ORCID Profile
0000-0002-4445-654X
Current Organisation
University of Leeds
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Publisher: Society for Neuroscience
Date: 18-08-2004
DOI: 10.1523/JNEUROSCI.1979-04.2004
Abstract: Fast inhibition in the nervous system is commonly mediated by GABA A receptors comprised of 2α/2β/1γ subunits. In contrast, GABA C receptors containing onlyρ subunits (ρ1-ρ3) have been predominantly detected in the retina. However, here using reverse transcription-PCR and in situ hybridization we show that mRNA encoding the ρ1 subunit is highly expressed in brainstem neurons. Immunohistochemistry localized the ρ1 subunit to neurons at light and electron microscopic levels, where it was detected at synaptic junctions. Application of the GABA C receptor agonist cis- 4-aminocrotonic acid (100-800 μM) requires the ρ1 subunit to elicit responses, which surprisingly are blocked independently by antagonists to GABA A (bicuculline, 10 μM) and GABA C [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) 40-160 μM] receptors. Responses to GABA C agonists were also enhanced by the GABA A receptor modulator pentobarbitone (300 μM). Spontaneous and evoked IPSPs were reduced in litude but never abolished by TPMPA, but were completely blocked by bicuculline. We therefore tested the hypothesis that GABA A and GABA C subunits formed a heteromeric receptor. Immunohistochemistry indicated that ρ1 and α1 subunits were colocalized at light and electron microscopic levels. Electrophysiology revealed that responses to GABA C receptor agonists were enhanced by the GABA A receptor modulator zolpidem (500 n m ), which acts on the α1 subunit when the γ2 subunit is also present. Finally, coimmunoprecipitation indicated that the ρ1 subunit formed complexes that also containedα1 and γ2 subunits. Taken together these separate lines of evidence suggest that the effects of GABA in central neurons can be mediated by heteromeric complexes of GABA A and GABA C receptor subunits.
Publisher: Society for Neuroscience
Date: 02-02-2005
DOI: 10.1523/JNEUROSCI.3740-04.2005
Abstract: Homeostatic maintenance of widespread functions is critically dependent on the activity of the sympathetic nervous system. This activity is generated by the CNS acting on the sole output cells in the spinal cord, sympathetic preganglionic neurons (SPNs). SPNs are subject to control from both supraspinal and spinal inputs that exert effects through activation of direct or indirect pathways. A high proportion of indirect control is attributable to activation of spinal interneurons in a number of locations. However, little is known about the different groups of interneurons with respect to their neurochemistry or function. In this study, we report on a novel group of GABAergic interneurons located in the spinal central autonomic area (CAA) that directly inhibit SPN activity. In situ hybridization studies demonstrated a group of neurons that contained mRNA for glutamic acid decarboxylase (GAD) 65 and GAD 67 within the CAA. Combining in situ hybridization with trans-synaptic labeling from the adrenal gland using pseudorabies virus identified presympathetic GABAergic neurons in the CAA. Electrical stimulation of the CAA elicited monosynaptic IPSPs in SPNs located laterally in the intermediolateral cell column. IPSPs were GABAergic, because they reversed at the chloride reversal potential and were blocked by bicuculline. Chemical activation of neurons in the CAA hyperpolarized SPNs, an effect that was also bicuculline sensitive. We conclude that the CAA contains GABAergic interneurons that impinge directly onto SPNs to inhibit their activity and suggest that these newly identified interneurons may play an essential role in the regulation of sympathetic activity and thus homeostasis.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.AUTNEU.2016.06.004
Abstract: The human ear seems an unlikely candidate for therapies aimed at improving cardiac function, but the ear and the heart share a common connection: the vagus nerve. In recent years there has been increasing interest in the auricular branch of the vagus nerve (ABVN), a unique cutaneous sub ision of the vagus distributed to the external ear. Non-invasive electrical stimulation of this nerve through the skin may offer a simple, cost-effective alternative to the established method of vagus nerve stimulation (VNS), which requires a surgical procedure and has generated mixed results in a number of clinical trials for heart failure. This review discusses the available evidence in support of modulating cardiac activity using this strange auricular nerve.
