Formação Reticular

Prévia do material em texto

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ELETROENCEFALOGRAMA (EEG)
-Voltagem registrada entre dois eletrodos aplicados ao couro cabeludo
-1929 – Hans Berger
-ALFA: 8-13Hz
-BETA:14-60Hz
-TETA: 4-7Hz
-DELTA: <4Hz
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Moruzzi, Magoun, 1949
-est. Junção ponto-mesencefálica
Hess
-est. Tálamo em baixa freq.
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Formação Reticular – modulação da dor
Substância cinzenta periaquedutal
Núcleos da Rafe 
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Beta
15-60Hz
30V
(vigília)
Teta 
4-8Hz
50-100 V
(fase I – 
sono lento)
Fusos do sono
10-15Hz
50-150 V
(fase II – 
sono lento)
2-4Hz
100-150 V
(fase III -
sono lento)
delta
0,5-2Hz
100-200 V
(fase IV -
sono lento)
REM
Sono paradoxal
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Sono REM
Privação : nenhum efeito comportamental adverso
Eliminação de padrões de conexões neuronais
Reforço de comportamentos não observados em vigília
Transferência de memória entre o hipocampo e o neo-córtex
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Sono REM:
-FR ponto-mesenc.(Ach) – Tálamo
-atonia (GABA)
-sonho
-REM (FRPP – colículo superior)
-atividade ponto-geniculada occipital (FR-CGL-lobo occipital)
-ereção
-aumento da PA e FC
-aumento do metabolismo
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Vigília: 
ACh +
 NE +
 Serotonina +
Sono REM on: 
ACh +
serotonina -
Sono REM off: 
NE +
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Privação do sono - conseqüências
Comprometimento da memória
Redução das habilidades cognitivas
Alteração do humor
Alucinações
264 H (11 dias)
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-Aumento da ingesta alimentar
-Perda de peso
-Falha regulação temperatura corpórea
-Infecções 
-Morte 
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Há um relógio biológico interno que continua a operar na ausência de informação externa sobre a hora do dia
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Activation of specific neural circuits triggers sleep and wakefulness. (A) Electrical stimulation of the cholinergic neurons near the junction of pons and midbrain (the reticular activating system) causes a sleeping cat to awaken. (B) Electrical stimulation of the thalamus causes an awake cat to fall asleep. Graphs show EEG recordings before and during stimulation. 
The Physiological Basis of Pain Modulation Understanding the central modulation of pain perception (on which the placebo effect is presumably based) was greatly advanced by the finding that electrical or pharmacological stimulation of certain regions of the midbrain produces relief of pain (see Figure 10.5). This analgesic effect arises from activation of descending pain-modulating pathways that project, via the medulla, to neurons in the dorsal horn particularly in Rexed's lamina II that control the ascending information in the nociceptive system. The major brainstem regions that produce this effect are located in poorly defined nuclei in the periaqueductal gray matter and the rostral medulla. Electrical stimulation at each of these sites in experimental animals not only produces analgesia by behavioral criteria, but also demonstrably inhibits the activity of nociceptive projection neurons in the dorsal horn of the spinal cord.
A quite ordinary example of the modulation of painful stimuli is the ability to reduce the sensation of sharp pain by activating low-threshold mechanoreceptors: If you crack your shin or stub a toe, a natural (and effective) reaction is to vigorously rub the site of injury for a minute or two. Such observations, buttressed by experiments in animals, led Ronald Melzack and Patrick Wall to propose that the flow of nociceptive information through the spinal cord is modulated by concomitant activation of the large myelinated fibers associated with low-threshold mechanoreceptors. Even though further investigation led to modification of some of the original propositions in Melzack and Wall's gate theory of pain, the idea stimulated a great deal of work on pain modulation.
