Rhythms

Purves et al. Chapter 28

EEG

Fig. Box 28C p. 632-633
EEG (electroencephalogram) set of pooled potential waves recorded from head.
This is as opposed to the "evoked potential," evoked by some stimulus.
To get regular waves, there must be some synchrony in neuron firing.
Thalamus to cortex loop may contribute.
Reticular formation involved in arousal (reticular activating system) (RAS) may also contribute.

Fig. 28.6, p. 632
The relaxed EEG with eyes closed is 8-13 cycles per second (Hz), called alpha (not shown).
During arousal there is alpha-blocking, and with eyes open, 14-60 Hz (beta) makes it almost as if there were no rhythm.

Sleep

Landmark paper
EAserinsky & NKleitman, Regularly occurring periods of eye motility, and concomitant phenomena, during sleep, Science 118, 273-274, 1953 (see also J NIH Res, 4, 63-66, 1992).

Fig. 28.6 (continued)
There are various stages of non REM (rapid eye movement) sleep, as defined by the EEG.
Deep sleep - slow wave sleep- delta (and theta) rhythm-stage 3, 2 Hz - stage 4 (slow wave sleep).
REM is associated with dreaming.
There is an atonia (lack of muscle control) during REM sleep.
PGO spikes at onset of REM (pontine reticular formation -> geniculate -> occipital cortex).
Birds do not have REM sleep but most mammals do.

Fig. 28.7, p. 635
During a night of sleep, go back and forth
REM - heart rate, respiration, erection all increase.
Called "paradoxical sleep" because it seems like awake state.
Deprivation of paradoxical sleep makes a person or animal irritable.
Because of loss of muscle tone, a cat restrained over a dish of water will wake up when it goes into REM sleep.

Box 28A, p. 627
Dolphins sleep with one hemisphere at a time.

Why do we sleep (perchance why do we dream)? - lots of half-baked answers and speculations.

Landmark papers
Michel Jouvet, The states of sleep, Scientific American, February 1967, 62-72
Michel Jouvet- Biogenic amines and the states of sleep Science 163, 1969, 32-41

Hobson - raphe and locus coeruleus turned off in sleep. Note, the section which follows could have been placed in any of a number of places throughout this course, but, because of the involvement of several neurotransmitter systems in the wake-sleep patterns, it is here. Also, an important period of of historical excitement in the mid 1960's is underplayed in which Swedish workers (Dahlstrom and Fuxe) developed the techinique of histochemical fluorescence in which 5-HT, NE and DA pathways could be visualized since the products of transmitter reacted with paraformaldehyde vapor can be seen.

Transmitters in sleep

Table 28.1, p. 639
Ascending reticular activating system:
(1) Raphe (which means ridge or seam) nuclei uses 5-HT (serotonin)
The caudal part innervates downward, while the rostral part innervates upward.
Since it fires during wakefulness, it must be involved in sleep.
The hallucinogenic drug LSD (lysergic acid diethylamide) is an agonist of presynaptic raphe 5-HT receptors inhibits firing (like in sleep), working like peyote (cactus) Aztec and psilocybin (mushroom) Maya.
(2) The locus coeruleus (blue spot), bilateral in the pons, spreads NE around brain.
12,000 neurons (each) with lots (e.g. 250,000) of synapses.
Like sympathetic ganglion in brain- activated by sensory stimulation
(3)The pontomesocephalotegmental complex regulates thalamic sensory relays using acetylcholine.

Note that there are other systems which distribute acetylcholine in the brain:
septal area (->hippocampus)
basal nucleus of Meynert (->neocortex) [these cells die early in Alzheimer's disease]

Note that dopamine is also distributed via the nigrostriatal pathway, disrupted in Parkinson's and involved in the mesocorticolimbic (reward) system and from the tegmentum to the forebrain and limbic system.
Cocaine blocks DA reuptake, amphetamine blocks NE & DA reuptake, potentiating reward
Depletion by alpha-methyl-para-tyrosine blocks stimulant action.

Fig. 28.8, p. 636
Circuits
5HT & NE -> -> Glycine to spinal motor neuron to inhibit motor movement.
GABA to dorsal column nuclei to inhibit sensation.

Biological clocks

There are many rhythms in nature and man, for instance the 3/min Parkinson tremors, the 21 day cycle in manic-depression, the 28 day human menstrual cycle, circannual (about a year), ultradian (fast, less than a day).