Publisher: Wiley
Date: 06-06-2002
DOI: 10.1046/J.1471-4159.2002.00920.X
Abstract: Although originally cloned from rat brain, the P2X7 receptor has only recently been localized in neurones, and functional responses mediated by these neuronal P2X7 receptors (P2X7 R) are largely unknown. Here we studied the effect of P2X7 R activation on the release of neurotransmitters from superfused rat hippoc al slices. ATP (1-30 mm) and other ATP analogues elicited concentration-dependent [3 H]GABA outflow, with the following rank order of potency: benzoylbenzoylATP (BzATP) > ATP > ADP. PPADS, the non-selective P2-receptor antagonist (3-30 microm), Brilliant blue G (1-100 nm) the P2X7 -selective antagonist and Zn2+ (0.1-30 microm) inhibited, whereas lack of Mg2+ potentiated the response by ATP. In situ hybridization revealed that P2X7 R mRNA is expressed in the neurones of the cell body layers in the hippoc us. P2X7 R immunoreactivity was found in excitatory synaptic terminals in CA1 and CA3 region targeting the dendrites of pyramidal cells and parvalbumin labelled structures. ATP (3-30 microm) and BzATP (0.6-6 microm) elicited concentration-dependent [14 C]glutamate efflux, and blockade of the kainate receptor-mediated transmission by CNQX (10-100 microm) and gadolinium (100 microm), decreased ATP evoked [3 H]GABA efflux. The Na+ channel blocker TTX (1 microm), low temperature (12 degrees C), and the GABA uptake blocker nipecotic acid (1 mm) prevented ATP-induced [3 H]GABA efflux. Brilliant blue G and PPADS also reduced electrical field stimulation-induced [3 H]GABA efflux. In conclusion, P2X7 Rs are localized to the excitatory terminals in the hippoc us, and their activation regulates the release of glutamate and GABA from themselves and from their target cells.
Publisher: Society for Neuroscience
Date: 08-2007
DOI: 10.1523/JNEUROSCI.0638-07.2007
Abstract: Sensory afferent signals from neck muscles have been postulated to influence central cardiorespiratory control as components of postural reflexes, but neuronal pathways for this action have not been identified. The intermedius nucleus of the medulla (InM) is a target of neck muscle spindle afferents and is ideally located to influence such reflexes but is poorly investigated. To aid identification of the nucleus, we initially produced three-dimensional reconstructions of the InM in both mouse and rat. Neurochemical analysis including transgenic reporter mice expressing green fluorescent protein in GABA-synthesizing neurons, immunohistochemistry, and in situ hybridization revealed that the InM is neurochemically erse, containing GABAegric and glutamatergic neurons with some degree of colocalization with parvalbumin, neuronal nitric oxide synthase, and calretinin. Projections from the InM to the nucleus tractus solitarius (NTS) were studied electrophysiologically in rat brainstem slices. Electrical stimulation of the NTS resulted in antidromically activated action potentials within InM neurons. In addition, electrical stimulation of the InM resulted in EPSPs that were mediated by excitatory amino acids and IPSPs mediated solely by GABA A receptors or by GABA A and glycine receptors. Chemical stimulation of the InM resulted in (1) a depolarization of NTS neurons that were blocked by NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[ f ]quinoxaline-7-sulfonoamide) or kynurenic acid and (2) a hyperpolarization of NTS neurons that were blocked by bicuculline. Thus, the InM contains neurochemically erse neurons and sends both excitatory and inhibitory projections to the NTS. These data provide a novel pathway that may underlie possible reflex changes in autonomic variables after neck muscle spindle afferent activation.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.BRS.2019.05.002
Abstract: Electrical stimulation on select areas of the external auricular dermatome influences the autonomic nervous system. It has been postulated that activation of the Auricular Branch of the Vagus Nerve (ABVN) mediates such autonomic changes. However, the underlying neural pathways mediating these effects are unknown and, further, our understanding of the anatomical distribution of the ABVN in the auricle has now been questioned. To investigate the effects of electrical stimulation of the tragus on autonomic outputs in the rat and probe the underlying neural pathways. Central neuronal projections from nerves innervating the external auricle were investigated by injections of the transganglionic tracer cholera toxin B chain (CTB) into the right tragus of Wistar rats. Physiological recordings of heart rate, perfusion pressure, respiratory rate and sympathetic nerve activity were made in an anaesthetic free Working Heart Brainstem Preparation (WHBP) of the rat and changes in response to electrical stimulation of the tragus analysed. Neuronal tracing from the tragus revealed that the densest CTB labelling was within laminae III-IV of the dorsal horn of the upper cervical spinal cord, ipsilateral to the injection sites. In the medulla oblongata, CTB labelled afferents were observed in the paratrigeminal nucleus, spinal trigeminal tract and cuneate nucleus. Surprisingly, only sparse labelling was observed in the vagal afferent termination site, the nucleus tractus solitarius. Recordings made from rats at night time revealed more robust sympathetic activity in comparison to day time rats, thus subsequent experiments were conducted in rats at night time. Electrical stimulation was delivered across the tragus for 5 min. Direct recording from the sympathetic chain revealed a central sympathoinhibition by up to 36% following tragus stimulation. Sympathoinhibition remained following sectioning of the cervical vagus nerve ipsilateral to the stimulation site, but was attenuated by sectioning of the upper cervical afferent nerve roots. Inhibition of the sympathetic nervous system activity upon electrical stimulation of the tragus in the rat is mediated at least in part through sensory afferent projections to the upper cervical spinal cord. This challenges the notion that tragal stimulation is mediated by the auricular branch of the vagus nerve and suggests that alternative mechanisms may be involved.