The most exciting advance in this long-standing effort has been the discovery of endogenous opioids. For centuries it had been apparent that opium derivatives such as morphine are powerful analgesics indeed, they remain a mainstay of analgesic therapy today. Modern animal studies have shown that a variety of brain regions are susceptible to the action of opiate drugs, particularly and significantly the periaqueductal gray matter and the rostral ventral medulla. There are, in addition, opiate-sensitive regions at the level of the spinal cord. In other words, the areas that produce analgesia when stimulated are also responsive to exogenously administered opiates. It seems likely, then, that opiate drugs act at most or all of the sites shown in Figure 10.5 in producing their dramatic pain-relieving effects.
The analgesic action of opiates implied the existence of specific brain and spinal cord receptors for these drugs long before the receptors were actually found during the 1960s and 1970s. Since such receptors are unlikely to exist for the purpose of responding to the administration of opium and its derivatives, the conviction grew that there must be endogenous compounds for which these receptors had evolved (see Chapter 6). Several categories of endogenous opioids have now been isolated from the brain and intensively studied (Table 10.2). These agents are found in the same regions that are involved in the modulation of nociceptive afferents, although each of the families of endogenous opioid peptides has a somewhat different distribution. All three of the major groups (enkephalins, endorphins, and dynorphins) are present in the periaqueductal gray matter. The enkephalins and dynorphins have also been found in the rostral ventral medulla and in the spinal cord regions involved in the modulation of pain
The Possible Functions of REM Sleep and Dreaming Despite this wealth of descriptive information about the stages of sleep, the functional purposes of the various sleep states are not known. Whereas most sleep researchers accept the idea that the purpose of non-REM sleep is at least in part restorative, the function of REM sleep remains a matter of considerable controversy.
A possible clue about the purposes of REM sleep is the prevalence of dreams during these epochs of the sleep cycle. The occurrence of dreams can be tested by waking volunteers during either non-REM or REM sleep and asking them if they were dreaming. Subjects awakened from REM sleep recall elaborate, vivid, hallucinogenic and emotional dreams, whereas subjects awakened during non-REM sleep report fewer dreams, which, when they occur, are more conceptual, less vivid and less emotion-laden.
Dreams have been studied in a variety of ways, perhaps most notably within the psychoanalytic framework of revealing unconscious thought processes considered to be at the root of neuroses. Sigmund Freud's The Interpretation of Dreams, published in 1900, speaks eloquently to the complex relationship between conscious and unconscious mentation. It is by no means agreed upon, however, that dreams have the deep significance that Freud and others have given them, and the psychoanalytic interpretation of dreams has recently fallen into disfavor. Nevertheless, most people probably give some credence to the significance of dream content, at least privately. In more recent studies of dreams, about 65% are associated with sadness, apprehension, or anger; 20% with happiness or excitement; and, somewhat surprisingly, only 1% with sexual feelings or acts.
Adding to the uncertainty about the purposes of REM sleep and dreaming is the fact that deprivation of REM sleep in humans for as much as two weeks has little or no obvious effect on behavior. Such studies have been done by waking volunteers whenever their EEG recordings showed the characteristic signs of REM sleep. Although the subjects in these experiments compensate for the lack of REM sleep by having more of it after the period of deprivation has ended, they suffer no obvious adverse effects. Similarly, patientstaking certain antidepressants (MAO inhibitors) have little or no REM sleep, yet show no obvious ill effects, even after months or years of treatment. The apparent innocuousness of REM sleep deprivation contrasts markedly with the effects of total sleep deprivation (see earlier). The implication of these several findings is that we can get along without REM sleep, but need non-REM sleep in order to survive.
Several general hypotheses about dreams and REM sleep have been advanced. Francis Crick (of DNA fame) and Grahame Mitchison suggested that dreams act as an "unlearning" mechanism, whereby certain modes of neural activity are erased by random activation of cortical connections. The hypothesis is based on the idea that the human brain represents information by the activity of sets of neuronal networks that are widely distributed and overlapping. In computers, neural network architectures are subject to unwanted patterns of activity that can indeed degrade rather than enhance the information content of the system. By analogy, these "parasitic" modes of activity might be unwanted thoughts or erroneous information, which, if not expunged, could become the basis for obsession, paranoia, or other pathologies of thought that prevent the "system" from working as efficiently as it should. In a different vein, Michel Jouvet proposed that dreaming reinforces behaviors not commonly encountered during the awake state (aggression, fearful situations) by rehearsing them while dreaming. Yet another hypothesis is that REM sleep and dreams are involved in the transfer of memories between the hippocampus and neocortex. Finally, it has been suggested that dreaming is simply an incidental consequence of REM sleep. None of these ideas are generally accepted.
