Biological rhythms, Sleep & Consciousness

Sleep cycle

alternating cycles of REM and SWS every 90-110 min cycles early in the night are characterized by more Stage 3 & 4 SWS later, there are no more episodes of stage 3 & 4 SWS period of stage 2 SWS precedes a REM episode and a refractory period occurs after each occurrence of REM sleep as sleep progresses, the REM episodes get longer in duration (first episode is the shortest of 5-10 min, last REM episode before waking may be as much as 40 min) total sleep time of young adults ranges from 7-8 hrs with 45-50% of sleep time is spent ins SWS and 20% is spend in REM sleep normal waking up throughout the night

Mammalian circadian clock

composed of a transciptional-translational feedback network that uses a (-) feedback loop involving Clock genes, PER, and CRY. Heterodimerization of PER and CRY inhibit the transcription via negative feedback loop Once the PER-CRY complex is degraded, a new cycle of transcription can be initiated secondary autoregulatory feedback loop is composed of Rev-erba, which is a direct target of the CLOCK-BMAL1 transcription activator complex; REV-ERBA feeds back to repress Bmal1 transcription and competes with a retinoic acid-related orphan receptor (ROR) to bind ROR response elements (RREs) in the Bmal1 promoter in addition to the transcriptional activators and repressors, post translational modification and degradation of circadian cock proteins are crucial steps for determining circadian periodicity. (ex: the phrophorylation of clock proteins leading to polyubiquitination, which eventually degrades the proteins to proteasome) the per/cry/tau complex breaks down, releasing the clock/cycle dimer from inhibition

Physiological activity during sleep

consciousness during sleep is an altered state sensory info that is being brought into our CRNS is modified (dreamlike state) Dreams and nightmares usually begin during NREM sleep and peak REM sleep (80% occurs during REM): if we wake a person during REM, report that they were dreaming and they tend to be in a narrative form- storylike progression of events but if we wake a person during SWS, they will NOT report having dreams but may report the occurrence of a thought, an image, or some emotion Dreams that occur in the 1st part of the sleep cycle are oriented towards reality Dreams that occur in the 2nd part of the sleep cycle are more unusual and less readily connected to the days events, more emotionally intense and bizarre in REM sleep, we lose all muscle activity

Why do we sleep

1. adaptive response: sleep conserves energy and may prevent an animal from wasting energy during a time of day when food isn't available and tends to vary with environmental factors; it may also help animals avoid predators (dolphins and birds can "sleep" unilaterally- one hemisphere at a time) 2. period of restoration: certain anabolic physiological processes occur, wear and tear caused by activity during the waking period is repaired during sleep and makes sleep a physiologically necessary function; Deep slow wave sleep appears to be the most important stage of sleep in relation to the brains need to recuperate (animals that are sleep deprived do eventually die, but it is unclear whether is caused by the lack of sleep or the stress of the procedure needed to keep them awake...there is a definite connection with immune system), exercise can increase the amount of SWS- increasing brain temp induces sleep, like falling asleep while at the beach (if you keep the body temp cool, brain temp will remain cool, and sleepiness will not occur; remove waste- metabolites 3. aid memory consolidation: little or no learning occurs during sleep, but evidence suggests that memory for new material is improved if learning is followed by sleep, sleep following learning is characterized by the presence of more REM than usual, but memory encoding and retrieval take place most effectively during waking

Slow wave sleep: Stage 2

10 min after onset of stage 1 sleep EEG is generally irregular, contains periods of theta activity, sleep spindles and K complexes: brain actively working to shut down all of the sensory stimuli to fall asleep

Slow wave sleep: Stage 3

15 min later and signaled by occurance of delta activity ( <3.5 Hz)... about 25 min into sleep cycle contains 20-50% delta activity

Stages of Sleep

2 main classes: slow wave sleep (4 stages) and REM (rapid eye movement) sleep AASM guidelines: relabeled stage 1 as N1, stage 2 as N2, SWS as N3 and REM as R each class of sleep is defined in terms of the specific types of EEG activity

Attention cycle

40-65 min works in a cyclic kind of way

Metabolic activity (Adenosine)

Adenosine monophosphate (AMP) is broken down into adenosine and adenosine accumulates adenosine inhibits the neurons of the reticular formation that produce arousal- produces fatigue (brain drain- sleepiness) caffeine blocks adenosine receptors and "wakes" you up during sleep, adenosine levels decline and the inhibition of the arousal system is removed

