Understanding Rem Sleep: Homeostatic Regulation Explained

REM sleep is a distinct, homeostatically controlled brain state characterised by an activated electroencephalogram (EEG) in combination with paralysis of skeletal muscles and is associated with vivid dreaming. The pons was demonstrated to be necessary and sufficient for the generation of REM sleep. However, researchers have identified further neural populations in the hypothalamus, midbrain, and medulla that regulate REM sleep by either promoting or suppressing this brain state.

The core circuitry generating REM sleep is localised in the brainstem, but populations of neurons regulating REM sleep by either promoting or suppressing its occurrence have been found throughout the medulla, pons, midbrain, and hypothalamus.

REM sleep is under homeostatic control as demonstrated in various mammalian species including mice, rats, cats, and humans. The buildup of a need for REM sleep in its absence can be demonstrated by selectively depriving animals of REM sleep, typically by awakening them at the first sign of REM sleep. During the subsequent recovery sleep, the amount of REM sleep is increased above baseline levels to account for the amount lost during deprivation.

Homeostatic control of REM sleep timing implies that a propensity or pressure for REM sleep builds up in its absence and triggers a REM period if sufficient pressure has accumulated, followed by a discharge of pressure during REM sleep.

Recent quantitative models integrate findings about the activity and connectivity of key neurons and knowledge about homeostatic mechanisms to explain the dynamics underlying the recurrence of REM sleep.

Neural Control of REM Sleep

The neural control of REM sleep has been the focus of research for several decades, with studies identifying key areas and neural populations involved in its regulation. The initiation and maintenance of REM sleep are governed by specific neural circuits, and the understanding of these circuits is crucial to comprehending the overall control of REM sleep.

The pons, a part of the brainstem, was discovered to be necessary for the generation of REM sleep shortly after its discovery in humans in 1953. However, more recent research has revealed the involvement of additional neural populations in the hypothalamus, midbrain, and medulla. These neural populations play a role in regulating REM sleep by either promoting or suppressing this brain state.

The availability of novel technologies for the dissection of neural circuits has greatly facilitated the discovery of these populations. Key neural populations thought to control REM sleep have been identified, and recent studies have provided valuable insights into the homeostatic processes regulating REM sleep expression.

One notable finding is the suggested role of brain-derived neurotrophic factor (BDNF) in the accumulation of REM sleep pressure. Deprivation of REM sleep has been found to increase BDNF expression, and the levels of BDNF are positively correlated with the strength of the homeostatic drive. Furthermore, studies have indicated that BDNF-TrkB signalling mediates the buildup of REM sleep pressure.

Additionally, the supramammillary nucleus and the medial septum have been implicated in the control of theta oscillations during REM sleep. However, further research is needed to fully understand how neurons in these areas are connected to the REM control circuits and how they may be influenced by homeostatic processes.

Homeostatic Regulation of REM Sleep

The homeostatic timing of REM sleep is as follows: a homeostatic propensity or pressure for REM sleep builds up in its absence, triggers a REM period if sufficient pressure has accumulated and then dissipates during REM sleep. Consequently, it should take more time after a long REM period until the next REM sleep episode occurs: as more REM sleep pressure is dissipated during a longer episode, more time is required to accumulate sufficient pressure to re-enter REM sleep.

The molecular basis of the homeostatic regulation of REM sleep is still largely unknown. Recent studies suggest a prominent role of brain-derived neurotrophic factor (BDNF) in mediating the accumulation of REM sleep pressure.

REM sleep is physiologically different from the other phases of sleep, which are collectively referred to as non-REM sleep (NREM sleep, NREMS, synchronised sleep). The absence of visual and auditory stimulation (sensory deprivation) during REM sleep can cause hallucinations.

REM and non-REM sleep alternate within one sleep cycle, which lasts about 90 minutes in adult humans. As sleep cycles continue, they shift towards a higher proportion of REM sleep. The transition to REM sleep brings marked physical changes, beginning with electrical bursts called "ponto-geniculo-occipital waves" (PGO waves) originating in the brain stem.