Figure 28.6. Physiological changes in a male volunteer during the various sleep states in a typical 8-hour period of sleep (A). The duration of REM sleep increases from 10 minutes in the first cycle to up to 50 minutes in the final cycle; note that slow-wave (stage IV) sleep is attained only in the first two cycles. (B) The upper panels show the electro-oculogram (EOG) and the lower panels show changes in various muscular and autonomic functions. Movement of neck muscles was measured using an electromyogram (EMG). Other than the few slow eye movements approaching stage I sleep, all other eye movements evident in the EOG occur in REM sleep. The greatest EMG activity occurs during the onset of sleep and just prior to awakening. The heart rate (beats per minute) and respiration (breaths per minute) slow in non-REM sleep, but increase almost to the waking levels in REM sleep. Finally, penile erection occurs only during REM sleep. (After Schmidt et al., 1983.) 
Neural Circuits Governing Sleep From the descriptions of the physiological changes that occur during sleep, it is clear that periodic excitatory and inhibitory changes occur in many neural circuits. What follows is a brief overview of the still incompletely understood circuits and their interactions that govern sleeping and wakefulness.
One of the first clues about the circuits involved in the sleep-wake cycle was provided in 1949 by Horace Magoun and Giuseppe Moruzzi. They found that electrically stimulating a group of cholinergic neurons that lies near the junction of the pons and midbrain causes a state of wakefulness and arousal (the name "reticular activating system" was therefore given to this region of the brainstem) (Figure 28.7A). This observation implied that wakefulness requires a special mechanism, not just the presence of adequate sensory experience. About the same time, the Swiss physiologist Walter Hess found that stimulating the thalamus with low-frequency pulses in an awake animal produced a slow-wave sleep as measured by cortical EEG activity (Figure 28.7B). These important experiments showed that sleep entails a patterned interaction between the thalamus and cortex.
The saccade-like rapid eye movements that define REM sleep arise because, in the absence of external visual stimuli, endogenously generated signals from the pontine reticular formation are transmitted to the motor region of the superior colliculus. As described in Chapter 20, collicular neurons project to the paramedialpontine reticular formation (PPRF), which coordinates timing and direction of eye movements. REM sleep is also characterized by EEG waves that originate in the pontine reticular formation and propagate through the lateral geniculate nucleus of the thalamus to the occipital cortex. These pontine-geniculo-occipital (PGO) waves therefore provide a useful marker for the beginning of REM sleep; they also indicate yet another neural network by which brainstem nuclei can activate the cortex. As already noted, the function of these eye movements is not known.
Human MRI and PET studies have also been used to compare the activity in the awake state and in REM sleep. Activity in the amygdala, parahippocampus, pontine tegmentum, and anterior cingulate cortex are all increased in REM sleep, whereas activity in the dorsolateral prefrontal and posterior cingulate cortices is decreased (Figure 28.8). The increase in limbic system activity, coupled with a marked decrease in the influence of the frontal cortex during REM sleep, presumably explains some characteristics of dreams (e.g., their emotionality and the often inappropriate social content; see Chapter 26 for the normal role of the frontal cortex in determining behavior that is appropriate to circumstances in the waking state).
Most investigators now agree that a key component of the reticular activating system is a group of cholinergic nuclei near the pons-midbrain junction, which project to thalamocortical neurons. The relevant neurons in these nuclei are characterized by high discharge rates during waking and in REM sleep, and by quiescence during non-REM sleep. When stimulated, they cause "desynchronization" of the electroencephalogram (that is, a shift of EEG activity from high-amplitude, synchronized waves to lower-amplitude, higher-frequency, desynchronized ones) (see Figure 28.7A). These features imply that activity of cholinergic neurons in the reticular activating system is a primary cause of wakefulness and REM sleep, and that their relative inactivity is important for producing non-REM sleep.
