Thesis (Ph.D.) - University of Queensland, 2004. / Includes bibliographical references.

Thesis (M. Sc.)--University of Canterbury, 2006. / Typescript (photocopy). Includes bibliographical references (leaves 61-73). Also available via the World Wide Web.

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Reproductive senescence in females is a natural part of the aging process. However, the process by which it occurs, and the relative role of each level of the hypothalamic-pituitary-gonadal axis, remains largely unknown. The neural circuitry regulating the hypothalamic axis, including glutamate acting through N-Methyl-D-Aspartate receptors (NMDARs) on GnRH neurons, appears to be key to this process. The NMDAR is tetrameric and composed of an obligatory NR1 subunit together with NR2 subunits. The subunit composition determines the channel kinetics of the receptor and changes through the life span. This dissertation examines the physiological role of the NR2b subunit on LH pulsatile release and LH surge, both important for reproductive function. The expression of NR2b subunits in the anteroventral periventricular (AVPV) nucleus of the hypothalamus was also examined in aging rats. Experiment 1 showed that the NR2b-antagonist, ifenprodil, enhanced pulsatile LH release in estradioltreated females (both age groups). Experiment 2 showed that the LH surge in middle-aged animals was slightly accelerated and that results were dependent upon prior reproductive status of the animals. In Experiment 3, examination of the NR2b-immunoreactive cell population in young, middle-aged, and aged ovariectomized females given vehicle, estradiol, or estradiol with progesterone showed an age-associated decline in NR2b density. However, the immunofluorescent fraction volume of NR1 colocalized with NR2b increased with aging, and that of immunofluorescent fraction volume of NR2b increased with estradiol treatment. This is indicative of the amount of protein expressed in the AVPV. In total, NR2b cell density in the AVPV declines with age, but the amount of NR2b expressed in NR1-positive cells increases, suggesting a larger population of NR2b containing channels. This may translate to age-associated inhibition of GnRH/LH activity, which is relieved with blockade of NR2bcontaining NMDARs. Thus, this dissertation describes a novel way to examine the mechanism by which age-associated changes to neuromodulators of the HPG axis may affect the onset of reproductive senescence. / text

NMDA receptor antagonists such as Ketamine and PCP are potent psychoactive drugs used recreationally. This class of drug induces a number of phenomena in humans similar to those associated with schizophrenia including reduced selective attention, altered working memory, thought disorders and hallucinations. These psychotomimetic drugs have thus been used as a longstanding model to study this disease in animals. Importantly, such animal models allow for recording of brain activity using invasive techniques that are inappropriate in humans. Previous electrophysiological studies have shown that MK-801, a potent non-competitive NMDA receptor antagonist, increases gamma-frequency oscillations and produces a state of disinhibition in the prefrontal cortex of rats wherein the activity of putative excitatory pyramidal neurons increases while the activity of putative inhibitory interneurons decreases. These features are relevant to schizophrenia because molecular evidence suggests dysfunction of inhibitory cortical interneurons, while electroencephalographic recordings show altered gamma-frequency oscillations in this disease. It has been hypothesized that the disinhibited cortical state produces “noisy” information processing, but this has not been directly observed in the interaction of neuronal firing in either humans or animal models. We therefore tested this hypothesis by examining the synchronization of neural activity in the NMDA receptor antagonist model of schizophrenia. We used high-density electrophysiological recordings in the medial prefrontal cortex of freely moving rats before and after systemic injection of MK-801. Analysis of these recordings revealed that drug administration: (i) increases gamma power in field potentials in a manner dissociated from increased locomotion; (ii) does not change the gamma power in multi-unit activity; (iii) decreases spike synchronization among putative pyramidal neurons in the gamma range (30ms), and despite of this it (iv) does not change the synchronization between gamma-range field potentials or between sum-of-spikes and field potentials. These effects in synchronization may be revealing of potent cognitive effects associated with NMDA receptor antagonism, and may reflect impaired communication processing hypothesized to occur in schizophrenia. / xi, 42 leaves : ill. ; 29 cm

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Damage to one vestibular apparatus (unilateral vestibular deafferentation, UVD) results in severe postural and ocular motor disturbances (such as spontaneous nystagmus, SN) that recover over time in a process known as vestibular compensation. However, the underlying neurochemical mechanisms of vestibular compensation are poorly understood. While UVD affects many areas in the CNS, attention has focused upon the partially deafferented second order neurons in the vestibular nuclei complex (VNC). Several converging lines of evidence suggest that Ca�⁺-permeable ion channels (N-methyl-D-aspartate receptors and L-type voltage-gated Ca�⁺-channels) and intracellular Ca�⁺-dependent protein kinases play an important role in vestibular compensation. However, the nature of this involvement and the locus of these changes are unknown. The aim of this thesis was to investigate the role of Ca�⁺ signalling pathways in the VNC during vestibular compensation in guinea pig. These issues were investigated in three separate experiments that utilised two methodological approaches: i) in vitro assays were used to determine the nature and extent of protein phosphorylation within the VNC at various stages of compensation; and ii) ion channel blockers or cell-permeable kinase inhibitors were injected directly into the VNC immediately before UVD to determine whether or not these systems were causally involved in compensation. The results of experiment 1 (Chapter 5) showed that a bolus intra-VNC injection of an uncompetitive NMDA receptor antagonist, but not an L-type voltage-gated Ca�⁺ channel antagonist, temporarily reduced SN frequency at the earliest measurement time (6 hours post-UVD). These results suggested that the initial expression of SN required, in part, the activation of NMDA receptors in the VNC on the side of the UVD, and by inference, Ca�⁺ entry through the ion channel. The results of experiment 2 (Chapter 6) revealed that the medial VNC contains abundant Ca�⁺/calmodulin-dependent and Ca�⁺/phospholipid-dependent protein kinase activities. The same VNC tissue removed from animals at various times after UVD, showed that vestibular compensation is accompanied by specific changes in the phosphorylation of several major protein kinase C substrates. These included an unidentified 46-kDa band, and a 75-kDa band with similar characteristics to the myristoylated alanine-rich C kinase substrate (MARCKS). These results suggest that protein kinase C signalling pathways may be involved in vestibular compensation. The results of experiment 3 (Chapter 7) are consistent with these results showing that intra-VNC infusion of a protein kinase C inhibitor, but not a Ca�⁺/calmodulin-dependent protein kinase II inhibitor, significantly increased SN at the earliest measurement times (6 and 8 hours), but had no effect upon the time taken to achieve compensation or on postural compensation. These results suggest that the induction of SN compensation involves protein kinase C activity in the VNC. Taken together, these findings suggest that the mechanisms underlying the expression of SN (e.g., Ca�⁺ influx via NMDA receptors) are possibly distinct from those that initiate its compensation (e.g., PKC activation). The downstream effects of raised intracellular Ca�⁺ may involve protein kinase C-dependent phosphorylation of key intracellular proteins that initiate long-lasting changes in cellular function within the VNC.