EEG Patterns: Waking State

During wakefulness, the EEG of a normal person shows 2 basic patterns: alpha activity and beta activity (difference is amplitude of activities)

Hypothetical dream circuitry (Activation- Synthesis Hypothesis)

Hobson- suggest there are fluctuations in activity of the pons that trigger '"thoughts" that are random and then cortex tries to fit these together

Molecular clock

Much of the molecular machinery for the biological clock has been worked out in the fruit fly (Drosophilia melanogaster) and in mice glutamatergic input from the retina to the SCN leads to the increase in the transcription (DNA -> mRNA) of the per gene- which synchronizes or entrains the molecular clock to the day-night cycle

Molecular mechanisms of sleep/wake regulated by PGD2, adenosine and histamine

PGD2 is produced by the action of L-PCDS in arachnoid trabecular cells of the leptomeninges, choroid plexus, and oligodendrocytes, and circulates in the CSF activates the DP1R on these trabecular cells to promotes sleep by stimulating them to release a paracrine signaling molecule, adenosine released adenosine activates A2AR- expressing neurons located in the ventral region of the basal forebrain, the activation of which subsequently excites the VLPO VLPO neurons then send inhibitory signals to downregulate histaminergic tuberomammilary nucleus (TMN), which contributes to arousal through histamine H1Rs wakefulness is promoted by activation of the TMN through either PGE2 or orexin

Biological Clock: suprachiasmatic nucleus in a rat

SCN can be influnced via 3 major input pathways: the retinohypothalamic tract (RHT), the geniculohypothalamic tract (GHT), and serotonergic (5HT) input from the dorsal raphe nucleus (DRN), noradrenergic that gives info to SCN about activity that the animal is doing (exersion, excersice) and median nucleus (MRN) RHT- visual GHT (GABA) and DRN- nonvisual

Ventral and dorsal subparaventricular zones (vSPZ and dSPZ)

SCN serves as a biological clock, but has few outputs to sleep-regulatory systems: most of its output goes into the region in light brown, which includes the ventral (vSPZ) and dorsal (dSPZ) subparaventricular zone, and the dorsomedial nucleus of the hypothalamus (DMH) neurons in the vSPZ relay info necessary for organizing daily cycles of wake=sleep, whereas dSPZ neurons are crucial for rhythms of body temperature outputs from the SPZ are integrated in the DMH with other inputs, and DMH neurons drive circadian cycles of sleep, activity, feeding and corticosteroid secretion cycles of body temp are maintained by dSPZ projections back to the medial preoptic area (MPO), whereas the DMN is the origin of projections to the ventral lateal preoptic area (VLPO) for sleep cycles, to the corticotropin-releasing hormone (CRH) neurons of the paraventricular nucleus (PVH) for corticosteroid cycles, and to the lateral hypothalamic (LHA) orexin and melanin-concentrating hormone neurons for wakefulness and feeding cycles hypothalamic --> pituitary --> hormones that act on other endocrine glands that produce behaviors

Clock and Bmal1

Transcription factors Clock and Bmal1 interact and bind to the DNA and transcribe some RNA and when they are transcribed they are translated into proteins and activate PER and CRY expression by binding to an E box in their promoter regions; in turn, Per and Cry heterodimerize (posttranslational processing of phosphorylizing these proteins), translocate to the nucleus, and inhibit Clock/Bmal-induced gene expression (and TIMELESS) and stop production Both CLOCK (or NPAS2) and BMAL1 are basic helix-loop-helix PAS-domain containing transcription factors that activate transcription of the Per and Cry genes After the Per/Cry complex is degraded, the cycle starts again Post translational (Translation = mRNA -> protein) modification (mainly by phosphorylation) is fundamental for regulating translocation, dimerization and/or degradation of clock proteins the cycle of gene transcription, protein complex formation, and protein complex degradation takes about 24 hours

Measuring Brain Activity: Electroencephalogram

behavior along the arousal continuum ae actually defined in terms of EEG activity (electroencephalogram) used to measure the activation state of the cortex in cycles/seconds (ultradian activity) extracellular recording obtained by using macroelectrodes and recording from the cortex under the scalp record of the average fluctuations of the electrical activity of large # of neurons in the brain to record you need two electrodes: the potential diff is measured btwn the active electrode, the place that contains neural activity (all standardized locations), and an indff electrode, placed at some distance from the site or between 2 active

