Opioid Receptors (ORs) are involved in the pathophysiology of several neuropsychiatric conditions yet remain an untapped therapeutic resource. Although only mu-, delta-, and kappa-OR types have been cloned, additional subtypes result from complexes generated by direct receptor-receptor interactions. Mu- and delta-ORs form a heteromeric receptor complex with unique pharmacological and signalling properties distinct from those of mu- and delta-OR homomers. In these studies, we sought to characterize the ligand binding pocket and agonist-induced internalization profile of the mu-delta heteromer, to investigate mu-delta heteromer-specific signalling in brain, and to interrogate the contribution of this receptor complex to opioid-mediated behavioural effects. In competition radioligand binding studies, delta-agonists displaced high affinity mu-agonist binding from the mu-delta heteromer but not the muOR homomer, suggestive of delta-agonists occupying or allosterically modulating the muOR ligand binding pocket within the heteromer. Delta-agonists induced internalization of the mu-delta heteromer in a dose-dependent, pertussis toxin resistant, and muOR- and deltaOR-dependent manner from the cell surface via the clathrin and dynamin endocytic machinery. Agonist-induced internalization of the mu-delta heteromer persisted following chronic morphine treatment conditions which desensitized the muOR homomer. Using Galpha-specific GTPgammaS binding assays, we demonstrated that mu-delta heteromer signalling previously characterized in cell lines was present in the striatum and hippocampus, and did not desensitize following prolonged morphine treatment conditions which desensitized muOR homomer-mediated signalling. Since delta-agonists which also target the mu-delta heteromer possess antidepressant-like and anxiolytic-like properties, we investigated the role of this receptor complex in mood regulation. We devised a strategy to selectively analyze the effects of the mu-delta heteromer by dissociating it using a specific interfering peptide aimed at a sequence implicated in mu-delta heteromerization. The interfering peptide abolished the unique pharmacological and trafficking properties of delta-agonists at the mu-delta heteromer and dissociated this receptor complex in vitro. Intra-accumbens administration of the interfering peptide disrupted the mu-delta interaction in vivo and allowed for isolation of the mu-delta heteromer contribution to the mood-regulatory effects of a delta-agonist with activity at the heteromer. Activation of the mu-delta heteromer in the nucleus accumbens produced antidepressant-like and anxiolytic-like actions in animal models of depression and anxiety.

Opioid Receptors (ORs) are involved in the pathophysiology of several neuropsychiatric conditions yet remain an untapped therapeutic resource. Although only mu-, delta-, and kappa-OR types have been cloned, additional subtypes result from complexes generated by direct receptor-receptor interactions. Mu- and delta-ORs form a heteromeric receptor complex with unique pharmacological and signalling properties distinct from those of mu- and delta-OR homomers. In these studies, we sought to characterize the ligand binding pocket and agonist-induced internalization profile of the mu-delta heteromer, to investigate mu-delta heteromer-specific signalling in brain, and to interrogate the contribution of this receptor complex to opioid-mediated behavioural effects. In competition radioligand binding studies, delta-agonists displaced high affinity mu-agonist binding from the mu-delta heteromer but not the muOR homomer, suggestive of delta-agonists occupying or allosterically modulating the muOR ligand binding pocket within the heteromer. Delta-agonists induced internalization of the mu-delta heteromer in a dose-dependent, pertussis toxin resistant, and muOR- and deltaOR-dependent manner from the cell surface via the clathrin and dynamin endocytic machinery. Agonist-induced internalization of the mu-delta heteromer persisted following chronic morphine treatment conditions which desensitized the muOR homomer. Using Galpha-specific GTPgammaS binding assays, we demonstrated that mu-delta heteromer signalling previously characterized in cell lines was present in the striatum and hippocampus, and did not desensitize following prolonged morphine treatment conditions which desensitized muOR homomer-mediated signalling. Since delta-agonists which also target the mu-delta heteromer possess antidepressant-like and anxiolytic-like properties, we investigated the role of this receptor complex in mood regulation. We devised a strategy to selectively analyze the effects of the mu-delta heteromer by dissociating it using a specific interfering peptide aimed at a sequence implicated in mu-delta heteromerization. The interfering peptide abolished the unique pharmacological and trafficking properties of delta-agonists at the mu-delta heteromer and dissociated this receptor complex in vitro. Intra-accumbens administration of the interfering peptide disrupted the mu-delta interaction in vivo and allowed for isolation of the mu-delta heteromer contribution to the mood-regulatory effects of a delta-agonist with activity at the heteromer. Activation of the mu-delta heteromer in the nucleus accumbens produced antidepressant-like and anxiolytic-like actions in animal models of depression and anxiety.