Activity of these neurons is not, however, the only cellular basis of wakefulness; also involved are noradrenergic neurons of the locus coeruleus and serotonergic neurons of the raphe nuclei. The cholinergic and monoaminergic networks responsible for the awake state are periodically inhibited by neurons in the ventrolateral preoptic nucleus (VLPO) of the hypothalmus (see Figure 28.4). Thus, activation of VLPO neurons contributes to the onset of sleep, and lesions of VLPO neurons produce insomnia. These complex interactions and effects are summarized in Table 28.1. Both monoaminergic and cholinergic systems are active during the waking state and suppress REM sleep. Thus, decreased activity of the monoaminergic and cholinergic systems leads to the onset of non-REM sleep. In REM sleep, the monoaminergic and serotonin neurotransmitter levels markedly decrease, while the cholinergic levels increase to approximately the levels found in the awake state.
With so many systems and transmitters involved in the different phases of sleep, it is clear that a variety of drugs can influence the sleep cycle
Some animals can sleep one hemisphere at a time. These EEG tracings were taken simultaneously from left and right cerebral hemispheres of a dolphin. Slow-wave sleep is apparent in the left hemisphere (recording sites 1 3); the right hemisphere, however, shows low-voltage, high-frequency waking activity (sites 4 6). (After Mukhametoc, Supin, and Polyakova, 1977.) 
To feel rested and refreshed upon awaking, most adults require 7 8 hours of sleep, although this number varies among individuals (Figure 28.1A). As a result, a substantial fraction of our lives is spent in this mysteriousstate. For infants, the requirement is much higher (about 16 hours a day), and teenagers need on average about 9 hours of sleep. As people age, they tend to sleep more lightly and for shorter times, although often needing about the same amount of sleep as in early adulthood (Figure 28.1B). Getting too little sleep creates a "sleep debt" that must be repaid in the following days. In the meantime, judgment, reaction time, and other functions are impaired. Drivers who fall asleep at the wheel are estimated to cause some 56,000 traffic accidents annually and 1,500 highway deaths.
Sleep (or at least a physiological period of quiescence) is a highly conserved behavior that occurs in animals ranging from fruit flies to humans (Box A). This prevalence not withstanding, why we sleep is not well understood. Since animals are particularly vulnerable while sleeping, there must be advantages that outweigh this considerable disadvantage. Shakespeare characterized sleep as "nature's soft nurse," noting the restorative nature of sleep. From a perspective of energy conservation, one function of sleep is to replenish brain glycogen levels, which fall during the waking hours. In keeping with this idea, humans and many other animals sleep at night. Since it is generally colder at night, more energy would have to be expended to keep warm were we nocturnally active. Furthermore, body temperature has a 24-hour cycle, reaching a minimum at night and thus reducing heat loss. As might be expected, human metabolism measured by oxygen consumption decreases during sleep.
Whatever the reasons for sleeping, in mammals sleep is evidently necessary for survival. For instance, rats completely deprived of sleep die in a few weeks (Figure 28.2). Sleep-deprived rats lose weight despite increasing food intake, and progressively fail to regulate body temperature. They also develop infections, suggesting an impairment of the immune system.
In humans, lack of sleep leads to impaired memory and reduced cognitive abilities, and, if the deprivation persists, mood swings and even hallucinations. The longest documented period of voluntary sleeplessness is 264 hours (approximately 11 days), a record achieved without any pharmacological stimulation. The young man involved recovered after a few days, during which he slept only somewhat more than normal, and seemed none the worse for wear
The consequences of total sleep deprivation in rats. (A) In this apparatus, an experimental rat is kept awake because the onset of sleep (detected electroencephalographically) triggers movement of the cage floor. The control rat can thus sleep intermittently, whereas the experimantal animal cannot. (B) After two to three weeks of sleep deprivation, the experimental animals begin to lose weight, fail to control their body temperature, and eventually die. (After Bergmann et al., 1989.) 
