurotrophin signaling in cancer: The renaissance', Pharmacological Research, 135 12-17 (2018) [C1]
Nerve outgrowth in the tumor microenvironment (tumor neurogenesis) has recently been shown to be essential for cancer progression and the concept of nerve dependence is emerging i... [more]
Nerve outgrowth in the tumor microenvironment (tumor neurogenesis) has recently been shown to be essential for cancer progression and the concept of nerve dependence is emerging in oncology. Neurotrophins such as nerve growth factor (NGF) have long been identified as drivers of neurogenesis during development and regeneration, but intriguingly they were also known to be expressed in human tumors where they can stimulate cancer cell growth. Recent findings have unraveled that NGF released by cancer cells is also a driver of tumor neurogenesis, via the stimulation of NGF receptors on nerve endings. In return, nerves infiltrated in the tumor microenvironment secrete neurotransmitters, which can stimulate both the growth of tumor cells and angiogenesis. This neurotrophic role of NGF in cancer is likely to be relevant to a large variety of human malignancies, as well as other neurotrophins, and may have ramifications in cancer pain. Therefore, pharmacological interventions against neurotrophin signaling have the potential not only to target cancer cells directly, but also to inhibit neurogenesis and its stimulatory impact on cancer progression and pain.
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Nova |
2018 |
Poppi LA, Tabatabaee H, Drury HR, Jobling P, Callister RJ, Migliaccio AA, et al., 'ACh-induced hyperpolarization and decreased resistance in mammalian type II vestibular hair cells', Journal of Neurophysiology, 119 312-325 (2018) [C1]
In the mammalian vestibular periphery, electrical activation of the efferent vestibular system (EVS) has two effects on afferent activity: 1) it increases background afferent disc... [more]
In the mammalian vestibular periphery, electrical activation of the efferent vestibular system (EVS) has two effects on afferent activity: 1) it increases background afferent discharge and 2) decreases afferent sensitivity to rotational stimuli. Although the cellular mechanisms underlying these two contrasting afferent responses remain obscure, we postulated that the reduction in afferent sensitivity was attributed, in part, to the activation of a9- containing nicotinic acetylcholine (ACh) receptors (a9*nAChRs) and small-conductance potassium channels (SK) in vestibular type II hair cells, as demonstrated in the peripheral vestibular system of other vertebrates. To test this hypothesis, we examined the effects of the predominant EVS neurotransmitter ACh on vestibular type II hair cells from wild-type (wt) and a9-subunit nAChR knockout (a9 -/- ) mice. Immunostaining for choline acetyltransferase revealed there were no obvious gross morphological differences in the peripheral EVS innervation among any of these strains. ACh application onto wt type II hair cells, at resting potentials, produced a fast inward current followed by a slower outward current, resulting in membrane hyperpolarization and decreased membrane resistance. Hyperpolarization and decreased resistance were due to gating of SK channels. Consistent with activation of a9*nAChRs and SK channels, these ACh-sensitive currents were antagonized by the a9*nAChR blocker strychnine and SK blockers apamin and tamapin. Type II hair cells from a9 -/- mice, however, failed to respond to ACh at all. These results confirm the critical importance of a9nAChRs in efferent modulation of mammalian type II vestibular hair cells. Application of exogenous ACh reduces electrical impedance, thereby decreasing type II hair cell sensitivity. NEW & NOTEWORTHY Expression of a9 nicotinic subunit was crucial for fast cholinergic modulation of mammalian vestibular type II hair cells. These findings show a multifaceted efferent mechanism for altering hair cell membrane potential and decreasing membrane resistance that should reduce sensitivity to hair bundle displacements.
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Nova |
2018 |
Poppi LA, Tabatabaee H, Jobling P, Callister RJ, Migliaccio AA, Jordan PM, et al., 'ACh-induced hyperpolarization and decreased resistance in mammalian type II vestibular hair cells (vol 119, pg 312, 2018)', JOURNAL OF NEUROPHYSIOLOGY, 120 385-385 (2018)
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2018 |
Duchatel RJ, Meehan CL, Harms LR, Michie PT, Bigland MJ, Smith DW, et al., 'Increased complement component 4 (C4) gene expression in the cingulate cortex of rats exposed to late gestation immune activation', SCHIZOPHRENIA RESEARCH, 199 442-444 (2018)
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2018 |
Duchatel RJ, Meehan CL, Harms LR, Michie PT, Bigland MJ, Smith DW, et al., 'Late gestation immune activation increases IBA1-positive immunoreactivity levels in the corpus callosum of adult rat offspring', Psychiatry Research, 266 175-185 (2018) [C1]
Animal models of maternal immune activation study the effects of infection, an environmental risk factor for schizophrenia, on brain development. Microglia activation and cytokine... [more]
Animal models of maternal immune activation study the effects of infection, an environmental risk factor for schizophrenia, on brain development. Microglia activation and cytokine upregulation may have key roles in schizophrenia neuropathology. We hypothesised that maternal immune activation induces changes in microglia and cytokines in the brains of the adult offspring. Maternal immune activation was induced by injecting polyriboinosinic:polyribocytidylic acid into pregnant rats on gestational day (GD) 10 or GD19, with brain tissue collected from the offspring at adulthood. We observed no change in Iba1, Gfap, IL1-ß and TNF-a mRNA levels in the cingulate cortex (CC) in adult offspring exposed to maternal immune activation. Prenatal exposure to immune activation had a significant main effect on microglial IBA1-positive immunoreactive material (IBA1+IRM) in the corpus callosum; post-hoc analyses identified a significant increase in GD19 offspring, but not GD10. No change in was observed in the CC. In contrast, maternal immune activation had a significant main effect on GFAP+IRM in the CC at GD19 (not GD10); post-hoc analyses only identified a strong trend towards increased GFAP+IRM in the GD19 offspring, with no white matter changes. This suggests late gestation maternal immune activation causes subtle alterations to microglia and astrocytes in the adult offspring.
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Nova |
2018 |
Faulkner S, Jobling P, Rowe CW, Rodrigues Oliveira SM, Roselli S, Thorne RF, et al., 'Neurotrophin Receptors TrkA, p75
Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor k... [more]
Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75NTR, and the proneurotrophin receptor sortilin were analyzed with immunohistochemistry in a cohort of thyroid cancers (n = 128) and compared with adenomas and normal thyroid tissues (n = 62). TrkA was detected in 20% of thyroid cancers, compared with none of the benign samples (P = 0.0007). TrkA expression was independent of histologic subtypes but associated with lymph node metastasis (P = 0.0148), suggesting the involvement of TrkA in tumor invasiveness. Nerves in the tumor microenvironment were positive for TrkA. p75NTR was overexpressed in anaplastic thyroid cancers compared with papillary and follicular subtypes (P < 0.0001). Sortilin was overexpressed in thyroid cancers compared with benign thyroid tissues (P < 0.0001). Neurotrophin receptor expression was confirmed in a panel of thyroid cancer cell lines at the mRNA and protein levels. Functional investigations using the anaplastic thyroid cancer cell line CAL-62 found that siRNA against TrkA, p75NTR, and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Together, these data reveal TrkA, p75NTR, and sortilin as potential therapeutic targets in thyroid cancer.