Les neurones endommagés développent de l'activité ectopique, c'est-à-dire qu'ils déchargent en l'absence de stimulus, ce qui engendre ensuite des douleurs neuropathiques. Des mesures expérimentales ont lié cette activité ectopique à un décalage cinétique (coupled left-shift, CLS) des canaux sodiques tensiodépendants. Nous avons donc construit un modèle numérique d'axone où une portion endommagée subit un tel décalage. Deux résultats fondamentaux et nouveaux sont obtenus : 1) En présence d'activité ectopique, une stimulation à haute fréquence peut entraîner la zone ectopique de l'axone à décharger à la même fréquence que le stimulus. La propagation est alors presque normale. 2) Dans un axone faiblement endommagé, sans activité ectopique au départ, un stimulus temporaire peut déclencher une activité ectopique qui perdure. Ceci amplifie le stimulus et peut donc être lié aux symptômes de douleurs neuropathiques. En plus de ces travaux de recherche, cette thèse propose une imposante section pédagogique, adressé au physicien qui débute en neurosciences. Injured neurons exhibit ectopic activity (ie. they fire without being stimulated), leading to neuropathic pain. Experiments have linked this ectopic activity to a kinetic shift (coupled left-shift, CLS) of the voltage-gated sodium channels. Therefore, we have designed a computational model axon where a damaged zone is affected by such a left-shift. Two important novel results were obtained : 1) In an ectopic axon, high-frequency stimulation can force the ectopic zone to phase-lock to the stimulation frequency. Propagation is then almost normal. 2) In a weakly damaged axon, without initial ectopic activity, a short stimulus can trigger a long lasting ectopic activity. This amplifies the stimulus and can thus be linked to neuropathic pain-like symptoms. In addition to this research work, this thesis encompasses a large educational section, addressed to physicists just starting in neuroscience.

The thesis describes development and application of coupled resonant coil sensors, which is of growing interest for remote monitoring applications. An interrogation technique, which improves the accuracy and interrogation range of coupled resonant coil sensors, is introduced. The method uses time-domain gating to produce measurements that are dominated by the response of the sensor coil and are immune to surrounding object interference. For application in structural health monitoring a low cost embeddable coupled coil sensor, which is able to monitor the corrosion potential of reinforcement steel is presented. Results of an accelerated corrosion test using the sensor indicate that corrosion potential can be monitored with a resolution less than 10 mV and a sensitivity of 0.76 kHz/mV. The last part describes a coupled-coil pH sensor based on pH electrode potential measurement. A linear response over a 4 to 10 pH dynamic range and 50 kHz/pH sensitivity are achieved with a 0.1 pH resolution and 30 s response time.

After nearly a decade of development, human-implantable sensors for detection of muscle activity have recently been demonstrated in the literature. The implantable sensors are powered and communicate wirelessly through the skin using coupled inductor coils. The focus of the present work has been the development of a new approach to modeling the inductively coupled link by using the finite element method (FEM) to simulate a three-dimensional representation of the coils and surrounding magnetic field. The validity of the simulation is tested by comparison to analytically-developed formulas for self-inductance, ac resistance and mutual inductance of the coils. Determination of these parameters is necessary for calculation of the coupling coefficient between the coils, and to fully define the lumped circuit model of the link. This 3D FEM approach is novel and attractive because it is able to encompass physical geometric parameters and material properties that have been traditionally been a challenge to determine. In particular the contribution of a ferrite-core, and the case of non-symmetrical relative coil positioning can be evaluated. / Graduate

