http://hdl.handle.net/2262/38 Physiology Sat, 18 May 2013 11:32:12 GMT 2013-05-18T11:32:12Z http://hdl.handle.net/2262/64050 Title: Age-related changes in the hippocampus (loss of synaptophysin and glial-synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL Author: LYNCH, MARINA ANNETTA Abstract: Altered synaptic morphology, progressive loss of synapses and glial (astrocyte and microglial) cell activation are considered as characteristic hallmarks of ageing. Recent evidence suggests that there is a concomitant age-related decrease in expression of the presynaptic protein, synaptophysin, and the neuronal glycoprotein CD200, which, by interacting with its receptor, plays a role in maintaining microglia in a quiescent state. These age-related changes may be indicative of reduced neuroglial support of synapses. FG Loop (FGL) peptide synthesised from the second fibronectin type III module of neural cell adhesion molecule (NCAM), has previously been shown to attenuate age-related glial cell activation, and to ‘restore’ cognitive function in aged rats. The mechanisms by which FGL exerts these neuroprotective effects remain unclear, but could involve regulation of CD200, modifying glial-synaptic interactions (affecting neuroglial ‘support’ at synapses), or impacting directly on synaptic function. Light and electron microscopic (EM) analyses were undertaken to investigate whether systemic treatment with FGL (i) alters CD200, synaptophysin (presynaptic) and PSD95 (postsynaptic) immunohistochemical expression levels, (ii) affects synaptic number, or (iii) exerts any effects on glial-synaptic interactions within young (4 month-old) and aged (22 month-old) rat hippocampus. Treatment with FGL attenuated the age-related loss of synaptophysin immunoreactivity (-ir) within CA3 and hilus (with no major effect on PSD-95-ir), and of CD200-ir specifically in the CA3 region. Ultrastructural morphometric analyses showed that FGL treatment (i) prevented age-related loss in astrocyte-synaptic contacts, (ii) reduced microglia-synaptic contacts in the CA3 stratum radiatum, but (iii) had no effect on the mean number of synapses in this region. These data suggest that FGL mediates its neuroprotective effects by regulating glial-synaptic interaction. Description: IN_PRESS Sat, 01 Jan 2011 00:00:00 GMT http://hdl.handle.net/2262/64050 2011-01-01T00:00:00Z http://hdl.handle.net/2262/64045 Title: CD200 fusion protein decreases microglial activation in the hippocampus of aged rats Author: LYNCH, MARINA ANNETTA; COX, FRANCES FIONNUALA Abstract: The glycoprotein, CD200, is primarily expressed on neurons and its cognate receptor CD200R is expressed principally on cells of the myeloid lineage, including microglia. The interaction of CD200 with its receptor plays a significant role in maintaining microglia in a quiescent state and therefore a decrease in CD200 expression in brain is associated with evidence of microglial activation. Conversely, activation of CD200R, for example using a CD200 fusion protein (CD200Fc), should result in a decrease in microglial activation. Here we assessed the effect of delivery of CD200Fc intrahippocampally on microglial activation and on long-term potentiation (LTP) in perforant path-granule cell synapses in young and aged rats. We hypothesized that the age-related changes in microglial activation would be attenuated by CD200Fc resulting in an improved ability of aged rats to sustain LTP. The data indicate that expression of markers of microglial activation including major histocompatibility complex Class II (MHCII) and CD40 mRNA, as well as MHCII immunoreactivity, were increased in hippocampus of aged, compared with young, rats and that these changes were associated with a deficit in LTP; these changes were attenuated in hippocampal tissue prepared from aged rats which received CD200Fc. Microglial activation and a deficit in LTP have also been reported in lipopolysaccharide (LPS)-treated rats and, here, we report that these changes were also attenuated in CD200Fc-treated animals. Thus the negative impact of microglial activation on the ability of aged and LPS-treated rats to sustain LTP is ameliorated when CD200R is activated by CD200Fc. Description: IN_PRESS Sat, 01 Jan 2011 00:00:00 GMT http://hdl.handle.net/2262/64045 2011-01-01T00:00:00Z http://hdl.handle.net/2262/63906 Title: The impact of aging on the brain risk, resilience and repair Author: LYNCH, MARINA ANNETTA Abstract: This Brief Commentary describes a Special Issue that features a series of papers that provide new data on how aging and inflammation interact to affect behaviors that are regulated by the dialogue between the immune system and the brain. Description: IN_PRESS Sun, 01 Jan 2012 00:00:00 GMT http://hdl.handle.net/2262/63906 2012-01-01T00:00:00Z http://hdl.handle.net/2262/62631 Title: Adenosine A(2A) receptors control neuroinflammation and consequent hippocampal neuronal dysfunction. Author: LYNCH, MARINA ANNETTA; MILLS, KINGSTON Abstract: The blockade of adenosine A2A receptors (A2AR) affords a robust neuroprotection in different noxious brain conditions. However, the mechanisms underlying this general neuroprotection are unknown. One possible mechanism could be the control of neuroinflammation that is associated with brain damage, especially because A2AR efficiently control peripheral inflammation. Thus, we tested if the intracerebroventricular injection of a selective A2AR antagonist (SCH58261) would attenuate the changes in the hippocampus triggered by intraperitoneal administration