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0006-8993(03)03112-3
Abstract: The angiotensin II type 1 receptor (AT1R) in the central nervous system (CNS) plays a pivotal role in determining blood pressure. However, the relationship of the receptor to neurones in the spinal cord which are the final CNS contribution to sympathetic outflow is unknown. Here we first use RT-PCR to show that AT1A, AT1B and AT2 receptors are expressed in thoracic spinal cord of the rat. Using light microscopic immunohistochemistry we find that the AT1 receptor in the thoracic spinal cord is located on neurones and ependymal cells. Neurones with extensive immunostaining of somata and dendrites were located in the intermediolateral cell column (IML) and lamina X (the central autonomic area), regions associated with autonomic outflow, as well as in lamina V. Retrograde labelling and dual immunolabelling with nNOS revealed that those AT1R-immunopositive cells in the IML were sympathetic preganglionic neurones, while those in lamina X were unlikely to be. Punctate labelling resembling that of axonal fibres and terminals was evident in lamina II of the dorsal horn and throughout the cord. Electron microscopy in the IML and lamina X revealed that these puncta were presynaptic terminals, but also astrocyte processes. Immunolabelling was also evident beneath the plasma membrane in neuronal somata. These data show that the AT1R in the spinal cord is ideally located to influence autonomic outflow and hence participate in the CNS determination of blood pressure.
Publisher: Wiley
Date: 20-07-2006
DOI: 10.1111/J.1471-4159.2006.04010.X
Abstract: Release of distinct cellular cargoes in response to specific stimuli is a process fundamental to all higher eukaryotes and controlled by the regulated secretory pathway (RSP). However, the mechanism by which genes involved in the RSP are selectively expressed, leading to the establishment and appropriate functioning of regulated secretion remaining largely unknown. Using the rat pheochromocytoma cell line PC12, we provide evidence that, by controlling expression of many genes involved in the RSP, the transcriptional repressor REST can regulate this pathway and hence the neurosecretory phenotype. Introduction of REST transgenes into PC12 cells leads to the repression of many genes, the products of which are involved in regulated secretion. Moreover, chromatin immunoprecipitation assays show that many of the repressed genes recruit the recombinant REST protein to RE1 sites within their promoters and abrogation of REST function leads to reactivation of these transcripts. In addition to the observed transcriptional effects, PC12 cells expressing REST have fewer secretory granules and a reduction in the ability to store and release noradrenaline. Furthermore, an important trigger for synaptic release, influx of calcium through voltage-operated calcium channels, is compromised. This is the first demonstration of a transcription factor that directly controls expression of many major components of the RSP and provides further insight into the function of REST.
Publisher: Wiley
Date: 20-01-2005
Publisher: Springer Science and Business Media LLC
Date: 11-2002
DOI: 10.1038/420042A
Publisher: Wiley
Date: 03-12-2018
DOI: 10.1113/EP086433
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.BRAINRES.2006.01.019
Abstract: Hyperpolarization-activated cyclic nucleotide-gated (HCN) non-selective cation channels in neurons carry currents proposed to perform erse functions, including the hyperpolarization activated Ih current. The 4 HCN subunits have unique but overlapping patterns of expression in the CNS. Here, we examined the distribution of HCN1 channel subunits in the brainstem and spinal cord using immunohistochemistry. At all levels of the spinal cord dorsal horn, HCN1 immunoreactivity (HCN1-IR) was predominantly absent from laminae I and II, while a dense band of punctate labeling was visible in lamina III. Labeled neurons were identified in close vicinity to the central canal, in the lateral spinal nucleus, in the ventral horn and occasionally in lamina II and III. Those in the ventral horn were identified as alpha motor neurons using retrograde tracing and/or double or triple immunostaining with neuronal markers neurofilament 200 (NF200) and choline acetyltransferase. HCN1-IR neurons in the brainstem included neurons in sensory pathways such as the dorsal column nuclei, the area postrema, the spinal trigeminal nucleus as well as identified motor neurons in motor nuclei. In the nucleus ambiguus, a mixed visceral/motor nucleus, HCN1-IR was present only in NF200-IR cells, suggesting that it is expressed in motor but not autonomic preganglionic neurons. HCN1-IR motor neurons in the nucleus ambiguus also expressed the neurokinin 1 receptor and were labeled retrogradely from the larnyx. At the light microscopic level, the NTS and inferior olive contained punctate labeling, which ultrastructural examination revealed to be present in predominantly synaptic terminals or dendrites respectively. These data therefore described the first localization of the HCN1 subunit in the spinal cord and extend previous reports from the brainstem.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jim Deuchars.