Sleep deprivation

cause difficulty in performing tasks that require concentration, and perceptual distortions and sometimes (rare) mild hallucinations can occur does impair cerebral functioning disorders: insomnia (difficulty falling asleep or staying asleep), narcolepsy (frequency and unexpected periods of sleepiness during the day- 1 in 1000 individuals- appear to run in families), sleep apnea (respiration becomes unreliable during sleep) during recovery from sleep deprivation, tend to payback your REM sleep can die faster from sleep deprivation than food deprivation

Sleep Patterns

change dramatically over time infants: 12-14 hrs, children: 8-10 hrs, adults: 6-8 hrs, older adults: 4-5 hrs decrease in the amount of REM and SWS sleep across age: most of the SWS decrease is due to a decline in Stage 3 SWS and an absence of Stage 4 SWS, which begins at about age 30 and disappears by age 90 infants can go from awake to REM states until about 4 month of age when you see SWS prior to REM

Ultradian clock

clock modified by second to second types of rhythms

Slow wave sleep: Stage 4

deepest stage of sleep only loud noises will cause a person to awaken person feels groggy and confused when awoken (30 min naps are good, so you dont reach stage 4) contains >50% delta activity night terrors (fear and ANS activation) and bedwetting occurs during stage 3 & 4 SWS

Circannual behaviors

do not appear to be just counting 365 circadian rhythms occur once per year like many seasonal behaviors, such as autumn deer mating, winter chipmunk hibernation, and the instinct that drives the swallows back to Capistrano, CA on Mar 19

Memory consolidation in SWS vs REM

during SWS, active system consolidation involved the repeated reactivation of memories newly encoded in the temporary store, which drives concurrent reactivation of respective representations in the long term store together with similar associated representations. this process promotes the reorganization and integration of the new memories in the network of pre-existing long-term memories during REM , sleep synaptic consolidation occurs, which strengthen the memory representations that underwent system consolidation (reorganization) during prior SWS (thicker lines) in general, memory benefits optimally from the sequence of SWS and REM sleep but declarative memory, b/c of its integrative nature (binds features from diff memories to diff memory systems), benefits more from SWS associated system consolidation, whereas procedural memories, b/c of their specificity and discrete nature, might benefit more from REM sleep associated synaptic consolidation in localized brain circuits

Sleep neurochemical control

firing of the VLPO neurons inhibits the monoaminergic cell groups, thereby relieving their own inhibition allows it to inhibit the orexin neurons, further preventing monoaminergic activation that might interrupt sleep increase amount of adenosine --> sleep onset increase in prostaglandins (immune function- needs to recharge immune system) --> sleep onset decrease histamine (maintains arousal) --> sleep onset

Primary clocks/generators

for circadian rhythms are not astronomical (the sun and the earth), but are biological in the brain controlled by hypothalamus and change on of the clocks, changes that occur in many other behaviors

Biological clock: suprachiasmatic nucleus

for circadian rhythms, the biological clock lies within the hypothalamus and is known as the SCN are two small nuclei located above the optic chiasm and on either side of the 3rd ventricle stimulation of SCN results in a predictable shift in circadian rhythms removal of the SCN and then transplantation of a new SCN can restore circadian function within a 2-4 week period controls circadian and circannual rhythms/biological clock melatonin that is released by the pineal gland increases sleepiness and if given during the day can reset the circadian rhythms external cues from our gastrointestinal system work as zeitgebers for our internal clock. this is done via the connection of the arcuate nucleus to the SCN

Zeitgebers

german "time givers" external stimuli that help to adjust and SET the biological clocks and to keep them synchronized (hypothalamus) entrain animals to maintain an activity cycle of exactly 24 hours primary zeitgeber for mammals is the light-dark cycle earliest zeitgeber for mammals was probably he maternal hormone levels other zeitgebers that adjust and synchronize behaviors- periodic availability of food or water, social contact, environmental temps, and noise-quiet cycles in bears, when food is not available --> hibernate to lower metabolism and store energy light serves as a zeitgeber for our circadian rhythms it does this through increases in the Glu which comes from ipRGCs