The interaction of light and matter at nanoscale is the subject of study of this dissertation. Particularly, the coupling of light to surface plasmons and their applications in the fields of spectroscopy and sensing is the focus of this work. In terms of spectroscopy, the simple reason of using light to study the chemical structures of different materials is the fact that the energy of light lies in the range of vibrational and electronic transitions of matter. Further, the ability to squeeze light to subwavelength dimensions opens up new possibilities of designing nano-optical devices. In this work we explore surface plasmons for two major applications: (i) Directivity enhanced Raman spectroscopy and (ii) Chemical/biological sensing. Here a new enhancement phenomenon has been demonstrated experimentally in regards to Raman spectroscopy. Typically, Raman enhancement is considered in terms of local fields only. Here we show the use of directive nanoantennas to provide additional enhancement of two orders of magnitude. The nanoantenna design is optimal in the sense that almost all of the scattered light is coupled into the numerical aperture of the collecting lens. It is shown that the additional enhancement from directivity pushes the sensitivity to single molecule regime. Further, the out of plane radiation and simplicity of the design makes it an ideal candidate for use with typical commercial microscope setups. Extra ordinary transmission through nanohole arrays in metallic films is studied for refractive index sensing. Bulk resolution of 6×10-7 is demonstrated by optimizing array dimensions, wavelength of operation, noise reduction and consideration of sensitivity of the detecting CCD camera. Self-assembled nanostructures are investigated for spectroscopic applications. Time dependent studies of nanorods assembled in end-to-end and side-by-side configurations are conducted. The end-to-end configuration results in higher local field enhancements whereas; the side-by-side configuration shows a reduction in local fields because of the cancellation of radial field components between the neighbouring nanorods. It should be noted that higher fields are desirable for Raman spectroscopy. Grating structures have been analysed using reduced coupled mode theory. In most cases, only three lowest order modes prove to be sufficient for accurate description of the system response. Here we present design guidelines for broadband operation and optimization of high quality factor resonators. Finally the complex reflection coefficient from arbitrary terminated nanorods has been investigated. Phase of reflection plays an important role in the determination of resonance wavelength of nanoantennas. It is shown that the localized surface plasmon resonance of nanoparticles can be considered in terms of propagating surface plasmons along a nanorod of similar geometry where the length of the nanorod approaches zero accompanied with π degrees of phase of reflection. The contributions made in this work can prove useful in the fields of analytical chemistry and biomedical sensing. The directive nanoantenna can find applications in a number of areas such as light emitting devices, photovoltaics, single photon sources and high resolution microscopy. Our work related to EOT based sensing is already approaching the resolution of commercially available refractive index sensors with the added advantage of multiplexed detection. / Graduate

No description available.

Microelectromechanical resonators have found widespread applications in timing, sensing and spectral processing. One of the important performance metrics of MEMS resonators is the temperature sensitivity of their frequency. The main objective of this dissertation is the compensation and control of the temperature sensitivity of silicon resonators through engineering of device geometry and structural composition. This has been accomplished through formation of composite platforms or novel geometries based on dispersion characteristics of guided acoustic waves in single crystalline silicon (SCS) microstructures. Furthermore, another objective of this dissertation is to develop efficient longitudinal piezoelectric transduction for in-plane resonance modes of SCS resonators that have lithographically-defined frequencies, to reduce their motional resistance (Rm). A uniformly distributed matrix of silicon dioxide pillars is embedded inside the silicon substrate to form a homogenous composite silicon-oxide platform (SilOx) with nearly perfect temperature-compensated stiffness moduli. Temperature-stable micro-resonators implemented in SilOx platform operating in any desired in- and out-of-plane resonance modes show full compensation of linear temperature coefficient of frequency (TCF). Overall frequency drifts as small as 80 ppm has been achieved over the industrial temperature range (-40°C to 80°C) showing a 40x improvement compared to uncompensated native silicon resonators. A 27 MHz temperature-compensated MEMS oscillator implemented using SilOx resonator demonstrated sub-ppm instability over the industrial temperature range. Besides this, a new formulation of different resonance modes of SCS resonators based on their constituent acoustic waves is presented in this dissertation. This enables engineering of the acoustic resonator to provide several resonance modes with mechanical energy trapped in central part of the resonator, thus obviating narrow tethers traditionally used for anchoring the cavity to the substrate. This facilitates simultaneous piezoelectric-transduction of multiple modes with different TCFs through independent electrical ports, which can realize highly accurate self-temperature sensing of the device using a beat frequency (fb) generated from linear combination of different modes. Piezoelectrically-transduced multi-port silicon resonators implemented using this technique provide highly temperature-sensitive fb with a large TCF of ~8500 ppm/°C showing 100x improvement compared to other Quartz/MEMS counterparts, suggesting these devices as highly sensitive temperature sensors for environmental sensing and temperature-compensated/oven-controlled crystal oscillator (TCXO/OCXO) applications. Another part of this dissertation introduces a novel longitudinal piezoelectric transduction technique developed for implementation of low Rm silicon resonators operating in lithographically defined in-plane modes. Aluminum nitride films deposited on the sidewalls of thick silicon microstructures provides efficient electromechanical transduction required to achieve low Rm. 100 MHz SCS bulk acoustic resonators implemented using this transduction technique demonstrates Rm of 33Ω showing a 100x improvement compared to electrostatically transduced counterparts. Low-loss narrow-band filters with tunable bandwidth and frequency have been implemented by electrical coupling of these devices, showing their potential for realization of truly reconfigurable and programmable filter arrays required for software-defined radios.