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Nova |
2017 |
van Helden DF, Kamiya A, Kelsey S, Laver DR, Jobling P, Mitsui R, Hashitani H, 'Nerve-induced responses of mouse vaginal smooth muscle', Pflugers Archiv European Journal of Physiology, 469 1373-1385 (2017) [C1]
Neural and agonist-induced contractions of proximal (i.e. upper half adjacent to the cervix) and distal mouse vaginal smooth muscle strips were investigated. We hypothesised that ... [more]
Neural and agonist-induced contractions of proximal (i.e. upper half adjacent to the cervix) and distal mouse vaginal smooth muscle strips were investigated. We hypothesised that nerve-mediated vaginal contractions arise through activity of cholinergic nerves. Nerve activation by bursts of electrical field stimulation (EFS) caused a primary transient contraction often accompanied by a secondary transient contraction, both larger in proximal than distal tissues (i.e. primary: 7-fold larger; secondary: 3-fold larger). Our hypothesis was supported as we found that cholinergic nerves mediated the primary transient contraction in both proximal and distal vaginal strips, as EFS responses were enhanced by neostigmine an anticholinesterase, massively inhibited by the competitive muscarinic receptor antagonist atropine and not affected by the non-selective a-adrenergic receptor antagonist phentolamine. Primary transient contractions were halved in amplitude by the L-type Ca2+ channel blocker nifedipine and markedly inhibited by the sarco-endoplasmic reticulum calcium ATPase (SERCA) inhibitor cyclopiazonic acid (CPA). Resultant secondary transient contractions were abolished by nifedipine. Notably, the selective a1-adrenergic receptor agonist phenylephrine caused tonic contracture in distal but not proximal strips. Low-frequency EFS often initiated recurrent transient contractions similar to those elicited by CCh. Immunohistochemical studies demonstrated innervation of the smooth muscle. Findings of enhanced proximal cholinergic nerve-induced transient contractions, evidence that maintained nerve stimulation could cause recurrent contractions and the finding of distal phenylephrine-mediated tonic contraction have implications on insemination.
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Nova |
2017 |
Boilly B, Faulkner S, Jobling P, Hondermarck H, 'Nerve Dependence: From Regeneration to Cancer', Cancer Cell, 31 342-354 (2017) [C1]
Nerve dependence has long been described in animal regeneration, where the outgrowth of axons is necessary to the reconstitution of lost body parts and tissue remodeling in variou... [more]
Nerve dependence has long been described in animal regeneration, where the outgrowth of axons is necessary to the reconstitution of lost body parts and tissue remodeling in various species. Recent discoveries have demonstrated that denervation can suppress tumor growth and metastasis, pointing to nerve dependence in cancer. Regeneration and cancer share similarities in regard to the stimulatory role of nerves, and there are indications that the stem cell compartment is a preferred target of innervation. Thus, the neurobiology of cancer is an emerging discipline that opens new perspectives in oncology.
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Nova |
2017 |
Rutledge A, Jobling P, Walker MM, Denham JW, Hondermarck H, 'Spinal Cord Injuries and Nerve Dependence in Prostate Cancer', Trends in Cancer, 3 812-815 (2017) [C1]
Nerves are emerging as drivers of tumorigenesis, as demonstrated in the mouse where denervation suppresses prostate cancer; however, clinical evidence is needed. Patients with spi... [more]
Nerves are emerging as drivers of tumorigenesis, as demonstrated in the mouse where denervation suppresses prostate cancer; however, clinical evidence is needed. Patients with spinal cord injuries (SCIs) resulting in functional denervation of the prostate have a lower incidence of prostate cancer. This may constitute a clinical evidence for nerve dependence in human prostate tumorigenesis.
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Nova |
2017 |
Carreiro JN, Magnani M, Jobling P, van Helden DF, Nalivaiko E, Braga VA, 'Resveratrol restores uterine contractions during hypoxia by blockade of ATP-sensitive potassium channels', Journal of Functional Foods, 33 307-313 (2017) [C1]
This study assessed the¿effects of resveratrol, a polyphenol¿found in grapes and red wine¿on non-pregnant murine uteri under hypoxia. Resveratrol at 1, 3, 10, 30 and 100¿µM promot... [more]
This study assessed the¿effects of resveratrol, a polyphenol¿found in grapes and red wine¿on non-pregnant murine uteri under hypoxia. Resveratrol at 1, 3, 10, 30 and 100¿µM promoted uterine relaxation and decreased the amplitude and frequency of spontaneous uterine contractions. Assayed at 3, 10, 30¿µM, resveratrol inhibited the oxytocin-induced cumulative contractions reducing the maximum effect in a dose-dependent manner. In hypoxic uteri, resveratrol at 100¿µM restored the uterine contractions compromised by hypoxia. In addition, under hypoxia, resveratrol prevented the decrease in uterine contractions maintaining >75% of its contraction capability. The effects of resveratrol on uterine contractions under hypoxia were attenuated by tetraethylammonium (10¿mM) and almost abolished by glibenclamide (10¿µM). Our¿results show regenerative and protective effects of resveratrol in non-pregnant murine uteri under hypoxia and describes for the first time that these effects are mediated by blockade of ATP-sensitive potassium channels.
