Metamodulation of a spinal locomotor network by nitric oxide

Flexibility in the output of spinal networks can be accomplished by the actions of neuromodulators; however, little is known about how the process of neuromodulation itself may be modulated. Here we investigate the potential "meta"-modulatory hierarchy between nitric oxide (NO) and noradrenaline (NA) in Xenopus laevis tadpoles. NO and NA have similar effects on fictive swimming; both potentiate glycinergic inhibition to slow swimming frequency and GABAergic inhibition to reduce episode durations. In addition, both modulators have direct effects on the membrane properties of motor neurons. Here we report that antagonism of noradrenergic pathways with phentolamine dramatically influences the effect of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) on swimming frequency, but not its effect on episode durations. In contrast, scavenging extracellular NO with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide(PTIO) does not influence any of the effects of NA on fictive swimming. These data place NO above NA in the metamodulatory hierarchy, strongly suggesting that NO works via a noradrenergic pathway to control glycine release but directly promotes GABA release. We confirmed this possibility using intracellular recordings from motor neurons. In support of a natural role for NO in the Xenopus locomotor network, PTIO not only antagonized all of the effects of SNAP on swimming but also, when applied on its own, modulated both swimming frequency and episode durations in addition to the underlying glycinergic and GABAergic pathways. Collectively, our results illustrate that NO and NA have parallel effects on motor neuron membrane properties and GABAergic inhibition, but that NO serially metamodulates glycinergic inhibition via NA.Publisher PDFPeer reviewe

The Social Agency of Things? Animism and Materiality in the Andes

A major focus of inter-disciplinary debate has been the need to bridge the Cartesian divide between people as active subjects and inert passive objects, to better reflect how things provoke and resist human actions through their 'secondary agency'. Many Central Andean people express a deep concern about their relationship with places and things, which they communicate with through daily work and rituals involving 'sympathetic magic'. A consideration of Andean animism emphasizes how agency is located in the social relationship people have with the material world and how material objects can have social identities

Globalization without markets? Population movement and other integrative mechanisms in the ancient Andes

In late pre-Hispanic periods much of modern Peru, Bolivia, Chile, Argentina and Ecuador was connected by a network of intense interactions through the long distance movement of people as well as goods and ideas. Rather than prioritising an analysis of the movement of goods as a measure of globalisation this article stresses the more limited role of market exchange in the Andes but that the movement of people, knowledge and skills is strongly expressed in the transfer of technologies and sharing of stylistic elements. It presents a broad description of cross-cultural and interregional contacts that were taking places in the Andean highlands and Pacific coast from around 500 CE till the period of European colonization around 1600 CE, including the Wari and Inka Empires. It reviews mechanisms of social and economic integration that shaped the globalizing tendencies in the Andes through a review of archaeological evidence as well as early historical records

Miniatures and Animism: The communicative role of Inka carved stone conopa

Andean offerings use miniaturisation and synecdoche to enact connections within a relational animism (where people, places and things participate in an interactive network), allowing the person preparing the offering to make material links between them and more distant, non-human entities. Catholic priests working in the Andes during the Spanish colonial period tried to eradicate these practices within which small objects called conopa were used. Conopa included natural stones and carved stone figurines which were understood to be active agents that helped those who were preparing offering to communicate with animate locals in the landscape. An analysis of Inka and colonial period carved stone conopa in the form of camelids reveals that some of these were produced in an organized system of manufacture under the auspices of the Inka state. This contributes to a discussion of how Andean household rituals have adapted in response to distinct social, economic and political contexts

The building and rebuilding of walls: Aspirations, commitments and tensions within an Andean community and the archaeological monument they inhabit

Walls are at the foundation of 'civil society': physical and symbolic barriers that differentiate people and activities. Cooperation in construction work expresses people's aspirations and can be a focus for the development of group solidarity. However, walls change the control and use of space, causing tensions and social divisions. In Raqchi, a small Peruvian village whose houses and fields are located within the ruins of a major archaeological complex, walls are a major concern. The work involved in house building, community projects, a monumental Inka temple and recent heritage reconstruction shows how the choice of materials and techniques is influenced by social relations and labour exchange. Tensions are expressed over land ownership and community priorities as well as with heritage management. The community's identity and status are also strongly influenced by building work that is dependent on the Catholic Church, NGOs, the municipality and the nation state.Walls can be read as a document of this contested history. © The Author(s) 2013

Evolutionary Divergence in Developmental Strategies and Neuromodulatory Control Systems of Two Amphibian Locomotor Networks

Attempts to understand the neural mechanisms which produce behaviour must consider both prevailing sensory cues and the central cellular and synaptic changes they direct. At each level, neuromodulation can additionally shape the final output. We have investigated neuromodulation in the developing spinal motor networks in hatchling tadpoles of two closely related amphibians, Xenopus laevis and Rana temporaria to examine the subtle differences in their behaviours that could be attributed to their evolutionary divergence. At the point of hatching, both species can swim in response to a mechanosensory stimulus, however Rana embryos often display a more forceful, non-locomotory coiling behaviour. Whilst the synaptic drive that underlies these behaviours appears similar, subtle inter-specific differences in neuronal properties shape motor outputs in different ways. For example, Rana neurons express N-methyl-D-aspartate (NMDA)/serotonin (5-HT)-dependent oscillations, not present in hatchling Xenopus and many also exhibit a prominent slow spike after-hyperpolarisation. Such properties may endow the spinal circuitry of Rana with the ability to produce a more flexible range of outputs. Finally, we compare the roles of the neuromodulators 5-HT, noradrenaline (NA) and nitric oxide (NO) in shaping motor outputs. 5-HT increases burst durations during swimming in both Xenopus and Rana, but 5-HT dramatically slows the cycle period in Rana with little effect in Xenopus. Three distinct, but presumably homologous NO-containing brainstem clusters of neurons have been described, yet the effects of NO differ between species. In Xenopus, NO slows and shortens swimming in a manner similar to NA, yet in Rana NO and NA elicit the non-rhythmic coiling pattern