Fig. 28.4, p. 628
photophase, scotophase, free-run, endogenous
Entrainment, zeitgeber (time giver)
biological rhythms, periodicity, biological clocks
circadian (about a day)
Note human volunteer goes to >24 hr.

Ashoff - light on - nocturnal increase period - like waiting for night
light off - diurnal increase period - like waiting for day

What is the photoreceptor (it can be extraretinal in sparrows and fruitflies)? Where is the clock? (These are different questions.)
The pineal is important in small-headed animals like lizards.

Light may even hit the pineal in birds, and old experiments with enucleated sparrows used India ink under skin in head to decrease light and feather plucking to increase light

Landmark paper
M.Menaker, Nonvisual light reception, Scientific American, March, 1972, 22-29.

In seasonally reproductive birds, testes size in affected by more light in reproductive season. The pineal has photoreceptors, rhodopsin and molecules of the phototransduction cascade.

Fig. 28.5C, p. 631
In higher (bigger headed) animals, the zeitgeber (time giver) is usually a light-dark cycle, most likely with eye as sensory system.

Recent Paper S.Panda et al., Melanopsin is required for non-image-forming photic responses in blind mice, Science 301, 2003, 525-527
Pigment may be a different opsin (melanopsin [expressed in melanophores]) (and may be in ganglion cells).

The suprachiasmatic nucleus is important - lesions in SCN disrupt rhythm.
There is a mutant (named "tau") in the hamster affecting the SCN with altered rhythm.

(The melatonin story was here but is now consolidated in the transmitter lecture)

Drosophila

Box 28B, p. 629
Drosophila have locomotory rhythm and rhythm of pupal emergence.

Some classic work
Action spectrum for entrainment drops off dramatically above 500 nm.
Deprivation of carotenoids does not decrease sensitivity for entrainment.
Suggests thqat the photoreceptive pigment is not rhodopsin.

Seymour Benzer at Caltech used Drosophila in "genetic dissection" of various systems, and, with Ron Konopka, found "period" gene.
Mutants: per=period, l=long, s=short, 0=arythmic, perl 29 hr, pers 19 hr, per0 - arythmic or fast rhythm.
Clock or photoreceptor were localized to brain.
There is also a rhythm in courtship song, an ultradian rhythm, and it is affected by per.

Fig. Box 28B
The early excitment, imagining a clock in the head coded by a gene, was too simple.
PER is a nuclear protein whose mRNA and protein cycle.

Recent paper
A Busza et al., Roles of two Drosophila CRYPTOCHROME Structural domains in circadian photoreception, Science 304, 1503-1506, 2004.
Cryptochrome is blue sensitive protein (relates to points above about the pigment not using carotenoids and being short wavelength sensitive).
PERIOD and TIMELESS dimerize and act as negative transctiption factor.
Interfere with action of CLOCK and CYCLE.
CRY binds to TIM, and they are degraded by proteasome.

Exam questions from 2005 - 2012 relating to this outline

Pontine to (what?) to Occipital, these are "spikes that jerk you at the onset of sleeping.

geniculate

"During arousal, there is alpha blocking." Answer either (1) What is alpha? or (2) How would you observe alpha?

relaxed EEG with eyes closed 8-13 Hz, record EEG with electrodes on the scalp.

A sleep pathway involving serotonin and norepinephrine in the area between the pontine reticular formation and the midbrain goes to spinal motor neurons to mediate atonia with what neurotransmitter?

glycine

Why do they call REM sleep "paradoxical sleep?"

the EEG has the aroused pattern (alpha blocking)

Explain in terms of Ashoff''s rule how the human free-running circadian rhythm deviates from 24 hours.

it is longer than 24 hours when a diurnal animal is in the dark, it is like the person is waiting for dawn

For mice OR for Drosophila, state the name of a visual pigment molecule involved in entrainment that is not rhodopsin.

melanopsin, cryptochrome

The discoveries of long (29 hr) and short (19 hr) per (period) mutants paved the way to the characterization of how the PER gene and the protein it encodes function in the non-mutant animal. How does PER contribute to the biological clock?

the PER mRNA and protein increase and decrease on a daily cycle

Why is REM sleep called paradoxical sleep?

eeg resembles that of the aroused state

"It is like a sympathetic ganglion in the brain." Answer either (1) Why? Or (2) What structure?

puts out norepinephrine, locus coeruleus

What place in the brain has photoreceptors that are important in entraining circadian rhythms in vertebrates with small heads?