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Nova |
2016 |
Duchatel RJ, Jobling P, Graham BA, Harms LR, Michie PT, Hodgson DM, Tooney PA, 'Increased white matter neuron density in a rat model of maternal immune activation - Implications for schizophrenia', Progress in Neuro-Psychopharmacology and Biological Psychiatry, 65 118-126 (2016) [C1]
Interstitial neurons are located among white matter tracts of the human and rodent brain. Post-mortem studies have identified increased interstitial white matter neuron (IWMN) den... [more]
Interstitial neurons are located among white matter tracts of the human and rodent brain. Post-mortem studies have identified increased interstitial white matter neuron (IWMN) density in the fibre tracts below the cortex in people with schizophrenia. The current study assesses IWMN pathology in a model of maternal immune activation (MIA); a risk factor for schizophrenia. Experimental MIA was produced by an injection of polyinosinic:polycytidylic acid (PolyI:C) into pregnant rats on gestational day (GD) 10 or GD19. A separate control group received saline injections. The density of neuronal nuclear antigen (NeuN<sup>+</sup>) and somatostatin (SST<sup>+</sup>) IWMNs was determined in the white matter of the corpus callosum in two rostrocaudally adjacent areas in the 12week old offspring of GD10 (n=10) or GD19 polyI:C dams (n=18) compared to controls (n=20). NeuN<sup>+</sup> IWMN density trended to be higher in offspring from dams exposed to polyI:C at GD19, but not GD10. A subpopulation of these NeuN<sup>+</sup> IWMNs was shown to express SST. PolyI:C treatment of dams induced a significant increase in the density of SST<sup>+</sup> IWMNs in the offspring when delivered at both gestational stages with more regionally widespread effects observed at GD19. A positive correlation was observed between NeuN<sup>+</sup> and SST<sup>+</sup> IWMN density in animals exposed to polyI:C at GD19, but not controls. This is the first study to show that MIA increases IWMN density in adult offspring in a similar manner to that seen in the brain in schizophrenia. This suggests the MIA model will be useful in future studies aimed at probing the relationship between IWMNs and schizophrenia.
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Nova |
2016 |
Smith KM, Boyle KA, Mustapa M, Jobling P, Callister RJ, Hughes DI, Graham BA, 'Distinct forms of synaptic inhibition and neuromodulation regulate calretinin-positive neuron excitability in the spinal cord dorsal horn', Neuroscience, 326 10-21 (2016) [C1]
The dorsal horn (DH) of the spinal cord contains a heterogenous population of neurons that process incoming sensory signals before information ascends to the brain. We have recent... [more]
The dorsal horn (DH) of the spinal cord contains a heterogenous population of neurons that process incoming sensory signals before information ascends to the brain. We have recently characterized calretinin-expressing (CR+) neurons in the DH and shown that they can be divided into excitatory and inhibitory subpopulations. The excitatory population receives high-frequency excitatory synaptic input and expresses delayed firing action potential discharge, whereas the inhibitory population receives weak excitatory drive and exhibits tonic or initial bursting discharge. Here, we characterize inhibitory synaptic input and neuromodulation in the two CR+ populations, in order to determine how each is regulated. We show that excitatory CR+ neurons receive mixed inhibition from GABAergic and glycinergic sources, whereas inhibitory CR+ neurons receive inhibition, which is dominated by glycine. Noradrenaline and serotonin produced robust outward currents in excitatory CR+ neurons, predicting an inhibitory action on these neurons, but neither neuromodulator produced a response in CR+ inhibitory neurons. In contrast, enkephalin (along with selective mu and delta opioid receptor agonists) produced outward currents in inhibitory CR+ neurons, consistent with an inhibitory action but did not affect the excitatory CR+ population. Our findings show that the pharmacology of inhibitory inputs and neuromodulator actions on CR+ cells, along with their excitatory inputs can define these two subpopulations further, and this could be exploited to modulate discrete aspects of sensory processing selectively in the DH.
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Nova |
2015 |
Jobling P, 'Sympathy for the ganglion', Journal of Physiology, 593 755-756 (2015) [C3]
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2015 |
Smith KM, Boyle KA, Madden JF, Dickinson SA, Jobling P, Callister RJ, et al., 'Functional heterogeneity of calretinin-expressing neurons in the mouse superficial dorsal horn: Implications for spinal pain processing', Journal of Physiology, 593 4319-4339 (2015) [C1]
Neurons in the superficial dorsal horn (SDH) of the spinal cord play an important role in nociceptive, thermal, itch and light touch sensations. Excitatory interneurons comprise ~... [more]
Neurons in the superficial dorsal horn (SDH) of the spinal cord play an important role in nociceptive, thermal, itch and light touch sensations. Excitatory interneurons comprise ~65% of all SDH neurons but surprisingly few studies have investigated their role in spinal sensory processing. Here we use a transgenic mouse to study putative excitatory SDH neurons that express the calcium binding protein calretinin (CR). Our immunocytochemical, morphological and electrophysiological analysis identified two distinct populations of CR-expressing neurons, which we termed 'Typical' and 'Atypical'. Typical CR-expressing neurons comprised ~85% of the population and exhibited characteristic excitatory interneuron properties including delayed firing discharge, large rapid A-type potassium currents, and central, radial or vertical cell morphologies. Atypical neurons exhibited properties consistent with inhibitory interneurons, including tonic firing or initial bursting discharge, Ih currents, and islet cell morphology. Although both Typical and Atypical CR-expressing neurons responded to noxious peripheral stimulation, the excitatory drive onto Typical CR-expressing neurons was much stronger. Furthermore, Atypical CR-expressing cells comprise at least two functionally distinct subpopulations based on their responsiveness to noxious peripheral stimulation and neurochemical profile. Together our data suggest CR expression is not restricted to excitatory neurons in the SDH. Under normal conditions, the contribution of 'Typical' excitatory CR-expressing neurons to overall SDH excitability may be limited by the presence of A-type potassium currents, which limit the effectiveness of their strong excitatory input. Their contribution may, however, be increased in pathological situations where A-type potassium currents are decreased. By contrast, 'Atypical' inhibitory neurons with their excitable phenotype but weak excitatory input may be more easily recruited during increased peripheral stimulation.
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Nova |
2015 |
Jobling P, Pundavela J, Oliveira SMR, Roselli S, Walker MM, Hondermarck H, 'Nerve-Cancer Cell Cross-talk: A Novel Promoter of Tumor Progression', CANCER RESEARCH, 75 1777-1781 (2015) [C1]
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Nova |
2015 |
Pundavela J, Roselli S, Faulkner S, Attia J, Scott RJ, Thorne RF, et al., 'Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer', Molecular Oncology, 9 1626-1635 (2015) [C1]
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Nova |
2014 |
Pundavela J, Demont Y, Jobling P, Lincz LF, Roselli S, Thorne RF, et al., 'ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer', American Journal of Pathology, 184 3156-3162 (2014) [C1]
Nerve infiltration is essential to prostate cancer progression, but the mechanism by which nerves are attracted to prostate tumors remains unknown. We report that the precursor of... [more]
Nerve infiltration is essential to prostate cancer progression, but the mechanism by which nerves are attracted to prostate tumors remains unknown. We report that the precursor of nerve growth factor (proNGF) is overexpressed in prostate cancer and involved in the ability of prostate cancer cells to induce axonogenesis. A series of 120 prostate cancer and benign prostate hyperplasia (BPH) samples were analyzed by IHC for proNGF. ProNGF was mainly localized in the cytoplasm of epithelial cells, with marked expression in cancer compared with BPH. Importantly, the proNGF level positively correlated with the Gleason score (n = 104, tB = 0.51). A higher level of proNGF was observed in tumors with a Gleason score of =8 compared with a Gleason score of 7 and 6 (P < 0.001). In vitro, proNGF was detected in LNCaP, DU145, and PC-3 prostate cancer cells and BPH-1 cells but not in RWPE-1 immortalized nontumorigenic prostate epithelial cells or primary normal prostate epithelial cells. Co-culture of PC12 neuronal-like cells or 50B11 neurons with PC-3 cells resulted in neurite outgrowth in neuronal cells that was inhibited by blocking antibodies against proNGF, indicating that prostate cancer cells can induce axonogenesis via secretion of proNGF. These data reveal that ProNGF is a biomarker associated with high-risk prostate cancers and a potential driver of infiltration by nerves.