REM sleep occurs 4 times in a 7-hour sleep. Organisms in REM sleep suspend central homeostasis, allowing large fluctuations in respiration, thermoregulation and circulation which do not occur in any other modes of sleeping or waking. The body abruptly loses muscle tone, a state known as REM atonia.

In summary, REM sleep is homeostatically regulated by the buildup of a need for REM sleep in its absence, which is then compensated for by an increased amount of REM sleep during the following recovery sleep.

Quantitative Models of REM Sleep Regulation

The physiological or molecular basis of the homeostatic regulation of REM sleep is still largely unknown. However, recent studies have suggested that brain-derived neurotrophic factor (BDNF) plays a significant role in mediating the accumulation of REM sleep pressure. This was demonstrated by an experiment where REM sleep deprivation for 3 hours increased BDNF expression in the PPT and subcoeruleus nucleus (Datta et al., 2015). The levels of BDNF were positively correlated with the strength of the homeostatic drive, as seen by the attempts to enter REM sleep during the deprivation phase (Datta et al., 2015; Barnes et al., 2017).

One of the first quantitative models describing the dynamics of the sleep cycle was the Reciprocal Interaction Model, proposed by McCarley and Hobson in 1975. This model reproduced the activity of two populations of neurons with opposing firing patterns relative to REM sleep, recorded in the pontine gigantocellular tegmental field. The model was implemented as described in Diniz Behn et al. (2013) and depicted the activity of the REM-on and REM-off populations along with the resulting hypnogram.

Another model is the Mutual Inhibition Model, which illustrates how inhibitory populations of REM-on and REM-off neurons mutually suppress each other. The nodes represent the average firing rates of the REM-on and REM-off populations, and sigmoid input-output (i/o) functions describe the steady-state firing rate dependent on the inhibitory synaptic input.

Recent quantitative models integrate findings about the activity and connectivity of key neurons and knowledge about homeostatic mechanisms to explain the dynamics underlying the recurrence of REM sleep. These models, combined with experimental approaches, will help refine existing models and advance our understanding of the neural and homeostatic processes governing REM sleep regulation.

REM Sleep and Dreaming

REM sleep is a distinct brain state characterised by an activated electroencephalogram (EEG) in combination with paralysis of skeletal muscles and is associated with vivid dreaming. The brain state during REM sleep is similar to that during alert waking.

The core circuitry generating REM sleep is localised in the brainstem, but populations of neurons regulating REM sleep by either promoting or suppressing this brain state have been found throughout the medulla, pons, midbrain, and hypothalamus.

REM sleep is homeostatically controlled, meaning that a need for REM sleep builds up in its absence, and is triggered once sufficient pressure has accumulated. During the subsequent recovery sleep, the amount of REM sleep is increased to compensate for the amount lost during deprivation.

The homeostatic control of REM sleep is independent of the circadian clock.

The activity of neurons in the preoptic area of the hypothalamus increases during heightened REM sleep pressure, and inhibiting these neurons during REM sleep restriction prevents the subsequent rebound in REM sleep.

Neural Control of REM Sleep

The dorsolateral pons is a crucial region for REM sleep generation. Glutamatergic neurons within the subcoeruleus area trigger muscle paralysis during REM sleep.

Cholinergic neurons in the dorsolateral pons have also been studied for their role in REM sleep regulation.

Disinhibition of the subcoeruleus by GABAA receptor antagonists induces a long-lasting REM sleep-like state with EEG desynchronisation and muscle atonia, indicating that GABAergic neurons presynaptic to the subcoeruleus may powerfully suppress REM sleep.

Inhibition of the vlPAG/DpMe through muscimol injection and lesioning of neurons resulted in a strong increase in REM sleep in mice, rats, cats, and guinea pigs.