of lipopolysaccharide (LPS) that induces neuroinflammation through microglia activation. LPS administration triggers an increase in inflammatory mediators like interleukin-1b that causes biochemical changes (p38 and c-jun N-terminal kinase phosphorylation and caspase 3 activation) contributing to neuronal dysfunction typified by decreased long-term potentiation, a form of synaptic plasticity. Long-term potentiation, measured 30 min after the tetanus, was significantly lower in LPS-treated rats compared with control-treated rats, while SCH58261 attenuated the LPS-induced change. The LPS-induced increases in phosphorylation of c-jun N-terminal kinase and p38 and activation of caspase 3 were also prevented by SCH58261. Significantly, SCH58261 also prevented the LPS-induced recruitment of activated microglial cells and the increase in interleukin-1b concentration in the hippocampus, indicating that A2AR activation is a pivotal step in mediating the neuroinflammation triggered by LPS. These results indicate that A2AR antagonists prevent neuroinflammation and support the hypothesis that this mechanism might contribute for the ability of A2AR antagonists to control different neurodegenerative diseases known to involve neuroinflammation. Description: PUBLISHED Sat, 01 Jan 2011 00:00:00 GMT http://hdl.handle.net/2262/62631 2011-01-01T00:00:00Z http://hdl.handle.net/2262/62415 Title: Pharmacological inhibition of endocannabinoid degradation modulates the expression of inflammatory mediators in the hypothalamus following an immunological stressor Author: CONNOR, THOMAS JOSEPH Abstract: The endocannabinoid system is an important regulator of the nervous, neuroendocrine and immune systems, thus representing a novel therapeutic target for stress-related neuroinflammatory and psychiatric disorders. However, there is a paucity of data relating to the effects of endocannabinoids on neuroinflammatory mediators following an immune stress/challenge in vivo. This study investigated the effects of URB597, a selective inhibitor of fatty acid amine hydrolyase (FAAH), the enzyme that preferentially metabolises anandamide, on lipopolysaccharide (LPS)-induced increases in the expression of immune mediators in the hypothalamus. Systemic administration of URB597 increased the levels of anandamide and the related N -acylethanolamines, N -palmitoyl ethanolamide and N-oleoyl ethanolamide, but not 2-arachidonoyl glycerol, in the hypothalamus and spleen. URB597 attenuated the LPS-induced increase in interleukin (IL)-1β expression while concurrently augmenting the LPS-induced increase in suppressor of cytokine signalling (SOCS)-3 expression. In addition, URB597 tended to enhance and reduce the LPS-induced increase in IL-6 and IL-10 mRNA expression respectively. LPS-induced increases in peripheral cytokine levels or plasma corticosterone were not altered by URB597. The present study provides evidence for a role for FAAH in the regulation of LPS-induced expression of inflammatory mediators in the hypothalamus. Improved understanding of endocannabinoid-mediated regulation of neuroimmune function has fundamental physiological and potential therapeutic significance in the context of stress-related disorders. Description: PUBLISHED Sun, 01 Jan 2012 00:00:00 GMT http://hdl.handle.net/2262/62415 2012-01-01T00:00:00Z http://hdl.handle.net/2262/62202 Title: Effect of body tilt angle on fatigue and EMG activities in lower limbs during cycling Author: Egaña, Mikel; Ryan, Katie; Warmington, Stuart; Green, Simon Abstract: This study compared the rate of fatigue and lower limb EMG activities during high-intensity constantload cycling in upright and supine postures. Eleven active males performed seven cycling exercise tests: one upright graded test, four fatigue tests (two upright, two supine) and two EMG tests (one upright, one supine). During the fatigue tests participants initially performed a 10 s all-out effort followed by a constant-load test with 10 s all-out bouts interspersed every minute. The load for the initial two fatigue tests was 80% of the peak power (PP) achieved during the graded test and these continued until failure. The remaining two fatigue tests were performed at 20% PP and were limited to the times achieved during the 80% PP tests. During the EMG tests subjects performed a 10 s all-out effort followed by a constant-load test to failure at 80% PP. Normalised EMG activities (% maximum, NEMG) were assessed in five lower limb muscles. Maximum power and maximum EMG activity prior to each fatigue and EMG test were unaffected by posture. The rate of fatigue at 80% PP was significantly higher during supine compared with upright posture (-68 ± 14 vs. -26 ± 6 W min-1, respectively, P\0.05) and the divergence of the fatigue responses occurred by the second minute of exercise. NEMG responses were significantly higher in the supine posture by 1–4 min of exercise. Results show that fatigue is significantly greater during supine compared with upright high-intensity cycling and this effect is accompanied by a reduced activation Fri, 01 Jan 2010 00:00:00 GMT http://hdl.handle.net/2262/62202 2010-01-01T00:00:00Z http://hdl.handle.net/2262/61534 Title: Immunology meets neuroscience opportunities for immune intervention in neurodegenerative diseases Author: MILLS, KINGSTON; LYNCH, MARINA ANNETTA Abstract: Neuroinflammatory changes are characteristic of many, if not all, neurodegenerative diseases but the extent to which the immune system is involved in the pathogenesis of these diseases is unclear. The