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Nova |
2014 |
Gravina FS, Van Helden DF, Kerr KP, De Oliveira RB, Jobling P, 'Phasic contractions of the mouse vagina and cervix at different phases of the estrus cycle and during late pregnancy', PLoS ONE, 9 (2014) [C1]
Conclusions/Significance: Cervical smooth muscle strips taken from mice in estrus, metestrus or late pregnancy were generally spontaneously active. Vaginal smooth muscle strips we... [more]
Conclusions/Significance: Cervical smooth muscle strips taken from mice in estrus, metestrus or late pregnancy were generally spontaneously active. Vaginal smooth muscle strips were normally quiescent but could be induced to exhibit phasic contractions independent on phase of the estrus cycle or late pregnancy. Spontaneous cervical or TEA-induced vaginal phasic contractions were not mediated by ICs or intracellular Ca2+ stores. Given that vaginal smooth muscle is normally quiescent then it is likely that increases in hormones such as oxytocin, as might occur through sexual stimulation, enhance the effectiveness of such pacemaking until phasic contractile activity emerges.
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Nova |
2014 |
Jobling P, O'Hara K, Hua S, 'Female reproductive tract pain: Targets, challenges, and outcomes', Frontiers in Pharmacology, 5 FEB (2014) [C1]
Pain from the female reproductive tract (FRT) is a significant clinical problem for which there are few effective therapies. The complex neuroanatomy of pelvic organs not only mak... [more]
Pain from the female reproductive tract (FRT) is a significant clinical problem for which there are few effective therapies. The complex neuroanatomy of pelvic organs not only makes diagnosis of pelvic pain disorders difficult but represents a challenge to development of targeted therapies. A number of potential therapeutic targets have been identified on sensory neurons supplying the FRT but our knowledge on the basic neurophysiology of these neurons is limited compared with other viscera. Until this is addressed we can only guess if the new experimental therapies proposed for somatic, gastrointestinal, or bladder pain will translate to the FRT. Once suitable therapeutic targets become clear, the next challenge is drug delivery. The FRT represents a promising system for topical drug delivery that could be tailored to act locally or systemically depending on formulation. Development of these therapies and their delivery systems will need to be done in concert with more robust in vivo and in vitro models of FRT pain. © 2014 Jobling, O'Hara and Hua.
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Nova |
2013 |
Bobrovskaya L, Beard D, Bondarenko E, Beig MI, Jobling P, Walker FR, et al., 'Does exposure to chronic stress influence blood pressure in rats?', AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL, 177 217-223 (2013) [C1]
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Nova |
2012 |
Yeoh JW, James MH, Jobling P, Bains JS, Graham BA, Dayas CV, 'Cocaine potentiates excitatory drive in the perifornical/lateral hypothalamus', Journal of Physiology, 590 3677-3689 (2012) [C1]
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Nova |
2011 |
Jobling P, 'Autonomic control of the urogenital tract', Autonomic Neuroscience: Basic and Clinical, 165 113-126 (2011) [C1]
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Nova |
2011 |
Gravina FS, Jobling P, Kerr KP, De Oliveira R, Parkington HC, Van Helden DF, 'Oxytocin depolarizes mitochondria in isolated myometrial cells', Experimental Physiology, 96 949-956 (2011) [C1]
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Nova |
2010 |
Jobling P, Graham BA, Brichta AM, Callister RJ, 'Cervix stimulation evokes predominantly subthreshold synaptic responses in mouse thoracolumbar and lumbosacral superficial dorsal horn neurons', Journal of Sexual Medicine, 7 2068-2076 (2010) [C1]
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Nova |
2010 |
Gravina FS, Parkington HC, Kerr KP, De Oliveira R, Jobling P, Coleman HA, et al., 'Role of mitochondria in contraction and pacemaking in the mouse uterus', British Journal of Pharmacology, 161 1375-1390 (2010) [C1]
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Nova |
2009 |
Jobling P, 'W-conotoxin GVIA sensitive calcium channels on preganglionic nerve terminals in mouse pelvic and celiac ganglia', Autonomic Neuroscience: Basic and Clinical, 146 56-61 (2009) [C1]
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Nova |
2008 |
Jobling P, Lim R, 'Anatomical and physiological properties of pelvic ganglion neurons in female mice', Autonomic Neuroscience: Basic & Clinical, 140 30-39 (2008) [C1]
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Nova |
2005 |
Morris JL, Gibbins IL, Jobling P, 'Post-stimulus potentiation of transmission in pelvic ganglia enhances sympathetic dilatation of guinea-pig uterine artery in vitro', Journal of Physiology, 566 189-203 (2005) [C1]
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Nova |
2005 |
Morris JL, Konig P, Shimizu T, Jobling P, Gibbins IL, 'Most peptide-containing sensory neurons lack proteins for exocytotic release and vesicular transport of glutamate', Journal of Comparative Neurology, 483 1-16 (2005) [C1]
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Nova |
2004 |
Ozols D, Morris JL, Lewis RJ, Gibbins IL, Jobling P, 'Differential involvement of N-type calcium channels in transmitter release from vasoconstrictor and vasodilator neurons.', British Journal of Pharmacology, 141 961-970 (2004) [C1]
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2004 |
Jobling P, Gibbins IL, Lewis RJ, Morris JL, 'Differential expression of calcium channels in sympathetic and parasympathetic preganglionic inputs to neurons in paracervical ganglia of guinea-pigs.', Neuroscience, 127 455-466 (2004) [C1]
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2003 |
Jobling P, Gibbins IL, Morris JL, 'Functional organization of vasodilator neurons in pelvic ganglia of female guinea pigs: comparison with uterine motor neurons.', Journal of Comparative Neurology, 459 223-241 (2003) [C1]
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2003 |
Anderson RL, Jobling P, Matthew SE, Gibbins IL, 'Development of convergent synaptic inputs to subpopulations of autonomic neurons', Journal of Comparative Neurology, 447 218-233 (2003) [C1]
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2003 |
Gibbins IL, Teo EH, Jobling P, Morris JL, 'Synaptic density, convergence and dendritic complexity of prevertebral sympathetic neurons. Journal of Comparative Neurology', Journal of Comparative Neurology, 455 285-298 (2003) [C1]
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2003 |
Gibbins IL, Jobling P, Teo EH, Matthew SE, Morris JL, 'Heterogenous expression of SNAP-25 and synaptic vesicle proteins by central and peripheral inputs to sympathetic neurons.', Journal of Comparative Neurology, 459 25-43 (2003) [C1]
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2003 |
