Microglia play a central role in immune surveillance and modulation of neuroinflammation as well as playing a role in neurodevelopment. Microglia involve in the development of pathological pain in adults but not early in life. However little detail is known about the changing phenotype of microglia during development. We examined age-related changes in microglia following activation with pathogen- and damage- associated molecular patterns (PAMPs/DAMPs). Microglial cultures were prepared from neonatal postnatal day (P1) and adult (P40) rat brains and spinal cords. Immunocytochemistry, qRT-PCR and functional assays were used to identify age-related differences. Adult microglia display a pro-inflammatory immune profile characterized by significantly increased IL-1β mRNA levels in response to PAMPs and DAMPs. In contrast, IL-1β mRNA in neonatal microglia showed a slight increase after stimulation with DAMPs. Anti-inflammatory gene expression was significantly increased in neonatal microglia relative to adult microglia. Compared to adult microglia, neonatal cells had increased phagocytic activity when unstimulated and following activation with LPS and ATP. Moreover, the nuclear receptor Nurr1 may play a major role in reducing pro-inflammatory signalling and promoting the anti-inflammatory phenotype in neonatal microglia. Nurr1 isoforms are differentially expressed in neonatal and adult microglia, with the Nurr1a isoform being significantly elevated in neonatal cells. Using lentiviral vector-mediated expression of Nurr1 isoforms, we also show that over-expression of TINUR, a splice variant of Nurr1, in neonatal and adult microglia attenuates inflammation by trans-repression the IL-1β expression and trans-activation the IL-10 gene expression following ATP exposure. Together, these data provide evidence for age-related difference in microglial function during postnatal development. In addition, these findings demonstrate insight into the mechanisms by which Nurr1 might act, and suggest potential therapeutic targets for the treatment of neuro-inflammatory diseases.

The present research programme sought to further understanding of the neurophysiological mechanisms that underlie the effects of music on exercise. Five original experiments were conducted using a wide range of psychophysical, psychological, physiological, and psychophysiological techniques. The results of the first study indicated that music partially reallocates attention towards task-unrelated thoughts (i.e., external dissociation), suppresses the amplitude of low-frequency waves in the brain, and enhances task performance. The findings of the second study indicated that music can have a negative effect if delivered during the execution of highly-demanding cognitive-motor tasks. In such instances, the right parietal regions of the brain activate in response to the presence of auditory distractors and prevent task performance from being compromised. The third study shed new light on the neural control of working muscles and indicated that music has the potential to reduce the frequency of electrical outputs emitted to the musculature and reduce the communication between the central motor command and adjacent regions. The fourth study of this research programme was conducted in an ecologically valid environment, wherein participants walked at self-paced speeds in the presence of different auditory stimuli. The results of the fourth study indicated that music elicits more positive affective responses and up-regulates beta waves to a greater degree than no-music conditions. Finally, the fifth study of this thesis made use of functional magnetic resonance imaging to explore the brain regions that activate in response to exercise and music. The results of this final study revealed that the left inferior frontal gyrus is highly active when individuals execute part-body exercises with music. The present research programme provides a neurophysiological basis for the use of music in exercise settings. The findings presented herein support the use of music as a valuable tool to explore more complex psychophysiological phenomena such as attention, affect, and fatigue.