Biological Sensory: retinohypothalamic pathway

in mammals, the sensors (detectors) for the biological clock are in the eye (not photoreceptors) intrinsically photosensitive Retinal Ganglion Cells (ipRGC) or melanopsin containing ganglion cells act as a sensor which appears to involve a protein in specialized retinal ganglion cells of the retina, known as melanopsin- like hormone released by pineal gland (melatonin) retinal ganglion cells, along w/ the photoreceptors, send info directly to the SCN via the retinohypothalamic pathway ipRGC: send the axons back in the retinohypothalamic track, from retina to hypothalamus respond to light energy, main sensors for biological clocks pigments in these cells are known as melanopsin melanopsin and RGC conserved amount many animals and is just like melatonin, which is produced by pineal gland; the skull over pineal gland is really thin in some animals (like frogs- pineal gland is horizontal) so that the light can enter the pineal gland- more focused on long term rhythmic behaviors, around it is the cerebral cortex, seasonal kind of cyclic behaviors but also can play a role in daily rhythmic behavior (sleep cycle) there are other cells in the retina that also contribute to biological rhythms in some vertebrates, the receptors for the biological clock are located in the pineal gland (the thin skull allows the "third eye" in the back of the head to receive light)- for seasonal rhythms, the pineal gland and melatonin are important

Histamine neurons

in the hypothalamus play a role in the maintenance of arousal, which is why antihistamine produce sleep

Oxerin (hypocretin) neurons

in the lateral hypothalamus interact w/ the reticular formation, basal forebrain, and locus coeruleus may be the "switch" in the sleep center (ICC of hypocretin neurons in the lateral hypothalamus) found that people that have narcolepsy have a decrease of hypocretin binding in lateral hypothalamus direct mutual inhibition btwn the VLPO and the monoaminergic cell groups forms a classic flip-flop switch, which produces shart transitions in state, but is relatively unstable- the addition of the orexin neurons stabilizes the switch

REM

intense physiological activity 90 min after the onset of sleep (and 45 min after the onset of stage 4 sleep) EEG pattern that resembles the awake individual- beta and theta activity (why it is known as paradoxical sleep) cornea actually produces a bulge in the eyelid that we can actually see the eye moving around eyes dart about rapidly, the <3 rate shows sudden acceleration and decelerations, breathing becomes irregular, and the brain becomes more active loss of muscle tone elsewhere- reflexes, such as the patellar tendon reflex is gone twitching of the extremities and in males, erections may occur during this time- sometimes used to ascertain the cause of impotence...lets us know if the "equipment" is working active inhibitors of both spinal and cranial motor neurons during REM sleep dreams and nightmares that occur in NREM sleep peaks during REM sleep

Beta Activity

irregular, mostly low amplitude waves of 15- 20 Hz occurs when a person is alert and attentive to events in the environment or is actively thinking represents asynchornized neural activity: lots of people talking about different things at the same time, lots of info being passed on

Function of REM sleep and REM deprivation

less certain than SWS may promote vigilance, learning, species typical reprogramming or brain development permit an animal to become more sensitive to its environment and avoid being surprised by predators humans are more sensitive to meaningful stimuli- like the sound of their name memories of the events of the previous day- esp dealing with emotionally related info- are consolidated and integrated with existing memories and may also erase useless info may also help to integrate learned and species typical behaviors according to experiences gained during the day fact that infants spend most of their sleep cycle in REM suggests this stage is important for brain development when subjects undergo REM deprivation, they experience REM rebound (spend a greater than normal percentage of the recovery night in REM sleep)

Wake- and sleep- promoting neurons

monoaminergic nuclei inbiti the VLPO during wakefulness also inhibit the REM on and excite the REM off neurons in the REM switch thus making it nearly impossible for normal normal individuals to transition directly from wakefulness to a REM state when there is loss of orexin signaling in narcolepsy, both switches become destabilized and their normal cascading relationships is disrupted sot htat it is possible for individuals with narcolepsy to enter fragmentary components of REM sleep (cataplexy , sleep paralysis, and hypnagogic hallucinations) directly from the waking state the clinical phenomena encountered in narcolepsy when each population of wake-, sleep- or REM-promoting neurons fires at the wrong time is identified above [Belsomra- drug that targets and inhibits orexin]

Wakefulness neurochemical control

monoaminergic nuclei inhibit the VLPO, thereby relieving the inhibition of monoaminergic cells, and that of the orexin neurons, and the cholinergic pedunculopontine (PPT) and the laterodorsal tegmental nuclei (LDT)

Control of biological rhythms

need 3 components: a sensor (to adjust and synchronize the zeitgeber), a clock, and an output pathway

Melatonin

pineal gland releases this in the presence of dim light or dark abt 2 hrs after the release- you get sleep onset melatonin receptors in the SCN and melatonin agonists (Rozerem) induce sleep