Morris JL, Jobling P, Shimizu T, Gibbins IL, 'Interleukin-1 receptor immunoreactivity in sympathetic vascular and non vascular neurons in the guinea-pig coeliac ganglion', Neuroscience Letters, 333 54-58 (2003) [C1]
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2002 |
Morris JL, Jobling P, Gibbins IL, 'Botulinum neurotoxin A attenuates release of norepinepherine but not neuropeptide Y from vasoconstrictor neurons', American Journal of Physiology. 283: H2627-2635., 2627-2635 (2002) [C1]
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2001 |
Jobling P, Messenger JP, Gibbins IL, 'Differential expression of functionally identified and immunohistochemically identified NK1 receptors on sympathetic neurons.', Journal of Neurophysiology 85: 1888-1898., 1888-1898 (2001) [C1]
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2001 |
Anderson RL, Jobling P, Gibbins IL, 'Development of electrophysiological and morphological diversity in autonomic neurons.', Journal of Neurophysiology 86: 1237-1251., 1237-1251 (2001) [C1]
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2001 |
Morris JL, Jobling P, Gibbins IL, 'Differential inhibition by botulinum neurotoxin A of cotransmitters released from autonomic vasodilator neurons', American Journal of Physiology. 281: H2124-2132., 2124-2132 (2001) [C1]
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2000 |
Jobling P, Gibbins IL, 'Erratum: Electrophysiological and morphological diversity of mouse sympathetic neurons (Journal of Neurophysiology (November 1999) 82 (2747- 2764))', Journal of Neurophysiology, 83 (2000) |
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2000 |
Jobling P, Gibbins IL, 'Erratum: Electrophysiological and morphological diversity of mouse sympathetic neurons (Journal of Neurophysiology (Nov. 1999) 82 (2747-2764))', Journal of Neurophysiology, 83 (2000) |
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2000 |
Gibbins IL, Jobling P, Messenger JP, Teo EH, Morris JL, 'Neuronal morphology and the synaptic organisation of sympathetic ganglia', Journal of the Autonomic Nervous System, 81 104-109 (2000)
In this article, we provide a short review of the structure and synaptic organisation of the final motor neurons in the sympathetic ganglia of mammals. Combinations of pathway tra... [more]
In this article, we provide a short review of the structure and synaptic organisation of the final motor neurons in the sympathetic ganglia of mammals. Combinations of pathway tracing, multiple-labelling immunofluorescence and intracellular dye injection have shown that neurons in different functional pathways differ not only in their patterns of neuropeptide expression, but also in the size of their cell bodies and dendritic fields. Thus, vasoconstrictor neurons consistently are smaller than any other major functional class of neurons. Serial section ultrastructural analysis of dye filled neurons, together with electron microscopic and confocal microscopic analysis of immunolabelled synaptic inputs to sympathetic final motor neurons indicate that synapses are rare and randomly distributed over the surface of the neurons. The total number of synapses is simply proportional to the total surface area of the neurons. Many terminal boutons of peptide-containing preganglionic neurons do not make conventional synapses with target neurons. Furthermore, there is a spatial mismatch in the distribution of peptide-containing terminals and neurons expressing receptors for the corresponding peptides. Together, these results suggest that there are likely to be significant differences in the ways that the final sympathetic motor neurons in distinct functional pathways integrate their synaptic inputs. In at least some pathways, heterosynaptic actions of neuropeptides probably contribute to subtle modulation of ganglionic transmission. (C) 2000 Elsevier Science B.V.
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1999 |
Jobling P, Gibbins IL, 'Electrophysiological and morphological diversity of mouse sympathetic neurons', Journal of Neurophysiology, 82 2747-2764 (1999)
We have used multiple-labeling immunohistochemistry, intracellular dye- filling, and intracellular microelectrode recordings to characterize the morphological and electrical prope... [more]
We have used multiple-labeling immunohistochemistry, intracellular dye- filling, and intracellular microelectrode recordings to characterize the morphological and electrical properties of sympathetic neurons in the superior cervical, thoracic, and celiac ganglia of mice. Neurochemical and morphological characteristics of neurons varied between ganglia. Thoracic sympathetic ganglia contained three main populations of neurons based on differential patterns of expression of immunoreactivity to tyrosine hydroxylase, neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). In the celiac ganglion, nearly all neurons contained immunoreactivity to both tyrosine hydroxylase and NPY. Both the overall size of the dendritic tree and the number of primary dendrites were greater in neurons from the thoracic and celiac ganglia compared with those from the superior cervical ganglion. The electrophysiological properties of sympathetic neurons depended more on their ganglion of origin rather than their probable targets. All neurons in the superior cervical ganglion had phasic firing properties and large afterhyperpolarizations (AHPs). In addition, 34% of these neurons displayed an afterdepolarization preceding the AHP. Superior cervical ganglion neurons had prominent I(M), I(A), and I(H) currents and a linear currentvoltage relationship between -60 and -110 mV. Neurons from the thoracic ganglia had significantly smaller action potentials, AHPs, and apparent cell capacitance compared with superior cervical ganglion neurons, and only 18% showed an afterdepolarization. All neurons in superior cervical ganglia and most neurons in celiac ganglia received at least one strong preganglionic input. Nearly one-half the neurons in the celiac ganglion had tonic firing properties, and another 15% had firing properties intermediate between those of tonic and phasic neurons. Most celiac neurons showed significant inward rectification below -90 mV. They also expressed I(A), but with slower inactivation kinetics than that of superior cervical or thoracic neurons. Both phasic and tonic celiac ganglion neurons received synaptic inputs via the celiac nerves in addition to strong inputs via the splanchnic nerves. Multivariate statistical analysis revealed that the properties of the action potential, the AHP, and the apparent cell capacitance together were sufficient to correctly classify 80% of neurons according to their ganglion of origin. These results indicate that there is considerable heterogeneity in the morphological, neurochemical, and electrical properties of sympathetic neurons in mice. Although the morphological and neurochemical characteristics of the neurons are likely to be related to their peripheral projections, the expression of particular electrophysiological traits seems to be more closely related to the ganglia within which the neurons occur.