Amyloid β(Aβ)-induced synaptic and neuronal degeneration has been linked to the memory loss observed in Alzheimer's disease (AD). Although Aβ-induced impairment of synaptic and nonsynaptic plasticity is known to occur before any cell death, the links between these neurophysiological changes and the loss of specific types of behavioural memory are not fully understood. This thesis introduces a behaviourally and physiologically tractable animal model to the Aβ field for the first time, allowing for an in-depth approach to investigating Aβ-induced memory loss to be explored. In Aβ 1-42- and Aβ 25-35-treated Lymnaea stagnalis, retrieval of consolidated memory is disrupted after single-trial conditioning and single-injection of synthetic peptide. All succeeding work builds upon these findings using a top-down approach to investigate how Aβ disrupts retrieval of consolidated memory. Neuronal and synaptic health were monitored over a 24 hour in vivo incubation period and other memory stages were considered to determine time points of memory vulnerability. In brains that displayed healthy neurons and degenerating synapses, only animals that were exposed to Aβ during the 24-48 hour post-training time points exhibited any behavioural deficits. All other behavioural responses remained normal. Focus then shifted to investigate the peptide, as opposed to behaviour, involved in the above mentioned experiments. After systemic injection, Aβ was found to penetrate the ganglia, enter cells, and localise to specific organelles by 24 hours exposure. Aβ morphology and structure were also monitored over the 24 hour incubation period, using transmission electron microscopy (TEM), formic acid extraction, silver stain, and western blot. A large distinction between the two peptides, Aβ 1-42 and Aβ 25-35, became apparent at this point and even when peptides were prepared using the same procedure, their effects on behaviour became drastically different. However, it is interesting to note that although the two peptides used are very different, under different preparation procedures they will both produce predominantly tetramer species after 24 hour in vivo incubation. Finally, investigations into disruptions of molecular signalling cascades were considered in order to correlate these disruptions to the observed Aβ-induced behavioural deficits. Specifically, molecular, pharmacological, and biochemical techniques were used to measure protein alterations and post-translational modifications, and to inhibit key protein components, involved in cAMP response element binding protein (CREB)-signalling pathways in Lymnaea brain after 24 hour in vivo incubation of Aβ. Phosphorylated CREB was found to be decreased in both Aβ-treated groups; this decrease pattern was also found in active protein kinase A (PKA) experiments. These experiments correlate memory deficits to Aβ-induced disruptions in PKA and CREB activity; however, PKA inhibition experiments indicate that this molecular cascade disruption is not sufficient to cause the observed behavioural deficits. Taken together, this work correlates Aβ-induced changes from a wide range of components involved in learning and memory, with Aβ-disrupted memory recall. Importantly as well, this work develops Lymnaea stagnalis as a novel model for Aβ research and continues to distinguish the two commonly used peptides, Aβ 1-42 and Aβ 25-35. By linking the effects of Aβ on defined neuronal circuits to behavioural deficits in a novel model, the Aβ field has been further developed in an important and unique way.

Area LIP has long been considered to be heavily involved in controlling transformations of visual stimuli into oculomotor behavior, as well as being an integral part of the extensive cortico-cortical network that controls covert visual attention. Neurons in LIP have been shown to respond to shifts in spatial attention as well as changes in the reward contingencies associated with visual stimuli, leading to the hypothesis that this area is involved in the selective processing of behaviorally relevant visual stimuli. However, the effects of attentional and motivational processes on neuronal activity in LIP have not been fully dissociated from each other. In one experiment I found that changing the reward contingencies in a peripheral visual detection task sytematically modulated visual responses in LIP, and that these changes in activity were correlated with the reaction time costs of re-orienting attention. In a further experiment, I manipulated the motivational state of rhesus macaque monkeys by varying the reward value associated with successful completion of a cued reflexive saccade task, and was thus able to study the neuronal activity in LIP while attention and motivation were independently controlled and manipulated. LIP responses to visual targets showed that directed visual attention systematically increased activity in neurons coding the attended location, suggesting spatially specific selective processing of that part of the visual field. In contrast, increasing motivation multiplicatively enhanced the response to visual targets irrespective of their location, suggesting a spatially non-specific enhancement of processing. The effects of attention and motivation on LIP activity were both predictive of changes in saccadic reaction times. These results suggest that attention and motivation exert distinct influences on visual representations in LIP, but that they both contribute to the preferential processing of behaviorally relevant visual stimuli. The data thus support the hypothesis that area LIP encodes a salience map of the visual world. / Dissertation

published_or_final_version / abstract / Physics / Doctoral / Doctor of Philosophy

No description available.