findings of several studies during the past decade has established that there is a well-developed communication between the central nervous system (CNS) and the peripheral immune system, but also has revealed that the immune system in the CNS is much more sophisticated that previously acknowledged. In this mini-review, we discuss two major neurodegenerative disorders, Alzheimer’s Disease (AD) and multiple sclerosis (MS), and consider whether the therapies most likely to succeed are those that are identified by studying the marriage of neuroscience and immunology. Description: PUBLISHED Sat, 01 Jan 2011 00:00:00 GMT http://hdl.handle.net/2262/61534 2011-01-01T00:00:00Z http://hdl.handle.net/2262/60918 Title: The kinematics of phonotactic steering in the cricket Gryllus bimaculatus Author: WITNEY, ALICE Abstract: Female crickets, Gryllus bimaculatus, are attracted by the male calling song and approach singing males; a behaviour known as phonotaxis. Even tethered females walking on a trackball steer towards a computer-generated male song presented from their left or right side. High-speed video analysis showed how this auditory-evoked steering was integrated with walking. Typically all the front and middle legs showed kinematic adjustments during steering, with the trajectories tilted towards the side of acoustic stimulation. Furthermore, the average speed of the tarsi contralateral to song increased relative to the ipsilateral tarsi. Kinematic changes of the hind legs were small and may be a consequence of the front and middle leg adjustments. Although phonotactic steering generally led to stereotyped adjustments there were differences in the specific combination of kinematic changes in leg trajectories. The most reliable kinematic steering response was by the contralateral front leg, such that, during its swing phase the tarsus moved towards the side of acoustic stimulation through an increased forward rotation of the femur and an increased extension of the tibia. Relating the changes in tarsal positioning of each leg to the steering velocity of the animal indicated that typically the front and middle legs contralateral to song generated the turning forces. Phonotactic steering was integrated into forward walking without changes to the walking motor cycle. Description: PUBLISHED Sat, 01 Jan 2011 00:00:00 GMT http://hdl.handle.net/2262/60918 2011-01-01T00:00:00Z http://hdl.handle.net/2262/60697 Title: A neural cell adhesion molecule-derived peptide, FGL, attenuates glial cell activation in the aged hippocampus Author: LYNCH, MARINA ANNETTA; COWLEY, THELMA Abstract: Neuroglial activation is a typical hallmark of ageing within the hippocampus, and correlates with age-related cognitive deficits. We have used quantitative immunohistochemistry and morphometric analyses to investigate whether systemic treatment with the Neural Cell Adhesion Molecule (NCAM)-derived peptide FG Loop (FGL) specifically alters neuroglial activation and population densities within the aged rat hippocampus (22 months of age). A series of 50 μm paraformaldehyde/acrolein-fixed sections taken throughout the dorsal hippocampus (5 animals per group) were immunostained to detect astrocytes (GFAP and S100ß) and microglial cells (CD11b/OX42 and MHCII/OX6), and analyzed using computerised image analysis and optical segmentation (Image-Pro Plus, Media Cybernetics). FGL treatment reduced the density of CD11b + and MHCII + microglia in aged animals, concomitant with a reduction in immunoreactivity for these phenotypic markers. FGL treatment also markedly reduced GFAP immunoreactivity within all hippocampal subfields in aged animals, without exerting an appreciable effect on the density of S100ß + cells. These results demonstrate that FGL can indeed regulate neuroglial activation and reduce microglial cell density in the aged hippocampus, and support its potential use as a therapeutic agent in age-related brain disorders. Description: PUBLISHED Sat, 01 Jan 2011 00:00:00 GMT http://hdl.handle.net/2262/60697 2011-01-01T00:00:00Z http://hdl.handle.net/2262/60169 Title: Androgen receptor signaling in prostate cancer development and progression Author: LONERGAN, PETER EOIN Abstract: The androgen receptor (AR) signaling axis plays a critical role in the development, function and homeostasis of the prostate. The classical action of AR is to regulate gene transcriptional processes via AR nuclear translocation, binding to androgen response elements on target genes and recruitment of, or crosstalk with, transcription factors. Prostate cancer initiation and progression is also uniquely dependent on AR. Androgen deprivation therapy remains the standard of care for treatment of advanced prostate cancer. Despite an initial favorable response, almost all patients invariably progress to a more aggressive, castrate-resistant phenotype. Considerable evidence now supports the concept that development of castrate-resistant prostate cancer (CRPC) is causally related to continued transactivation of AR. Understanding the critical events and complexities of AR signaling in the progression to CRPC is essential in developing successful future therapies. This review provides a synopsis of AR structure and signaling in prostate cancer progression, with a special focus on recent findings on the role of AR in CRPC. Clinical implications of these findings and potential directions for future research are also outlined. Description: PUBLISHED Sat, 01 Jan 2011 00:00:00 GMT http://hdl.handle.net/2262/60169 2011-01-01T00:00:00Z