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1999 |
Gibbins IL, Matthew SE, Jobling P, 'Pathway-specific expression of PKC and PKA in sympathetic neurons', NeuroReport, 10 975-979 (1999)
We used multiple-labelling immunofluorescence, intracellular dye injection, electrophysiological recording and confocal microscopy to examine the expression of immunoreactivity to... [more]
We used multiple-labelling immunofluorescence, intracellular dye injection, electrophysiological recording and confocal microscopy to examine the expression of immunoreactivity to protein kinase C (PKC) and protein kinase A (PKA) in sympathetic ganglia of guinea-pigs. PKCa and PKC¿ were widespread in vasoconstrictor and pilomotor neurons. High levels of PKA RIIa and RIIß were restricted to neurons that lacked significant expression of PKC, including somatostatin-containing neurons projecting to the gut, and non-noradrenergic vasodilator neurons. In coeliac ganglia, most neurons with PKC contained neuropeptide Y and displayed phasic patterns of action potential firing, often with a long after-hyperpolarization. Tonically firing neurons lacked both neuropeptide Y and PKC. These results show remarkably pathway-specific expression of protein kinases in functionally identified populations of sympathetic neurons.
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1997 |
Brookes SJH, Meedeniya ACB, Jobling P, Costa M, 'Orally projecting interneurones in the guinea-pig small intestine', Journal of Physiology, 505 473-491 (1997)
1. Orally projecting, cholinergic interneurones are important in mediating ascending excitatory reflexes in the small intestine. We have shown that there is just one major class o... [more]
1. Orally projecting, cholinergic interneurones are important in mediating ascending excitatory reflexes in the small intestine. We have shown that there is just one major class of orally projecting interneurone, which we have characterized using retrograde labelling in organ culture, combined with immunohistochemistry, intracellular recording and dye filling. 2. Orally projecting interneurones, previously shown to be immunoreactive for choline acetyltransferase, tachykinins, enkephalin, calretinin and neurofilament protein triplet, have axons up to 14 mm long and are the only class of cells with orally directed axons more than 8.5 mm long. 3. They are all small Dogiel type I neurones with short dendrites, usually lamellar in form, and a single axon which sometimes bifurcates. Their axons give rise to short varicose collaterals in myenteric ganglia more than 3 mm oral to their cell bodies. 4. Orally projecting interneurones receive prominent fast excitatory post synaptic potentials (fast EPSPs). A major source of fast EPSPs is other ascending interneurones located further aborally. They also receive fast EPSPs from circumferential pathways. 5. In the stretched preparations used in this study orally projecting interneurones were highly excitable, firing repeatedly to depolarizing current pulses and had negligible long after-hyperpolarizations following their action potentials. They did not receive measurable noncholinergic slow excitatory synaptic inputs. 6. Ascending interneurones had a characteristic inflection in their membrane responses to depolarizing current pulses and their first action potential was typically delayed by approximately 30 ms. Under single electrode voltage clamp, ascending interneurones had a transient outward current when depolarized above -70 mV from more hyperpolarized holding potentials. Ascending interneurones also consistently showed marked inward rectification under both current clamp and voltage clamp conditions. 7. This class of cells has consistent morphological, neurochemical and electrophysiological characteristics and are important in mediating orally directed enteric reflexes.
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1996 |
Jobling P, Horn JP, 'In vitro relation between preganglionic sympathetic stimulation and activity of cutaneous glands in the bullfrog', Journal of Physiology, 494 287-296 (1996)
1. Activation of cutaneous glands was studied by measuring changes in transepithelial potential (TEP) after pre- and postganglionic sympathetic stimulation in the bullfrog, Rana c... [more]
1. Activation of cutaneous glands was studied by measuring changes in transepithelial potential (TEP) after pre- and postganglionic sympathetic stimulation in the bullfrog, Rana catesbeiana. 2. In normal Ringer solution, TEP was 20-90 mV with the basolateral (inside) surface positive. Single shocks to the preganglionic B pathway decreased TEP by up to 3 mV. Cutaneous depolarizations had a latency of 1.2 s, a rise time of 2.5 s, and decayed with an exponential time constant of 15 s. Similar depolarizations were evoked by postganglionic stimulation. 3. Cutaneous depolarizations summed during repetitive stimulation at > 0.05 Hz. For trains of three stimuli, peak amplitude increased with frequency and saturated at 2 Hz. In some preparations, longer trains evoked polyphasic changes in TEP. Preganglionically evoked cutaneous responses were abolished by (+)-tubocurarine. Postganglionically evoked cutaneous depolarizations were antagonized by phentolamine, but not propranolol. 4. Repetitive preganglionic stimulation of the C pathway (> 100 at 20 Hz) evoked little change in TEP and did not modulate depolarizations evoked through the B pathway. In nicotine, peptidergic cotransmission was enhanced in the ganglia, and repetitive C pathway stimulation evoked cutaneous depolarizations whose time course mirrored that of the postganglionic peptidergic after-discharge. The after-discharge and associated cutaneous depolarization were blocked by a luteinizing hormone-releasing hormone antagonist. 5. The results show cutaneous glands are selectively innervated by B neurones and respond to low levels of neural activity. Asynchronous postganglionic firing mediated by peptidergic cotransmission can provide a basis for heterosynaptic interactions between the B and C pathways.
