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The studies presented in this thesis were undertaken to investigate the cellular and molecular mechanisms responsible for sympathetic hyperactivity that is observed in the Spontaneous Hypertensive Rat (SHR) and whether these abnormalities arise even before the onset of hypertension. Moreover, selected molecular candidates related to oxidative state in cardiac autonomic signalling have been explored for their potential therapeutic effects. <b>Chapter One</b> is an overview of (i) the relevance of autonomic dysfunction in cardiovascular disease in both human and animal models, (ii) the physiological basis of cardiac sympathetic neurotransmission, (iii) the neuromodulators of peripheral cardiac sympathetic-vagal balance discussed along with how they may be involved in cardiac adrenergic control of neurotransmission and NO-cGMP signalling. This develops the formulation of the specific aims of the thesis. <b>Chapter Two</b> outlines a detailed rationale for the experimental approach taken to (i) characterise protein expression in the pre-hypertensive animal model with immunohistochemistry and Western blotting, (ii) manipulate selected gene expression to amplify NO-cGMP signalling in vivo and in vitro via viral gene transfer, (iii) investigate calcium handling in cardiac sympathetic stellate neurons with calcium imaging , (iv) measure cardiac noradrenergic neurotransmission from double atria using radioactive-labelled [³H]-noradrenaline. <b>Chapter Three</b> demonstrated abnormal NO-cGMP signalling in pre-hypertensive SHRs. Endogenous nNOS protein residing in both cardiac parasympathetic and sympathetic neurons was significantly lower in the pre-hypertensive SHR compared to aged-matched WKYs. This was associated with lower cGMP levels. An enhanced depolarization evoked [Ca²⁺]i transient was observed in cardiac stellate neurons from pre-hypertensive SHR when compared with the WKY, an effect that was reversed by nNOS or sGC inhibition. <b>Chapter Four</b> investigated the role of nNOS and brain natriuretic peptide (BNP) in cGMP signalling pathways. Gene transfer of nNOS via adenoviral vector in SHR cardiac sympathetic neurons increased cGMP concentration and normalised neuronal calcium handling during depolarization. BNP significantly reduces [3H]- noradrenaline release. Overexpression of PDE2 which facilitates the breakdown of cGMP caused an increase in [³H]- noradrenaline release in response to field stimulation and also prevented the inhibitory action of BNP. <b>Chapter Five</b> examined the role of the nNOS adaptor protein, CAPON in NO-cGMP signalling. Endogenous CAPON protein is present in cardiac sympathetic neurons in the WKY, and is significantly reduced in pre-hypertensive SHR cardiac neurons. Artificial up-regulation of cardiac sympathetic CAPON via targeted gene transfer directly attenuated neuronal Ca²⁺ transients, resulting in decreased noradrenaline release in the SHR. <b>Chapter Six</b> is a concluding discussion summarising the main findings from this thesis, placing them in a physiological context and discussing avenues for further research.

How the neural representations of different sensory modalities transition from one to another is an unexplored issue of cortical organization. The present experiments addressed this problem by examining auditory projections to the lateral suprasylvian visual area (LSS) of the cat using neuroanatomical tract tracing methods. Injections of tracer (Biotinylated Dextran Amine, BDA) were made into defined areas of the cat auditory cortex. Following transport and tissue processing, a light microscope with a digitizing stage was used to visualize and plot labeled auditory projections to the LSS. The results showed that all auditory cortices tested demonstrated projections to a restricted portion of the LSS. While these projections were concentrated on the outer lip of the lateral bank of the LSS, some scattered auditory projections were found along the entire depth of the lateral bank. These data indicate that, at least in the LSS, projections from different sensory modalities do not form abrupt borders but exhibit areas of overlap. These overlapped projections may provide the anatomical basis for multisensory properties of neurons within transition areas between representations of different sensory modalities.

Call number: LD2668 .T4 1959 P45

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Neuroanatomical work has shown that the auditory system is different in different mammals, with primates and bats representing two extremes in this regard. It has been suggested that these differences are related to auditory localization. The present work examined auditory localization in several representative mammalian speciesa squirrel monkey, bat {Phyllostomus hastatus), albino rat and cat. A semi-naturalistic localization situation was used. The animal was placed in a wire cage located in a sound-deadened room. Two loudspeakers were located one on either side of the cage. Two response lavers were located in the front wall of the cage, flanking a liquid food dispenser. When tone bursts were presented from one of the loudspeakers, a response on the "correct" lever resulted in the delivery of a small amount of food to the animal. The left-hand lever was correct when the tone bursts were from the left-hand loudspeaker, the right-hand lever was correct when the tone bursts were from the right-hand loudspeaker. The percentage of correct responses on both levers was the measure of performance on the discrimination under a given set of conditions. [TRUNCATED] / 2031-01-01

Dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree Master of Science. 2013 / The Babinski sign is a pathological response elicited by a stimulus to the lateral plantar border of thesole of the foot. The resulting reflex involves dorsiflexion (upward motion) of the toes, most notably the hallux, with accompanying flexion in the ankle, knee and hip. It is an important part of the clinical neurological examination and aids in the diagnosis of central nervous system dysfunction. There is however no wholly standardised method to elicit this reflex or interpret it, resulting in possible variation in its utility. The resulting aim of the studies constituting this dissertation were therefore to: 1) assess what techniques and pressures are used to elicit the reflex in a group of neurologists;2) to investigate the relationship between input variables of the reflex and the resultant output variables as measured with the use of electromyography and kinematics;3) compare objective variables, relating to toe, foot and leg movement, of the pathological reflex to the healthy response; 4) assess the inter-rater reliability of the reflex and 5) determine what aspects of the reflex are most closely related to the ratings of the students and neurologists. A specialized custom-built Babinski hammer was constructed to measure the duration of the stroke and pressures exerted on the foot of a single healthy subject by neurologists (n=12). The relationship between the recorded pressures and the movement of the toes (measured kinematically), muscle activity in the tibialis anterior and the pain felt by the subject (gauged using a visual analogue scale) were evaluated. Following this, the average pressure used by the neurologists was used to elicit the reflex in six patients with known positive Babinski responses and six healthy gender and age matched controls. These reflexes were compared with kinematic (measurement of toe, foot and leg movement) and electromyographic (muscle activity of the involved muscles) methods. These reflexes were recorded and the recorded footage was shown to 12 medical students and 12 neurologists who were asked to interpret if 3 the responses were pathological or non-pathological. Kinematic and electromyographic descriptions of each reflex made it possible to assess what aspects of the reflex are important for classification of a pathological response for both medical students and neurologists. A large amount of intra- and inter-rater variability was shown amongst the neurologists in how they elicited the reflex. The amount of pressure applied was shown to be significantly related to hallux movement (p<0.01) as well as to the degree of pain felt by the subject (p<0.01). Significant differences were found between the patients and controls for change in hallux angle (p<0.0001), movement latency (p<0.05)and the maximum electromyographic amplitude of tibialis anterior(p<0.01). The inter-rater reliability of the medical students and the neurologists showed substantial agreement between raters (kappa = 0.67 and 0.72 respectively). Both neurologists and students made use of the change in hallux angle, time taken to reach maximum ankle angle, movement latency and the maximum amplitude of gastrocnemius when rating the reflex. Neurologists alone observed time taken to reach maximum hallux angle and change in ankle angle as being important while medical students‘ alone looked at maximum amplitude of biceps femoris. In conclusion, I found a large variation between the techniques of neurologists when assessing the Babinski reflex. This variation is related to variation in aspects of the resultant reflex. The pathological response (the Babinski sign) has shorter movement latency and less activity in the tibialis anterior muscle than the flexor response seen in healthy individuals. Ratings of pre-recorded Babinski responses had substantial agreement when both neurologists and medical students assessed pathology. In order to assess them both groups made use of the speed of the reflex, the direction of hallux movement and concurrent withdrawal activity in the leg to differentiate between a pathological and a healthy response.

<p>Recently discovered neuropeptides orexins (orexin-A and -B) act as endogenous ligands for G-protein-coupled receptors called OX₁ and OX₂ receptors. Our previous studies have established model systems for investigation of the pharmacology and signaling of these receptors in recombinant CHO cells. OX₁ receptor-expressing CHO cells were mainly utilized in this thesis.</p><p>Orexin-A and -B activate both OX₁ and OX₂ receptors. However, orexin-B is less potent in activating OX₁ receptors than orexin-A, whereas the peptides are equipotent on OX₂ receptors. We have performed mutagenesis on orexin-A to investigate the basis for this selectivity. We show that OX₂ receptor is generally less affected by the mutations and thus OX₂receptor appears to have less strict requirements for ligand binding, likely explaining the lack of difference in affinity/potency between orexin-A and orexin-B on OX₂ receptor.</p><p>The other studies focus on orexin receptor signaling. OX₁ receptors are shown to regulate adenylyl cyclase both in positive and negative manner, activate different MAP-kinases (ERK1/2 and p38) and induce cell death after long-lasting stimulation. Adenylyl cyclase regulation occurs likely through three different G-protein families, Gi, Gs and Gq. For ERK1/2, several downstream pathways, such as Ras, Src, PI3-kinase and protein kinase C (PKC) are implicated. OX₁ receptor-mediated activation of ERK is suggested to be cytoprotective whereas p38 MAP-kinase induces programmed cell death. </p><p>Three particularly interesting findings were made. Firstly, novel PKC δ (delta) is suggested to regulate adenylyl cyclase, whereas conventional and atypical PKCs are involved in activation of ERK. Secondly, adenylyl cyclase and ERK activation is fully dependent on extracellular Ca²⁺. Further experiments suggest that the previously discovered receptor-operated Ca²⁺ influx is not affecting the downstream effectors of orexin receptors but that it instead enables orexin receptors to couple to several signal cascades. Thirdly, upon inhibition of caspases, classical mediators of programmed cell death, OX₁receptor-mediated cell death is not reversed, but instead the pathways to death are altered so de novo gene transcription is no longer required for cell death.</p>