Slow wave sleep: Stage 1

presence of theta activity (4-7 Hz slower than alpha or beta) and vertex spike high amplitude but low frequency transition btwn sleep and wakefulness and is the easiest stage to be awakened in reduction of muscle tension and a slowing of the heart rate eyelid will slowly open and close, and eyes will roll upward only lasts for a few min

VLOP and MnPO neurons

primarily active during sleep contain the inhibitory NT, galanin and GABA VLPO is responsible for increasing GABAergic activity and turning off the ARAS why benzodiazepines and barbiturates work as sleep-inducing agents VERY addictive so they arent good to use on a regular basis

SCN Control of Rhythmic behaviors

principal biological clock appears to be the suprachiasmatic nucleus in the hypothalamus but may not be the only biological clock; in fact, this may only be the coordinator work showing that environmental stimuli (like depletion of food sources) could play a role in circadian rhythms- when food is restricted another area of the hypothalamus may take over control of rhythmic function- like activity levels- to increase the chances that the animal can successfully locate additional food sources the integrative steps in the subparaventricular and dorsal medial hypothalamus allow circadian rhythms to adapt to environmental stimuli, such as food availability) as well as visceral sensory inputs, cognitive influences from the prefrontal cortex and emotional inputs from the limbic system (inset) metabolic signals also regulate the "biological clock" of the SCN- endogenous environments there are a number of output pathways from the SCN feeding behavior: do a lot to modify other circadian behaviors (leptin and ghrelin) that communicate with DMH so when you are hungry, affects on all other behaviors that you have

Alpha Activity

regular, medium amplitude waves of 9-12 Hz (cycles/sec) brain produces alpha activity when a person is resting quietly, not particularly aroused or excited and not engaged in strenuous mental activity (such as problem solving) sometimes occur when a person's eyes are open, much more prevalent when the eyes are closed produced by a regular synchronized pattern of activity in a large # of neurons reflects synchrony- lots of people saying the same word at the same time; not a lot of info is being relayed

Prostaglandins

related to the immune system like adenosine, increase during the day until they provoke sleep work by activating neurons that inhibit the hypothalamic cells that increase arousal

Sleep spindles

short bursts of waves at 8-14 Hz, occurs btwn 2-5 times a min during stages 1-4 sleep some believe they represent the activity of a mechanism that decreases the brain's sensitivity to sensory input and keeps the person asleep (differences could define light vs heavy sleepers) sleep of older people contain fewer sleep spindles and older people typically have more awakenings during the night

Irving Zucker experiments (1970s)

showed that lesions of the SCN abolished the circadian rhythmicity of physical activity- feeding and drinking, and adrenal steroid secretion

Sleep and waking states

spend 1/3 of our lives asleep sleep is a fundamental behavior ubiquitous in the animal kingdom, necessary for the support of physical health and in humans for the maintenance of cognitive function sleep is actually a set of behaviors that is on one end of the brain arousal continuum sleep is a conscious state b/c when you are unconscious there is no perception going on but when you are asleep and there is a pain signal, you will wake up; this makes sleep conscious activity, which happens to be controlled by the Ascending Reticular Activation System (ARAS) do not sleep b/c our brains are "run down", there are active brain mechanisms that cause us to engage in the behavior of sleep wakefulness, or arousal, is a non-uniform process: there are many times that we are awake and yet we are not alert or attentive (eyes open- zoning out), frightening or surprising stimuli can cause us to become more activated and aware of our surroundings arousal then can be thought of as a continuum... with awake, alert and attentive behavior at one end and sleep in the middle (attentive behaviors are run in 90 min cycles for adults (changes with age- 5, 10, 20, min)

Why is there less stage 3 and stage 4 as our sleep cycle progresses?

stage 3 and 4 are needed b/c the longer REM & those stages is just preparing our brain stage 3 & 4 repairs wear and tear of the body and brain so it doesn't need to keep on doing it b/c it does it in the beginning

K complexes

sudden, sharp waveforms that are only found during stage 2 sleep spontaneously occur at the rate of approx 1/min but can often be triggered by noises may represent a mechanism that keeps the animal asleep no perception of sleep: if awakened during this time- the person may insist that they were not asleep