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1995 |
Brock JA, McLachlan EM, Jobling P, Lewis RJ, 'Electrical activity in rat tail artery during asynchronous activation of postganglionic nerve terminals by ciguatoxin-1', British Journal of Pharmacology, 116 2213-2220 (1995)
The effects of ciguatoxin-1 (CTX-1) on the membrane potential of smooth muscle cells have been examined in rat proximal tail arteries isolated in vitro. CTX-1 (= 10 pM) increased ... [more]
The effects of ciguatoxin-1 (CTX-1) on the membrane potential of smooth muscle cells have been examined in rat proximal tail arteries isolated in vitro. CTX-1 (= 10 pM) increased the frequency of spontaneous excitatory junction potentials (s.ej.ps). At 100¿400 pM, there was also a marked and maintained depolarization (19.7 ± 1.4 mV, n=14, at 400 pM). In 20¿400 pM CTX-1, perivascular stimuli evoked excitatory junction potentials (s.e.j.ps) which were prolonged in time course relative to control. Although threshold and latency of the e.j.p. were not affected by CTX-1 (=400 pM), propagated impulses were blocked at = 100 pM. The spontaneous activity and the depolarization produced by CTX-1 were reduced in the presence of Ca2+ (0.1 mM)/Mg2+ (25 mM), ¿-conotoxin (0.1 µm) or Cd2+ (50¿100 µm) All effects of CTX-1 were abolished by tetrodotoxin (0.3 µm). Raised Ca2+ (6 mM) reduced the depolarization and spontaneous activity produced by CTX-1. In 400 pM CTX-1, the membrane repolarized (17 ± 3.2 mV, n=4) following the addition of phentolamine (1 µm). S.e.j.ps and e.j.ps were selectively abolished by suramin (1 mM), and the membrane repolarized by 1.3±1.6 mV (n=4). We conclude that CTX-1 releases noradrenaline and ATP by initiating asynchronous discharge of postganglionic perivascular axons. In 100¿400 pM CTX-1, the smooth muscle was depolarized to levels resembling those recorded in this artery during ongoing vasoconstrictor discharge in vivo. 1995 British Pharmacological Society
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1994 |
Shen W, Jobling P, Horn JP, 'The sensitivity of nicotinic synapses in bullfrog sympathetic ganglia to a-bungarotoxin and neuronal-bungarotoxin', British Journal of Pharmacology, 113 898-902 (1994)
The sensitivity of nicotinic synapses to a-bungarotoxin (a-Bgt) and neuronal-bungarotoxin (n-Bgt) was measured in the B and C cell systems of bullfrog paravertebral sympathetic ga... [more]
The sensitivity of nicotinic synapses to a-bungarotoxin (a-Bgt) and neuronal-bungarotoxin (n-Bgt) was measured in the B and C cell systems of bullfrog paravertebral sympathetic ganglia 9 and 10 by recording extracellular compound postganglionic action potentials from the rami communicantes. High concentrations (10 µm) of a-Bgt applied for up to 8 h had no effect upon synaptic transmission in either the B or C cell system. Ganglia pretreated with collagenase were also insensitive to a-Bgt. In control experiments on isolated sartorius muscle preparations, nerve-evoked twitches were fully blocked by 30-100nM a-Bgt. Nicotinic transmission in the B and C cell systems was reversibly blocked by 30¿300 nm n-Bgt. Block appeared within 25¿45 min of exposure to toxin and reversed fully with a half-time of 40-80min. This was indistinguishable from washout times after block by 100 µm (+)-tubocurarine. The results demonstrate close parallels between the bungarotoxin sensitivity of neuronal nicotinic receptors mediating ganglionic transmission in functional subclasses of bullfrog sympathetic neurones and the bungarotoxin sensitivity which has been reported for autonomic neurones in avian and mammalian preparations. 1994 British Pharmacological Society
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1994 |
Jobling P, 'Electrophysiological events during neuroeffector transmission in the spleen of guinea-pigs and rats.', The Journal of Physiology, 476 153-165 (1994)
Intracellular recordings were made from smooth muscle cells of arterioles and the capsule of the spleen of guinea-pig and rat, and the responses to periarterial or subcapsular ner... [more]
Intracellular recordings were made from smooth muscle cells of arterioles and the capsule of the spleen of guinea-pig and rat, and the responses to periarterial or subcapsular nerve stimulation were recorded. The innervation of the spleen was studied using fluorescence and immunohistochemical techniques. Catecholamine-containing axons were associated with smooth muscle of the splenic capsule, trabeculae, arterioles and amongst cells of the periarteriolar lymphoid sheath. Axons immunoreactive for neuropeptide Y (NPY) and tyrosine hydroxylase were distributed in an identical manner to catecholamine-containing axons, whereas axons immunoreactive for substance P or calcitonin gene-related peptide were present at a very low density in spleens from both species. In segments of arterioles, single transmural stimuli evoked excitatory junction potentials (EJPs) of 1-10 mV amplitude. EJPs facilitated during short trains of stimuli (1-10 Hz) and summated at 10 Hz, often initiating a muscle action potential. EJPs persisted in the presence of prazosin (1 microM) and idazoxan (1 microM), but were abolished by the P2x-purinoceptor antagonist suramin (1 mM). Spontaneous depolarizations were observed in smooth muscle cells of arterioles and capsule. Some events in arterioles were observed in the presence of suramin and so may originate postjunctionally independently of transmitter release. As single transmural stimuli failed to evoke a depolarization in capsular smooth muscle, spontaneous depolarizations in this tissue probably also arise postjunctionally. Short trains of high frequency stimuli (10-35 Hz) evoked biphasic depolarizations of capsular smooth muscle cells. The initial component peaked 2.5 s following the onset of stimulation; the second component peaked 15 s following the onset and decayed exponentially with a time constant of 15 s. By fitting a product of exponentials to the second component, it was possible to define the initial component, which decayed with a time constant of around 1.5 s. Neurally evoked depolarizations of capsular smooth muscle were abolished by 1 microM TTX. Blockade of alpha 1-adrenoceptors with prazosin reduced the initial component of the depolarization, whereas alpha 2-adrenoceptor blockade with idazoxan virtually abolished the second component. In some cells a small, faster depolarization persisted after alpha-adrenoceptor blockade. The slow alpha 2-adrenoceptor-mediated depolarization was identical to that recorded in the rat tail artery and in the guinea-pig mesenteric vein. The data indicate that sympathetic neuroeffector transmission from noradrenergic axons containing NPY to splenic arterial and capsular smooth muscle occur by different mechanisms. © 1994 The Physiological Society
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1993 |
Jobling P, McLachlan EM, Sah P, 'Calcium induced calcium release is involved in the afterhyperpolarization in one class of guinea pig sympathetic neurone', Journal of the Autonomic Nervous System, 42 251-257 (1993)
The mechanisms underlying two potassium conductances which are activated by Ca2+ influx during the action potential in ympathetic prevertebral neurones of guinea pigs have been in... [more]
The mechanisms underlying two potassium conductances which are activated by Ca2+ influx during the action potential in ympathetic prevertebral neurones of guinea pigs have been investigated pharmacologically. One Ca-activated K+ conductance, which is present in all mammalian sympathetic postganglionic neurones, is maximal after the action potential and decays exponentially with a time constant of about 130 ms; this conductance was inhibited by apamin (50-100 nM) consistent with the involvement of SK channels. A second Ca-activated K+ conductance with much slower kinetics is present in a large subpopulation of coeliac neurones. This conductance was resistant to apamin but markedly inhibited by application of ryanodine (5-20 µM). suggesting that Ca2+ influx during the action potential triggers release of Ca2+ from intracellular stores which in turn activates a different class of K+ channel. Noradrenaline (100 µM) depressed the second K+ conductance selectively. © 1993.