This study is concerned with the compositional analysis of Roman and early post-Roman glass from both domestic assemblages and the remains derived from glass working and producing sites in Britain, using Inductively Coupled Plasma Spectrometry (ICPS). Samples analysed were from glassworking waste from Mancetter (midsecond century), Leicester (third century) and Worcester (first to third centuries), glass production debris, probably manufactured from the raw materials, in conjuncton with a domestic assemblage, from Coppergate (first to fourth centuries, or possibly later), and a domestic assemblage from Fishergate (spanning both the Roman and immediate post- Roman periods). All the glass analysed was shown to be of a typical and uniform soda-limesilica composition, except for a small number of vessel fragments from York which were higher in calcium. Any compositional differences between blue-green glasses typologically dated either to the Roman or Saxon periods, were found not to be consistent. Analysis of the colourless glass showed that the majority appeared to be actively decolorized using antimony, in conjunction with apparent differences in the compositions of the raw materials, when compared to glass of the same date in other colours. Compositional differences between melted waste from Mancetter, Leicester and Worcester, were apparent, but not to an extent which allowed characterization to be successful. Analysis of glassmelting pots from Coppergate showed some high temperature glassworking (and possibly glassmaking) could have occurred. Other debris, thought to be indicative of glassmaking was also analysed and compared to the composition of the Roman domestic assemblage.

An innovative mathematical architecture for modelling neuronal electrical activity is presented, called the cognitive rhythm generator (CRG), wherein the proposed architecture is a hybrid model comprised of three interconnected stages, namely: (1) a bank of neuronal modes; (2) a ring device (limit-cycle oscillator); and (3) a static output nonlinearity (mapper). Coupled CRG networks are employed to emulate and elucidate the dynamics of biological neural networks, including the recurrent networks in the hippocampus. Several species of ring devices are described and investigated, including the clock, labile clock, hourglass and multistable ring systems, and their applications to neuronal modelling explored. Complexity measures such as the maximum Lyapunov exponent, correlation dimension and detrended fluctuation analysis are applied to compare model and biological records and validate the CRG methodology. The basis of neural coding is also examined in mathematical detail, with particular regard to its description by Volterra-Wiener kernel formalism, from which the neuronal modes are derived. Applications to theta-gamma coding are discussed. Further on in the thesis, a CRG epileptiform network model of spontaneous seizure-like events (SLEs) is developed and used as a platform to test neuromodulation approaches for seizure abatement. (Neuromodulation mentioned here refers to methods involving electrical stimulation of neural tissue for therapeutic benefit). Spontaneous SLE transitions in the epileptiform network are shown to be related to the mechanism of intermittency, as determined by examining the state space dynamics of the model. The onset of SLEs is associated with increased network excitability and decreased stability, consistent with experimental results from the low-magnesium/high-potassium in vitro model of epilepsy. Lastly, a novel strategy for therapeutic neuromodulation is presented wherein a coupled CRG network (called the “therapeutic network”) is interfaced with the epileptiform network model, forming a closed loop for responsive, biomimetic neuromodulation of the epileptiform network. Relevance to clinical applications and future work is discussed.