This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.

/pdf/control-of-sleep-and-wakefulness-51vkuya5ho.pdf

Control of Sleep and Wakefulness

Sleep and immunity are bidirectionally linked. Immune system activation alters sleep, and sleep in turn affects the innate and adaptive arm of our body’s defense system. Stimulation of the immune s...

/pdf/the-sleep-immune-crosstalk-in-health-and-disease-27ylhsniq6.pdf

The Sleep-Immune Crosstalk in Health and Disease

Neurobiology of REM and NREM sleep.

CD8 T cells respond to viral infections but also participate in defense against bacterial and protozoal infections. In the last few years, as new methods to accurately quantify and characterize pathogen-specific CD8 T cells have become available, our understanding of in vivo T cell responses has increased dramatically. Pathogen-specific T cells, once thought to be quite rare following infection, are now known to be present at very high frequencies, particularly in peripheral, nonlymphoid tissues. With the ability to visualize in vivo CD8 T cell responses has come the recognition that T cell expansion is programmed and, to a great extent, independent of antigen concentrations. Comparison of CD8 T cell responses to different pathogens also highlights the intricate relationship between microbially induced innate inflammatory responses and the kinetics, magnitude, and character of long-term T cell responses. This review describes recent progress in some of the major murine models of CD8 T cell-mediated immunity to viral, bacterial, and protozoal infection.

CD8 T cell responses to infectious pathogens.

Prostanoids are cyclic, oxygenated products of ω3 and ω6 20- and 22-carbon essential fatty acids (FAs) that are formed enzymatically through “cyclooxygenases”. Prostaglandin endoperoxide synthases -1 and -2 (PGHS-1 and -2)a, which are also known as cyclooxygenases -1 and -2 (COX-1 and -2), catalyze the committed step in the biosynthesis of prostanoids (Figure 1). These compounds include what are sometimes referred to as the “classical” prostaglandins (PGs) PGD, PGE, and PGF as well as prostacyclins denoted as PGI's and the thromboxanes abbreviated Tx's; monohydroxy acids can also be formed via PGHSs, but information on the possible physiologic importance of such compounds is incomplete.1-3 The most abundant prostanoids are the “2-series” compounds (e.g. PGE2) that are formed from arachidonic acid (AA; 5Z, 8Z, 11Z, 14Z- eicosatetraenoic acid; 20:4 ω6; Figure 1). The “2” denotes the number of carbon-carbon double bonds in the product.



Figure 1

Biosynthetic pathway for the formation of prostanoids



PGHSs catalyze two distinct reactions that occur at physically distinct but functionally interacting sites. The cyclooxygenase (COX) reaction is a bis-oxygenation in which two O2 molecules are inserted into the carbon backbone of AA to yield PGG2 (Figure 1). The peroxidase (POX) reaction is a transformation in which the 15-hydroperoxyl group of PGG2 undergoes a net two electron reduction to PGH2 plus water. The POX reaction is important in the enzyme mechanism, but other peroxidases such as glutathione peroxidase may contribute importantly to the reduction of PGG2 to PGH2 in vivo.

PGH2 is thought not to accumulate in cells but rather to be converted quickly to what are considered the biologically relevant, downstream products. There are specific synthases involved in forming PGD2, PGE2, PGF2α, PGI2 and TxA2 from PGH2. Except for the case of PGF2α, which is formed by a two electron reduction of PGH2, these enzymes catalyze non-oxidative rearrangements. Finally, there is a PGH 19-hydoxylase that converts PGHs to their corresponding 19-hydroxy derivatives which themselves are substrates for PGE synthase(s). There are one or more specific G protein-linked receptors for each prostanoid, and in some cases prostanoids may also act through nuclear peroxisome proliferator activated receptors.

AA and other 20- and 22-carbon, highly unsaturated FAs are found esterified at the sn2 position of glycerophospholipids. Basal prostanoid formation generally occurs at a low rate relative to stimulated formation. A major factor limiting prostanoid formation is AA availability, which is controlled through the net rates of deacylation and reacylation of glycerophospholipids. Prostanoid formation is enhanced when phospholipase A2 (PLA2) activity is increased, and thus PLA2s play a substrate-limiting role in regulating prostanoid biosynthesis. Although reacylation may also be important, its possible role in regulating prostanoid biosynthesis is largely unexplored.

In this chapter we review the biochemistry and the biochemical pharmacology of the enzymes involved in converting AA to various prostanoid products. These enzymes include PGHS-1, PGHS-2, hematopoietic PGD synthase (H-PGDS), lipocalin-type PGD synthase (L-PGDS), microsomal PGE synthase-1 (mPGES-1), microsomal PGE synthase-2 (mPGES-2), cytosolic PGE synthase (cPGES), PGF synthase (PGFS), PGI synthase (PGIS) and TXA synthase (TXAS). The PLA2s involved in mobilizing AA and the receptors through which prostanoids function are surveyed in other chapters of this volume.

Enzymes of the Cyclooxygenase Pathways of Prostanoid Biosynthesis

To help to elucidate the changes induced by Trypanosoma brucei gambiense in the central nervous system (CNS) in advanced sleeping sickness patients, levels of interleukin-1 (IL-1) and prostaglandins D2 (PGD2) and E2 (PGE2) were measured by radioimmunoassay in the cerebrospinal fluid (CSF) from 24 patients diagnosed on the criteria of CSF protein, leucocyte count and parasite presence as having CNS (i.e. late stage) involvement, and from 12 patients without CNS involvement. PGD2 concentrations were selectively and markedly elevated in the late stage patients. The increased PGD2 may in part account for the increased somnolence and the immunosuppression within the CNS. Measurement of PGD2 levels in CSF may be a useful criterion for CNS involvement.

The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in cerebrospinal fluid of advanced sleeping sickness patients.

Damage to the nervous system occurs in both African and American trypanosomiases, but it differs considerably in form and extent in each disease, and with different strains and disease stages. With Trypanosoma brucei infections there is a progressive central nervous system (CNS) pathology which involves the meninges, choroid, blood-brain barrier, and immunopathological changes including perivascular infiltrations, astrocyte activation and alterations in the cytokine/mediator network. These changes underly the altered behaviour in the late or secondary disease stages, prevalent in the chronic gambian form, characterized by hypersomnia leading, if untreated or if treatment is followed by reactive changes, to coma and death. T. cruzi infections can be divided into 3 stages; acute, intermediate and chronic. Each stage has a different neurological involvement. In the acute stage the parasite produces direct destructive and inflammatory changes in the CNS which can be life-threatening, but which normally resolve, giving way to an intermediate period with effective parasite suppression and little or no perpetuation in the nervous system. The chronic stage is characterized by alteration to a progressive peripheral neuroimmunopathology, with autoimmune destruction of many nerve components, especially the autonomic innervation of the heart and gut.

V.W. Pentreath

Papers

The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in cerebrospinal fluid of advanced sleeping sickness patients.

Trypanosomiasis and the nervous system: Pathology and immunology

The search for primary events causing the pathology in African sleeping sickness

Preliminary observations on the intestinal pathology of mice infected with Trypanosoma brucei brucei.