Anesthesia-induced spatial learning impairments in aged rats model postoperative cognitive dysfunction (POCD) in the elderly surgical population. Mechanisms underlying both normal age-related cognitive decline and anesthesia-induced spatial learning deficits in aged rats were investigated. With respect to the involvement of inflammasome activation and age-related cognitive decline, I hypothesized that the aged hippocampus exhibits an elevated activation of inflammasome components contributing to elevated levels of IL-1β in the aged brain. Age-related cognitive decline was identified in a subpopulation of male Fischer 344 rats. Activation of the NLRP1 inflammasome was elevated in the aged brain, contributing to spatial learning deficits in aged rats. With respect to anesthesia-induced spatial learning impairment in aged rats, I hypothesized that an increase in NR2B subunit in the hippocampus and cortex during and following isoflurane anesthesia exposure resulting in spatial learning impairment in aged rats via disruption of downstream signaling molecule, extracellular-signal regulated protein kinase (ERK). Anesthesia exposure resulted in chronic spatial learning impairment in aged rats that were previously unimpaired in spatial learning tasks. Additionally, anesthesia induced elevated levels of N-methyl-D-aspartate (NMDA) receptor NR2B subunit protein expression in aged. It was concluded that various factors contribute to age-related spatial impairment including: NLRP1 inflammasome activation and NMDA receptor NR2B protein expression elevation. It was also concluded that anesthesia exposure exacerbates the elevation in NR2B protein expression in the aged brain, with subsequent disruption of ERK activation leading to chronic spatial learning deficits in aged rats. In the final chapter, a relationship for the interplay between inflammation and NMDA receptor function in the aged brain is discussed. In addition, a novel mechanism for anesthesia-induced cognitive deficits is presented. Therapeutic treatments for cognitive decline and anesthesia-induced cognitive deficits are explored. Finally, future lines of research are proposed.

<p>The neurosteroids constitute a group of powerful hormones synthesized and acting in the central nervous system. They participate in a number of important central processes, such as memory and learning, mood and neuroprotection. Their effects emerge from rapid interactions with membrane bound receptors, such as the N-methyl-D-aspartate (NMDA) receptor, the gamma-amino-butyric acid receptor and the sigma 1 receptor. The mechanisms of action are separate from classical genomic interactions. </p><p>The aims of this thesis were to identify and characterize the molecular mechanisms underlying the effects of nanomolar concentrations of neurosteroids at the NMDA receptor. </p><p>The results show that the neurosteroids pregnenolone sulfate (PS) and pregnanolone sulfate 3α5βS) differently modulate the NMDA receptor, changing the kinetics for the NMDA receptor antagonist ifenprodil, through unique and separate targets at the NR2B subunit. The effects that appear to be temperature independent were further confirmed in a calcium imagining functional assay. A second functional study demonstrated that PS and 3α5βS affect glutamate-stimulated neurite outgrowth in NG108-15 cells. </p><p>Misuse of anabolic androgenic steroids (AAS) has powerful effects on emotional states. Since neurosteroids regulate processes involved in mood it can be hypothesised that AAS can interact with the action of neurosteroids in the brain. However, chronic administration of the AAS nandrolone decanoate did not alter the allosteric effects of PS or 3α5βS at the NMDA receptor, but changed the affinity for PS, 3α5βS and dehydroepiandrosterone sulfate to the sigma 1 receptor. The results also showed that the neurosteroids displace ³H-ifenprodil from the sigma 1 and 2 receptors without directly sharing the binding site for ³H-ifenprodil at the sigma 1 receptor. The decreased affinity for the neurosteroids at the sigma 1 receptor may be involved in the depressive symptoms associated with AAS misuse.</p><p>The NMDA receptor system is deeply involved in neurodegeneration and the NMDA receptor antagonist ifenprodil exert neuroprotective actions. The findings that neurosteroids interact with ifenprodil at the NMDA receptor may be an opportunity to obtain synergistic effects in neuroprotective treatment.</p>

The neurosteroids constitute a group of powerful hormones synthesized and acting in the central nervous system. They participate in a number of important central processes, such as memory and learning, mood and neuroprotection. Their effects emerge from rapid interactions with membrane bound receptors, such as the N-methyl-D-aspartate (NMDA) receptor, the gamma-amino-butyric acid receptor and the sigma 1 receptor. The mechanisms of action are separate from classical genomic interactions. The aims of this thesis were to identify and characterize the molecular mechanisms underlying the effects of nanomolar concentrations of neurosteroids at the NMDA receptor. The results show that the neurosteroids pregnenolone sulfate (PS) and pregnanolone sulfate 3α5βS) differently modulate the NMDA receptor, changing the kinetics for the NMDA receptor antagonist ifenprodil, through unique and separate targets at the NR2B subunit. The effects that appear to be temperature independent were further confirmed in a calcium imagining functional assay. A second functional study demonstrated that PS and 3α5βS affect glutamate-stimulated neurite outgrowth in NG108-15 cells. Misuse of anabolic androgenic steroids (AAS) has powerful effects on emotional states. Since neurosteroids regulate processes involved in mood it can be hypothesised that AAS can interact with the action of neurosteroids in the brain. However, chronic administration of the AAS nandrolone decanoate did not alter the allosteric effects of PS or 3α5βS at the NMDA receptor, but changed the affinity for PS, 3α5βS and dehydroepiandrosterone sulfate to the sigma 1 receptor. The results also showed that the neurosteroids displace 3H-ifenprodil from the sigma 1 and 2 receptors without directly sharing the binding site for 3H-ifenprodil at the sigma 1 receptor. The decreased affinity for the neurosteroids at the sigma 1 receptor may be involved in the depressive symptoms associated with AAS misuse. The NMDA receptor system is deeply involved in neurodegeneration and the NMDA receptor antagonist ifenprodil exert neuroprotective actions. The findings that neurosteroids interact with ifenprodil at the NMDA receptor may be an opportunity to obtain synergistic effects in neuroprotective treatment.

Nonspecific NMDA receptor antagonists induce hyperlocomotion in rats. The aim of this work is to determine whether the NMDA receptor antagonist specific for NR2 subunit exhibit similar negative effect as nonspecific antagonists. This subunit is predominant in the brain in the early postnatal period. The introduction summarizes the data on NMDA receptors and the development of rat. The experimental part deals with the action of a specific NMDA receptor antagonist Ro 25-6981 on motor performance of developing rats. Substance was repeatedly administered to rats at postnatal days 7 to 11. Spontaneous locomotion and motor performance of the animals were repeatedly tested up to adulthood by battery of tests appropriate for individual ages. Our research demonstrated that this substance does not have significant effect on motor system of laboratory rat and that it might be further tested as a possible age-bound antiepileptic drug.