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1992 |
Jobling P, McLachlan EM, 'An electrophysiological study of responses evoked in isolated segments of rat tail artery during growth and maturation.', The Journal of Physiology, 454 83-105 (1992)
1. Intracellular recordings from the smooth muscle of isolated segments of the main caudal artery of rats at various ages between 45 and 150 days postnatal were made in order to r... [more]
1. Intracellular recordings from the smooth muscle of isolated segments of the main caudal artery of rats at various ages between 45 and 150 days postnatal were made in order to relate the spontaneous depolarizations and responses to perivascular stimulation at different levels along the artery to the differences in vessel structure and innervation density during growth of the animals. 2. In the outermost smooth muscle cells close to the neuromuscular junctions, spontaneous depolarizations with fast time courses (spontaneous excitatory junction potentials or SEJPs) were recorded. In cells lying deeper in the media, spontaneous depolarizations had a wide range of time courses and amplitudes, but only a few of those could be attributed to electrotonic attenuation of SEJPs. 3. In arterial segments taken from animals of all ages, stimuli which evoked maximal amplitude excitatory junction potentials (EJPs) 1-2 mm caudal to a suction electrode also evoked neurogenic alpha-depolarizations (NADs) with time to peak of 15 s and duration nearly 1 min. Both responses decreased progressively in amplitude along the length of the artery. NADs were blocked by phentolamine (10(-6) M) or idazoxan (10(-7) M) which were without effects on EJPs. 4. During short trains of stimuli (5 at 1 or 10 Hz), EJPs facilitated but to a lesser extent with distance along the tail. Such trains evoked NADs of greater amplitude than those following a single stimulus; these were often preceded by contractions of the artery which were restricted to the region close to the stimulating electrode. 5. Increasing stimulus voltage led to progressive prolongation of the decay phase of the EJP. After the addition of tetrodotoxin (10(-7) M), or in the presence of reduced Ca2+ and raised Mg2+ concentration, slow depolarizing potentials (SDPs) (with time to peak of 150-300 ms and decay lasting > 2 s) were recorded which were graded in amplitude with stimulus voltage. SDPs were attenuated by increasing Ca2+ concentration to 5 mM. These responses often added to the EJP at supramaximal stimulus voltages. 6. The mean amplitudes of the EJP and NAD declined significantly with age, the former to a greater degree than the latter. These changes may be explained by changes in the electrical properties of the media related to hypertrophy of smooth muscle cells as the animals grew, and emphasize the need to allow for such growth effects in studies of young rats.(ABSTRACT TRUNCATED AT 400 WORDS) © 1992 The Physiological Society
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1992 |
Jobling P, McLachlan EM, Jänig W, Anderson CR, 'Electrophysiological responses in the rat tail artery during reinnervation following lesions of the sympathetic supply.', The Journal of Physiology, 454 107-128 (1992)
1. Responses to perivascular stimuli have been recorded with intracellular microelectrodes from the smooth muscle of isolated segments of the main caudal artery of rats at various... [more]
1. Responses to perivascular stimuli have been recorded with intracellular microelectrodes from the smooth muscle of isolated segments of the main caudal artery of rats at various times between 7 and 128 days after all four collector nerve trunks had been lesioned near the base of the tail at 21 days of age. 2. In proximal segments (< 40 mm distal to the lesions), excitatory junction potentials (EJPs) and neurogenic alpha-depolarizations (NADs) evoked by stimuli presented via a proximally located suction electrode were similar to those in the same segments of unoperated control animals of the same age. Supramaximal EJPs in these segments decreased in amplitude with age. 3. Stimuli just supramaximal for EJPs in innervated preparations failed to evoke responses in segments farther than 30-40 mm distal to the lesions at any time after the nerves had been cut and 1 cm excised. Higher voltages evoked slow depolarizing potentials (SDPs) which were of longer time course than EJPs. Similar responses occurred in segments over 60 mm distal to the lesions at 20-50 days after the nerves had been frozen, and in all segments sampled over 100 mm distal to nerve lesions. 4. Spontaneous transient depolarizations (STDs) were recorded at all depths of the media in denervated segments. These occurred at frequencies similar to those of spontaneous events (including attenuated spontaneous EJPs) in innervated segments. 5. The earliest signs of reinnervation (24-42 days after freeze lesions) consisted of very small amplitude EJPs of normal time course which facilitated markedly during a short train of stimuli (5-10 Hz); these were followed by NADs which were large relative to the amplitudes of the EJPs. Less commonly, small focal EJPs of brief time course (resembling spontaneous EJPs in superficial cells of innervated arteries) were evoked in very restricted regions of the vessel wall. 6. At later times (57-128 days postoperative), six of eight segments located 40-70 mm distal to freeze lesions showed EJPs of nearly control amplitude, but NADs that were larger than in equivalent segments from control animals. In the remaining two cases, reinnervation at this level was similar to that seen at the earliest postoperative times. High stimulus voltages prolonged the decay of EJPs in both control and reinnervated arteries. 7. Sensitivity to exogenous noradrenaline, assessed in terms of membrane depolarization, was increased in both denervated and reinnervated segments. 8. Catecholamine fluorescence disappeared from the arteries at a distance greater than 30-40 mm distal to the site of the nerve lesions.(ABSTRACT TRUNCATED AT 400 WORDS) © 1992 The Physiological Society
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1989 |
Hirst GDS, Jobling P, 'The distribution of -adrenoceptors and P
1. Membrane potential changes and contractions were recorded from mesenteric arteries and veins of the guinea-pig, during perivascular nerve stimulation or application of noradren... [more]
1. Membrane potential changes and contractions were recorded from mesenteric arteries and veins of the guinea-pig, during perivascular nerve stimulation or application of noradrenaline or adenosine triphosphate (ATP). 2. After a-adrenoceptor blockade, noradrenaline activated low affinity adrenoceptors (¿-adrenoceptors) causing depolarization and arterial contraction only in the presence of an inhibitor of catecholamine uptake. 3. Noradrenaline did not cause depolarization or contraction of the vein after a-adrenoceptor blockade even after catecholamine uptake was blocked. 4. Adenosine triphosphate caused depolarization and contraction of both arteries and veins. These responses were abolished by a-,ß-,methylene adenosine triphosphate (Me-ATP). 5. Me-ATP abolished rapid excitatory junction potentials (e.j.ps) caused by perivascular nerve stimulation of arteries but had no effect on arterial responses mediated by ¿-adrenoceptors. 6. In veins, perivascular nerve stimulation evoked slow e.j.ps which persisted in the presence of Me-ATP but were abolished after blockade of a-adrenoceptors. 7. The observations indicate that P2 purinoceptors are present on both mesenteric artery and vein whilst ¿-adrenoceptors are localized near the neuromuscular junction of the artery. However ¿-adrenoceptors do not appear to be directly involved in the generation of arterial e.j.ps.
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