<p>The bradykinin and neuropeptide Y (NPY) receptors belong to the superfamily of G-protein coupled receptors (GPCRs). The GPCRs form the largest class of therapeutic targets and it is therefore of great interest to investigate the pharmacological properties, functions and evolution of these receptors.</p><p>Bradykinin (BK) is a nonapeptide that contributes to inflammatory responses, mediates pain signals and influences blood pressure. The two bradykinin receptor subtypes B1 and B2 are well characterized in mammals, but have received little attention in non-mammals. This thesis describes the cloning and characterization of the first piscine bradykinin receptor, from the <i>Danio rerio</i> (zebrafish). Ligand-receptor interactions were measured as production of intracellular inositol phosphate. Zebrafish BK activated the receptor with highest potency (pEC₅₀=6.97±0.1) while mammalian BK was almost inactive. A complete alanine and D-amino acid scan of the BK peptide revealed important roles for receptor interaction for residues Gly4, Ser6, Pro7, Leu8 and Arg9. The receptor gene was mapped to chromosome 17 in the zebrafish genome in a region that shows conserved synteny to the human B1-B2 gene region on chromosome 14. The release of the zebrafish and pufferfish genomes enabled us to identify both B1 and B2 genes in <i>Danio rerio</i> and pufferfishes (<i>Takifugu rubripes</i> and <i>Tetraodon nigroviridis</i>) as well as the B1 gene in chicken. All of these species display conserved synteny of the gene region. Interestingly, the evolutionary rate is clearly greater for B1 than for B2. Kininogen, the precursor for bradykinin, is also located in a chromosome region with extensive conserved synteny.</p><p>Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) comprise a family of related peptides and are involved in a variety of neuronal and endocrine functions. Receptor subtypes Y6 and Y7 were cloned and pharmacologically characterized in chicken. The genes are located one megabase apart on chromosome 13 in a region with conserved synteny to human chromosome 5. Porcine PYY bound to chicken Y6 with a K_d of 0.80±0.36 nM and chicken Y7 with a K_d of 0.14±0.01 nM. The Y6 mRNA is expressed in hypothalamus, gastrointestinal tract and adipose tissue and may be involved in appetite regulation like other NPY receptors. Chicken Y7 mRNA was only detected in adrenal gland. These results may help explain why these receptors have lost function in humans.</p>

Klaus Putter. / "January 13, 1954." This report is identical with a thesis submitted to the Department of Electrical Engineering ... for the degree of Master of Science. / Bibliography: p. 33. / Army Signal Corps Contract DA36-039 sc-100 Project 8-102B-0 Dept. of the Army Project 3-99-10-022

Recently discovered neuropeptides orexins (orexin-A and -B) act as endogenous ligands for G-protein-coupled receptors called OX1 and OX2 receptors. Our previous studies have established model systems for investigation of the pharmacology and signaling of these receptors in recombinant CHO cells. OX1 receptor-expressing CHO cells were mainly utilized in this thesis. Orexin-A and -B activate both OX1 and OX2 receptors. However, orexin-B is less potent in activating OX1 receptors than orexin-A, whereas the peptides are equipotent on OX2 receptors. We have performed mutagenesis on orexin-A to investigate the basis for this selectivity. We show that OX2 receptor is generally less affected by the mutations and thus OX2 receptor appears to have less strict requirements for ligand binding, likely explaining the lack of difference in affinity/potency between orexin-A and orexin-B on OX2 receptor. The other studies focus on orexin receptor signaling. OX1 receptors are shown to regulate adenylyl cyclase both in positive and negative manner, activate different MAP-kinases (ERK1/2 and p38) and induce cell death after long-lasting stimulation. Adenylyl cyclase regulation occurs likely through three different G-protein families, Gi, Gs and Gq. For ERK1/2, several downstream pathways, such as Ras, Src, PI3-kinase and protein kinase C (PKC) are implicated. OX1 receptor-mediated activation of ERK is suggested to be cytoprotective whereas p38 MAP-kinase induces programmed cell death. Three particularly interesting findings were made. Firstly, novel PKC δ (delta) is suggested to regulate adenylyl cyclase, whereas conventional and atypical PKCs are involved in activation of ERK. Secondly, adenylyl cyclase and ERK activation is fully dependent on extracellular Ca2+. Further experiments suggest that the previously discovered receptor-operated Ca2+ influx is not affecting the downstream effectors of orexin receptors but that it instead enables orexin receptors to couple to several signal cascades. Thirdly, upon inhibition of caspases, classical mediators of programmed cell death, OX1 receptor-mediated cell death is not reversed, but instead the pathways to death are altered so de novo gene transcription is no longer required for cell death.