Ascending Reticular Activating System (ARAS)

system that modifies levels of consciousness largely originated from a series of well defined cell groups with identified NT 2 major branches: 1. ascending pathway to the thalamus that activates the thalamic relay neurons that are crucial for transmission of into the cerebral cortex, major source of upper brainstem input to the thalamic-relay nuclei, as well as to the reticular nucleus of the thalamus, is a pair of acetylcholine producing cell groups: the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) that has neurons that fire most rapidly during wakefulness and REM sleep 2. ascending arousal system bypasses the thalamus and instead activating neurons in the lateral hypothalamic are and VF, and throughout the cerebral cortex, pathway originates from monoaminergic neurons in the upper brainstem and caudal hypothalamus, including the noradrenergic locus coeruleus (LC), serotoninergic dorsal (DR) and median raphe nuclei, dopaminergic ventral periaqueductal grey matter and histaminergic tuberomammillary neurons, input to the cerebral cortex is augmented by lateral hypothalamic petidergic neurons (containing melanin-concentrating hormone (MCH) or oxerin/hypocretin), and BF neurons (containing acetylcholine or GABA)

Synchronization of Peripheral clocks

the biological clock in the SCN is either controlled by input from the retina- retinohypothalamic tract and from the pineal gland- exogenous environment, but there are also signals going into the SCN from other influences the SCN central pacemaker must establish phase coherence in the body by synchronizing billions of individual cell clocks every day: the SCN uses many routes to establish phase coherency in the periphery; thus, feeding rhythms, driven by rest-activity rhythms, are strong Zeitgebers for many tissues body temp rhythms, influenced directly by the SCN and by activity cycles controlled by the SCN, appear to play a role in the resetting of peripheral timekeeprs SCN also uses more direct timing cues (such as humoral and neuronal signals) to entrain the phases of peripheral clocks daily feeding-fasting cycles appear to be the dominant Zeitgebers for several peripheral organs, including liver, kidney, pancreas, and <3: the timing of food intake influences the expression profile of many circadian genes in these organs; normally the feeding-fasting cycles are in phase with the rest-activity cycles the entrainment pathways from feeding-fasting cycles may include hormones secreted upon feeding and fasting, postprandial temp elevations, and intracellular redox state when a behavior is really important it doesnt rely on one signal but on multiple signals so organs have to releasing signals and when they do so it is in response to needs the organs have

Circadian rhythms

the daily cycles of light and dark that result from the spin of the earth almost all land animals coordinate their behavior to this precise schedules vary among species, but most physiological and biochemical processes in the body rise and fall with daily rhythms (alertness, body temp, growth hormone levels, hair growth, urine production (not excretion), blood flow and metabolic rate all fluctuate daily) when the cycle of daylight and darkness are removed from the animal's environment, circadian rhythms continue on more or less the same schedules circadian clock mechanism involved transcription-translation feedback loops comprised of a set of core clock genes temperature, growth hormones, cortisol level (stress hormones), and ion levels fluctuate on daily cycle

Jet lag and shift work

two different disruptions of circadian rhythmicity imposed by society jet lag- produces phase advances (going east) and phase delays (going west) of the zeitgebers that control the phases of the circadian rhythms shift work- forces individuals to shift their normal sleep-waking cycles, while the zeitgebers stay the same (whenever possible phase delays- go to bed later- work better than phase advances- to go bed earlier) both of these cause disturbances in sleep, fatigue, general malaise, and deficits on tests of physical and cognitive function

Biological Rhythms

ubiquitous in the mammalian CN they range in frequencies from behaviors that are ultradian- which are seconds to minutes to hours cycles

Neural mechanisms of sleep

until 1940s: believed that sleep was a passive process- if you deprived the brain of sensory input, you would fall asleep but when the sensory afferents to the brain are blocked, the animal continues to have cycles of waking and sleep early 1950s: Moruzzi and Magoun's work led to the concept of ARAS which plays a role in the maintenance of cortical arousal and waking- we now know that sleep is an active process that requires the participation of a variety of brain regions 1970s-1980s: clarified nature of ARAS pathways 1980-1990s: examine the inputs to the monoaminergic cell groups that might be responsible for their remarkable, stereotyped and coordinated changes in firing patterns associated with sleep: the ventrolateral preoptic are (VLPO) and the median preoptic nucleus (MnPO) sends outputs to all of the major cell groups in the hypothalamus and brainstem that participate in arousal inhibits ARAS: VLPO (GABA & galanin) --> increase in GABA activity so it shuts down ARAS

Free run period

when all zeitgebers are removed, maintain these periods natural period of humans is between 24.5-25.5 hrs, mics ~23 hrs, hamster ~24 hrs