Rhythm of waking (blue lines) and sleeping (red lines) of a volunteer in an isolation chamber with and without cues about the day-night cycle. Numbers represent the mean ± standard deviation of a complete waking/sleeping cycle during each period (blue triangles represent times when the rectal temperature was maximum). (After Aschoff, 1965, as reproduced in Schmidt et. al., 1983.) 
The Circadian Cycle of Sleep and Wakefulness Human sleep occurs with circadian (circa = about, and dia = day) periodicity, and biologists interested in circadian rhythms have explored a number of questions about this daily cycle. What happens, for example, when individuals are prevented from sensing the cues they normally have about night and day? This question has been answered by placing volunteers in an environment (caves or bunkers have sometimes been used) without external cues about time (Figure 28.3). During a five-day period of acclimation that included social interactions, meals at normal times, and temporal cues (radio, TV), the subjects arose and went to sleep at the usual times and maintained a 24-hour sleep-wake rhythm. After removing these cues, however, the subjects awakened later each day, and the cycle of sleep and wakefulness gradually lengthened to about 28 hours instead of the normal 24. When the volunteers were returned to a normal environment, the 24-hour cycle was rapidly restored. Thus, humans (and many other animals; see Box B) have an internal "clock" that continues to operate in the absence of any external information about the time of day; under these conditions, the clock is said to be "free running."
Presumably, circadian clocks evolved to maintain appropriate periods of sleep and wakefulness in spite of the variable amount of daylight and darkness in different seasons and at different places on the planet. To synchronize physiological processes with the day-night cycle (called photoentrainment), the biological clock must detect decreases in light levels as night approaches. The receptors that sense these light changes are, not surprisingly, in the outer nuclear layer of the retina; although removing the eye abolishes photoentrainment. The detectors are not, however, the rods or cones. Rather, these poorly understood cells lie within the ganglion and amacrine cell layers of the primate and murine retinas, and project to the suprachiasmatic nucleus (SCN) of the hypothalamus, the site of the circadian control of homeostatic functions generally (Figure 28.4A). These peculiar retinal photoreceptors contain a novel photopigment called melanopsin. Perhaps the most convincing evidence of the SCN's role as a sort of master biological clock is that its removal in experimental animals abolishes their circadian rhythm of sleep and waking. The SCN also governs other functions that are synchronized with the sleep-wake cycle, including body temperature (see Figure 28.3), hormone secretion, urine production, and changes in blood pressure. The cellular mechanisms of circadian control are summarized in Box B.
Activation of the superchiasmatic nucleus evokes responses in neurons whose axons descend to the preganglionic sympathetic neurons in the lateral horn of the spinal cord (Figure 28.4B). These cells, in turn, modulate neurons in the superior cervical ganglia whose postganglionic axons project to the pineal gland (pineal means shaped like a pinecone) in the midline near the dorsal thalamus. The pineal gland synthesizes the sleep promoting neurohormone melatonin (N-acetyl-5-methoxytryptamine) from tryptophan, and secretes it into the bloodstream to help modulate the brainstem circuits that ultimately govern the sleep-wake cycle (see p. 615 ff.). Predictably, melatonin synthesis increases as light decreases and reaches it maximal level between 2:00 and 4:00 a.m. In the elderly, the pineal gland calcifies and less melatonin is produced, perhaps explaining why older people sleep fewer hours and are more often afflicted with insomnia
Summary of subcortical/cortical interactions that generate wakefulness and sleep. A variety of brainstem nuclei using several different neurotransmitters determine mental status on a continuum that ranges from deep sleep to a high level of alertness. These nuclei, which include the cholinergic nuclei of the pons-midbrain junction, the locus coeruleus, and the raphe nuclei, all have widespread ascending and descending connections (arrows) to other regions, which explain their numerous effects. Curved arrows along the perimeter of the cortex indicate the innervation of lateral cortical regions not shown in this plane of section.