Cellular Mechanisms of Sleep Homeostasis : Studies on Brain Energy Metabolism and Aging

Sleep is governed by a homeostatic process in which the duration and quality of previous wake regulate the subsequent sleep. Active wakefulness is characterized with high frequency cortical oscillations and depends on stimulating influence of the arousal systems, such as the cholinergic basal forebrain (BF), while cessation of the activity in the arousal systems is required for slow wave sleep (SWS) to occur. The site-specific accumulation of adenosine (a by-product of ATP breakdown) in the BF during prolonged waking /sleep deprivation (SD) is known to induce sleep, thus coupling energy demand to sleep promotion. The adenosine release in the BF is accompanied with increases in extracellular lactate and nitric oxide (NO) levels. This thesis was aimed at further understanding the cellular processes by which the BF is involved in sleep-wake regulation and how these processes are affected by aging. The BF function was studied simultaneously at three levels of organization: 1) locally at a cellular level by measuring energy metabolites 2) globally at a cortical level (the out-put area of the BF) by measuring EEG oscillations and 3) at a behavioral level by studying changes in vigilance states. Study I showed that wake-promoting BF activation, particularly with glutamate receptor agonist N-methyl-D-aspatate (NMDA), increased extracellular adenosine and lactate levels and led to a homeostatic increase in the subsequent sleep. Blocking NMDA activation during SD reduced the high frequency (HF) EEG theta (7-9 Hz) power and attenuated the subsequent sleep. In aging, activation of the BF during SD or experimentally with NMDA (studies III, IV), did not induce lactate or adenosine release and the increases in the HF EEG theta power during SD and SWS during the subsequent sleep were attenuated as compared to the young. These findings implicate that increased or continuous BF activity is important for active wake maintenance during SD as well as for the generation of homeostatic sleep pressure, and that in aging these mechanisms are impaired. Study II found that induction of the inducible NO synthase (iNOS) during SD is accompanied with activation of the AMP-activated protein kinase (AMPK) in the BF. Because decreased cellular energy charge is the most common cause for AMPK activation, this finding implicates that the BF is selectively sensitive to the metabolic demands of SD as increases were not found in the cortex. In aging (study III), iNOS expression and extracellular levels of NO and adenosine were not significantly increased during SD in the BF. Furthermore, infusion of NO donor into the BF did not lead to sleep promotion as it did in the young. These findings indicated that the NO (and adenosine) mediated sleep induction is impaired in aging and that it could at least partly be due to the reduced sensitivity of the BF to sleep-inducing factors. Taken together, these findings show that reduced sleep promotion by the BF contributes to the attenuated homeostatic sleep response in aging.

The Church and Its Boundaries : A Study of the Special Commission on Orthodox Participation in the WCC

The relationship between the Orthodox Churches and the World Council of Churches (WCC) became a crisis just before the 8th Assembly of the WCC in Harare, Zimbabwe in 1998. The Special Commission on Orthodox Participation in the WCC (SC), inaugurated in Harare, worked during the period 1999 2002 to solve the crisis and to secure the Orthodox participation in the WCC. The purpose of this study is: 1) to clarify the theological motives for the inauguration of the SC and the theological argumentation of the Orthodox criticism; 2) to write a reliable history and analysis of the SC; 3) to outline the theological argumentation, which structures the debate, and 4) to investigate the ecclesiological questions that arise from the SC material. The study spans the years 1998 to 2006, from the WCC Harare Assembly to the Porto Alegre Assembly. Hence, the initiation and immediate reception of the Special Commission are included in the study. The sources of this study are all the material produced by and for the SC. The method employed is systematic analysis. The focus of the study is on theological argumentation; the historical context and political motives that played a part in the Orthodox-WCC relations are not discussed in detail. The study shows how the initial, specific and individual Orthodox concerns developed into a profound ecclesiological discussion and also led to concrete changes in WCC practices, the best known of which is the change to decision-making by consensus. The Final Report of the SC contains five main themes, namely, ecclesiology, decision-making, worship/common prayer, membership and representation, and social and ethical issues. The main achievement of the SC was that it secured the Orthodox membership in the WCC. The ecclesiological conclusions made in the Final Report are twofold. On the one hand, it confirms that the very act of belonging to the WCC means the commitment to discuss the relationship between a church and churches. The SC recommended that baptism should be added as a criterion for membership in the WCC, and the member churches should continue to work towards the mutual recognition of each other s baptism. These elements strengthen the ecclesiological character of the WCC. On the other hand, when the Final Report discusses common prayer, the ecclesiological conclusions are much more cautious, and the ecclesiological neutrality of the WCC is emphasized several times. The SC repeatedly emphasized that the WCC is a fellowship of churches. The concept of koinonia, which has otherwise been important in recent ecclesiological questions, was not much applied by the SC. The comparison of the results of the SC to parallel ecclesiological documents of the WCC (Nature and Mission of the Church, Called to Be the One Church) shows that they all acknowledge the different ecclesiological starting points of the member churches, and, following that, a variety of legitimate views on the relation of the Church to the churches. Despite the change from preserving the koinonia to promises of eschatological koinonia, all the documents affirm that the goal of the ecumenical movement is still full, visible unity.