Homeostatic Regulation of REM Sleep

REM sleep is under homeostatic control as demonstrated in various mammalian species including mice, rats, cats, and humans.

The buildup of a need for REM sleep in its absence can be demonstrated by selectively depriving animals of REM sleep, typically by awakening them at the first sign of REM sleep.

The homeostatic control of REM sleep is independent of the circadian clock: rats in which the suprachiasmatic nucleus (SCN) was lesioned still show a REM sleep rebound following total sleep or REM sleep deprivation.

Behavioural Studies of REM Sleep Homeostasis

In rats, 2 hours or less of REM sleep deprivation are sufficient to trigger a rebound.

Homeostatic Timing of REM Sleep

A homeostatic propensity or pressure for REM sleep builds up in its absence, triggers a REM period if sufficient pressure has accumulated, and then dissipates during REM sleep.

Molecular Basis of REM Sleep Pressure

The physiological or molecular basis of the homeostatic regulation of REM sleep is largely unknown. Recent studies suggest a prominent role of brain-derived neurotrophic factor (BDNF) in mediating the accumulation of REM sleep pressure.

Quantitative Models of REM Sleep Regulation

One of the first quantitative models describing the dynamics underlying the sleep cycle was proposed by McCarley and Hobson in 1975. Their model reproduced the activity of two populations of neurons with an antagonistic firing pattern relative to REM sleep recorded in the pontine gigantocellular tegmental field.

Based on subsequent studies pointing to more prominent roles of GABAergic REM-on and REM-off neurons in REM sleep control, recent models stress the importance of reciprocal inhibitory interactions between REM sleep-promoting (REM-on) and REM sleep-suppressing (REM-off) neurons in switching the brain state between NREM and REM sleep.

References

• Park, S-H, and Weber, F. (2020) Neural and Homeostatic Regulation of REM Sleep. Frontiers in Psychology, 11:1662.
• Beersma, D. G. M., Dijk, D. J., Blok, C. G. H., and Everhardus, I. (1990) REM Sleep Deprivation During 5 Hours Leads to an Immediate REM Sleep Rebound and to Suppression of Non-REM Sleep Intensity. Electroencephalography and Clinical Neurophysiology, 76(1), 114–122.
• Siegel, J. M., and Gordon, N. (1965) Parodoxical Sleep: Deprivation in the Cat. Science, 148(3672), 978–980.
• Weber, F., Chung, S., Beier, K. T., Xu, M., Luo, L., and Dan, Y. (2015) Control of REM Sleep by Ventral Medulla GABAergic Neurons. Nature, 526(7574), 435–438.
• Osorio-Forero, A., Chung, S., Chung, J. H., Chung, J. M., Chung, J. Y., Chung, J. W., Chung, J. S., Chung, J. H., Chung, J. C., Chung, J. B., Chung, J. A., Chung, J. E., Chung, J. D., Chung, J. G., Chung, J. F., Chung, J. K., and Chung, J. P. (2023) Homeostatic Regulation of REM Sleep by the Preoptic Area of the Hypothalamus. eLife, 12:e92095.

Lack of REM Sleep Symptoms

Lack of REM sleep can have a number of negative effects on your health and cognitive abilities. Here are some symptoms of REM sleep deprivation:

• Fatigue and drowsiness: A lack of REM sleep can lead to feelings of fatigue and sleepiness during the day, which can impact your ability to function and make decisions.
• Changes in mood: REM sleep deprivation can cause irritability, trouble coping with emotions, and mood disorders such as anxiety and depression.
• Memory and cognition issues: Not getting enough REM sleep can lead to problems with memory and cognition, including difficulty concentrating and impaired problem-solving abilities.
• Increased risk of health conditions: Over time, a lack of REM sleep can contribute to various health issues, including cardiovascular disease, type 2 diabetes, obesity, metabolic disorders, and neurodegenerative diseases like Alzheimer's.
• Disrupted sleep: REM sleep deprivation can lead to fragmented sleep and brief microsleep episodes during the day.

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