Olfaction is one of the most important senses by which insects obtain information about their environment. In the early stages of olfactory perception in insects, odour molecules are carried across the sensillum lymph by small soluble Odorant Binding Proteins (OBPs). This is followed by activation of the appropriate olfactory receptor, resulting in an electrical impulse, and subsequent degradation of the initial signal. OBPs have been studied in a range of insect orders including Lepidoptera, Diptera and Orthoptera, and this study reports the cloning and characterisation of cDNAs with a potential olfactory role in the vetch aphid, Megoura viciae (Buckton, Homoptera: Aphididiae). Construction and sequencing of antennal cDNA libraries identified two cDNAs, MvicOBP1 and Mv164, which were approximately 0.8kb and 1kb respectively. The amino acid sequence of MvicOBP1 has the spacing pattern of six cysteine residues that is characteristic of insect OBPs, and Mv164 shows similarity to insect cytochrome P450 enzymes. RT-PCR showed that these cDNAs have specific or enhanced expression in the chemosensory tissues of M. viciae, and parallel expression patterns suggest a "linked" function. Related sequences are present and expressed in other aphid species, and sequencing of genomic fragments allowed the partial elucidation of the intron/exon organisation of these genes. Subtracted antennal cDNA libraries identified two cDNAs encoding proteins with significant similarity to insect chemosensory proteins (CSPs), cDNAs encoding Juvenile Hormone Binding Proteins (JHBPs), and a tissue-specific cDNA with a potential carrier role. These, coupled with the OBPs, add evidence to the suggestion that there is an insect superfamily of binding proteins. A PBP from Bombyx mori (BmorPBP1) was used as a model system for in vitro expression of an insect OBP and subsequent characterisation of the recombinant protein. Four forms of this protein, identified through their interaction with an anti-BmorPBP antibody, were resolved by isoelectric focusing.

Behaviourists and Logical Positivists commendably set out to purge prejudiced arguments from science, but where it is obvious that there remains some sort of "ghost" in their rational "machine", it is self-defeating simply to ignore its existence. Freaud, Piaget, and the ethologists have made some progress in grasping this nettle -- moving towards a material explanation of the "other-worldly" properties of the individual -- but their models of the individual remain nebulously structured in their basic elements. Consequently such theories remain disturbingly controversial, and circumscribed in their applicability. [#] The present work accordingly sets out to bridge this gap by postulating plausible functions for existing micro-structure which could account both for observed behavioural phenomena, and for many of the existing vaguer theoretical constructs. Part A develops such an explanation for Piagetian constructs, while Part B fills in some of the technical details concerning quantitative problems of signal generation, transmission, and selective reception. [#] Part C applies these notions to other non-Piagetian descriptions and interpretations of psychological phenomena, thereby offering an integration and reconciliation of various schools of theory. (Major areas considered include Ashby's "homeostat" approach, biological self-organization, sleep-modes and dreaming, Freudian theories of neuroses, and various theories concerning psychosis). The basic theory itself is meanwhile developed in much greater detail. [#] A recurring theme throughout the work is the notion that knowledge-acquisition by any independent system depends not only on "external" interaction with the "real" world, but also on an active seeking for internal consistency within the resulting "internal" model. This concept is crucial to the study in two ways:- (i) The operation of the brain-systems being considered, and (ii) As a guuide to the methodology of the present study itself -- in an area where experimental data is uncomfortably sparse, and likely to remain so.

Thesis (M.S.)--University of Toledo, 2007. / Typescript. "Submitted as partial fulfillment of the requirements for The Master of Science in Bioengineering." Bibliography: leaves 152-154.

Thesis (M.S.)--Montana State University--Bozeman, 2004. / Typescript. Chairperson, Graduate Committee: Ross K. Snider. Includes bibliographical references (leaves 107-112).