pineal

Say something about the location or function of melanopsin.

in ganglion cells, can mediate entrainment to light/dark cycle even if there are no rods

Explain why most people want to stay up late and get up late in terms of a "rule" proposed by a famous circadian biologist.
 
human (diurnal animal) circadian rhythm is longer than 24 hours according to Ashoffs rule
 
In a neurochemical circuit initiated by the serotonin and norepinephrine secreting parts of the brain, motor neurons are inhibited during sleep with what spinal cord inhibitory transmitter?
 
glycine
 
Say something (anything) about melanopsin, What animals have it? What cells have it? Why is it called "melanopsin?"
 
frogs have it in skin mediating melanin dispersal, in ganglion cells of mammals to mediate entrainment

 How would you know if a subject is in stage I, II, III, or IV sleep?
 
on the basis of EEG, slow waves for deep sleep
 
For REM sleep, what happens to the electroencephalogram (EEG)?
 
becomes like EEG of awake, aroused subject

Why would a cat restrained with a dish of water in front of it be specifically deprived of REM sleep?

loss of neck tone during REM would drop face in water and wake the cat up

Why is REM sleep called paradoxical sleep?

EEG appears like aroused state

A person put in the constant darkness after having been in a light-dark cycle of 12 hr on - 12 hr off will have an activity cycle that is not exactly 24 hr. Give details.

would go to >24 hrs, sleep in on Saturday morning

By what visual pigment do ganglion cells of the eye mediate entrainment of a circadian rhythm?

melanopsin

"Carotenoid deprivation decreases visual sensitivity in Drosophila (obviously) but not the sensitivity to stimuli to change the cycle for pupal emergence." What does that mean about the photoreceptive pigment?

it is not a rhodopsin based on retinoids (it is cryptochrome)

"Per mutations affect the ultradian rhythm of the courtship rhythm in the same way they affect the circadian rhythm." What does ultradian mean in this context?

way shorter than 24 hrs, courtship song is

During paradoxical sleep, what inhibitory transmitter goes down to spinal motor neurons?

glycine

Relate the conventional wisdom that most people would like to stay up later and stay asleep when the alarm goes off to the expression "circadian rhythm."

about a day is a little longer than 24 hrs for most people

In which cells does melanopsin reside to mediate photic entrainment in mammals?

ganglion cells

EEG spikes from pontine reticular formation to geniculate to occipital cortex (PGO spikes) are associated with the onset of what?

REM sleep

What is cryptochrome used for?

blue light receptor interacts with other proteins for circadian rhythm

What part of the brain spreads norepinephrine to a wide brain distribution?

locus coeruleus

When are there slow (delta) waves in the EEG?

deep (non REM)

What happens with the levels of the protein product of the period gene in Drosophila?

it cycles

In an experimental animal, what does the researcher change to go from entrainment to free-run?

the lighting cycle (to constant light or dark)

Why is REM (rapid eye movement) sleep called "paradoxical" sleep?

EEG as if awake (and respiration and circulation higher)

"A person's endogenous circadian rhythm has a period of >24 hours." What would you do to demonstrate that?

after entraining on a 24 hr photoperiod, go to constant lighting (free run) and watch it go to over 24 hr

Very recent literature demonstrated that mice lacking rod and cone photoreceptors are blind but they still could be entrained to a photoperiod. What is the photoreceptor (pigment and cell type)?

melanopsin ganglion cells

Sleep disorders and their treatments were put into the context of excitatory vs inhibitory transmitters. Serotonin was depicted as excitatory. What transmitter, derived from serotonin, was in the inhibitory category?

melatonin

"PGO spikes are seen at the onset of REM." Translate.

PGO (pontine reticular formation-geniculate-cortex) spikes are seen in the EEG at the beginning of rapid eye movement sleep

What is the transmitter of the locus coeruleus?

NE

Why do they call them "circadian" rhythms?

about (not exactly) a day for endogenous biological rhythms

In lizards, light stimulates the pineal. In humans, light affects the pineal. How?

from eye to hypothalamus by circuitous route to pineal

Cryptochrome is one interesting pigment and circadian receptor. Name another (other than rod and cone rhodopsins).

melanopsin

"PER is a nuclear protein whose mRNA and protein cycle." Translate.

the way circadian genes work in circadian timing is that the protein feeds back to regulate its mRNA (which of course makes the protein) hence levels go up and down


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