α_1L-adrenoceptors mediate contraction of human erectile tissue

α1-adrenoceptor antagonists can impact upon sexual function and have potential in the treatment of erectile dysfunction. Human erectile tissue contains predominantly α1A-adrenoceptors, and here we examined whether contractions of this tissue are mediated by the functional phenotype, the α1L-adrenoceptor. Functional experiments using subtype selective agonists and antagonists, along with radioligand ([3H]tamsulosin) binding assays, were used to determine the α1-adrenoceptor population. A61603, a α1A-adrenoceptor agonist, was a full agonist with a potency 21-fold greater than that of noradrenaline. The α1A- and α1D-adrenoceptor antagonist tamsulosin antagonized noradrenaline responses with high affinity (pKD = 9.7 ± 0.3), whilst BMY7378 (100 nM) (α1D-adrenoceptor antagonist) failed to antagonize responses. In contrast, relatively low affinity estimates were obtained for both prazosin (pKD = 8.2 ± 0.1) and RS17053 (pKD = 6.9 ± 0.2), antagonists which discriminate between the α1A- and α1L-adrenoceptors. [3H]Tamsulosin bound with high affinity to the receptors of human erectile tissue (pKD = 10.3 ± 0.1) with a receptor density of 28.1 ± 1.4 fmol mg−1 protein. Prazosin displacement of [3H]tamsulosin binding revealed a single homogenous population of binding sites with a relatively low affinity for prazosin (pKi = 8.9). Taken together these data confirm that the receptor mediating contraction in human erectile tissue has the pharmacological properties of the α1L-adrenoceptor. Keywords: Erectile tissue, α1-adrenoceptor subtypes, α1L-adrenoceptor, Tamsulosin, Prazosi

Mechanisms underlying the endogenous dopaminergic inhibition of spinal locomotor circuit function in Xenopus tadpoles

This work was supported by the Biotechnology and Biological Science Research Council (BBSRC) [grant number BB/J01446X/1].Dopamine plays important roles in the development and modulation of motor control circuits. Here we show that dopamine exerts potent effects on the central pattern generator circuit controlling locomotory swimming in post-embryonic Xenopus tadpoles. Dopamine (0.5–100 μM) reduced fictive swim bout occurrence and caused both spontaneous and evoked episodes to become shorter, slower and weaker. The D2-like receptor agonist quinpirole mimicked this repertoire of inhibitory effects on swimming, whilst the D4 receptor antagonist, L745,870, had the opposite effects. The dopamine reuptake inhibitor bupropion potently inhibited fictive swimming, demonstrating that dopamine constitutes an endogenous modulatory system. Both dopamine and quinpirole also inhibited swimming in spinalised preparations, suggesting spinally located dopamine receptors. Dopamine and quinpirole hyperpolarised identified rhythmically active spinal neurons, increased rheobase and reduced spike probability both during swimming and in response to current injection. The hyperpolarisation was TTX-resistant and was accompanied by decreased input resistance, suggesting that dopamine opens a K+ channel. The K+ channel blocker barium chloride (but not TEA, glybenclamide or tertiapin-Q) significantly occluded the hyperpolarisation. Overall, we show that endogenously released dopamine acts upon spinally located D2-like receptors, leading to a rapid inhibitory modulation of swimming via the opening of a K+ channel.Publisher PDFPeer reviewe

Sodium pumps mediate activity-dependent changes in mammalian motor networks

Funding: Laurence Picton [grant number BB/JO1446X/1] and Matthew Broadhead [grant number BB/M021793/1] were supported by the Biotechnology and Biological Science Research Council (BBSRC). Filipe Nascimento was supported by The Alfred Dunhill Links Foundation.Ubiquitously expressed sodium pumps are best known for maintaining the ionic gradients and resting membrane potential required for generating action potentials. However, activity- and state-dependent changes in pump activity can also influence neuronal firing and regulate rhythmic network output. Here we demonstrate that changes in sodium pump activity regulate locomotor networks in the spinal cord of neonatal mice. The sodium pump inhibitor, ouabain, increased the frequency and decreased the amplitude of drug-induced locomotor bursting, effects that were dependent on the presence of the neuromodulator dopamine. Conversely, activating the pump with the sodium ionophore monensin decreased burst frequency. When more "natural" locomotor output was evoked using dorsal-root stimulation, ouabain increased burst frequency and extended locomotor episode duration, whereas monensin slowed and shortened episodes. Decreasing the time between dorsal-root stimulation, and therefore interepisode interval, also shortened and slowed activity, suggesting that pump activity encodes information about past network output and contributes to feedforward control of subsequent locomotor bouts. Using whole-cell patch-clamp recordings from spinal motoneurons and interneurons, we describe a long-duration (∼60 s), activity-dependent, TTX- and ouabain-sensitive, hyperpolarization (∼5 mV), which is mediated by spike-dependent increases in pump activity. The duration of this dynamic pump potential is enhanced by dopamine. Our results therefore reveal sodium pumps as dynamic regulators of mammalian spinal motor networks that can also be affected by neuromodulatory systems. Given the involvement of sodium pumps in movement disorders, such as amyotrophic lateral sclerosis and rapid-onset dystonia parkinsonism, knowledge of their contribution to motor network regulation also has considerable clinical importance.Publisher PDFPeer reviewe