Neural Control of Sleep

Lectures 5 & 6

Sleep is regulated through many systems. There is a ______ drive & a ______ drive. There is possibly also an ______ component as well.

1. homeostatic

2. circadian

3. ultradian

Circadian Drive for Sleep

cycles once a day

Homeostatic Drive for Sleep

increases with wake; possibly some hormonal signal

Ultradian Drive for Sleep

happens more than once per day; cycle matches NREM to REM sleep

Old Hypothesis of Sleep Regulation

sleep results from decreased brain activity, induced by fatigue; wakefulness maintained by sensory stimulation; sleep occurs when fatigue decreases sensory input

2 main issues with the old hypothesis of sleep regulation?

1. when ascending sensory pathways are eliminated, sleep/wake cycles in brain activity persist

2. if you lesion the RF but leave sensory systems intact, you see a permanent sleep-like state

What are the 3 alternative hypotheses for sleep regulation?

1. wakefulness is maintained by tonic activity of RF driven by sensory input

2. anterior RF promotes wake, posterior RF inhibits the anterior RF & promotes sleep

3. sleep is actively induced & a highly organized brain state involving multiple integrated control systems

Describe the first alternative hypothesis for sleep regulation.

wakefulness maintained by tonic activity of RF driven by sensory input; decreased output of RF leads to sleep

Issue with the first alternative hypothesis for sleep regulation?

transecting brain through RF leads to decreased sleep

Describe the second alternative hypothesis for sleep regulation.

anterior RF promotes wake; posterior RF inhibits anterior RF to produce sleep

Major issue with the second alternative hypothesis for sleep regulation?

sleep is not on on/off state; there are at least 2 major states that alternate throughout the night (REM & NREM); not simply a period of reduced activity

Describe the third alternative hypothesis for sleep regulation.

sleep is actively induced and highly organized brain state; multiple integrated control systems throughout the brain regulate wake & the various sleep stages

The circadian system ______ and ______ sleep at appropriate times of the day.

1. organizes

2. consolidates

What happens if you lesion the circadian clock?

total sleep time is the same, but spread out over the 24 hour day

How do we know homeostatic component of sleep is still in play following circadian clock lesion?

after sleep deprivation, you still get rebound sleep

Does the circadian clock regulate sleep?

no

CSF from ______ ______ animals injected into the ventricles of ______-______ animals triggers sleep for 2-6 hrs.

1. sleep deprived

2. non-deprived

In rabbits with crossed blood supplies, if you stimulate the ______ in one, it induces ______ ______ ______ in both.

1. thalamus

2. slow wave sleep

2 studies evidencing hormonal/blood-born factor in sleep regulation?

1. CSF injections from SD animals to non-SD animals

2. stimulating the thalamus in rabbits with crossed blood supplies

3 issues with the hormonal/blood-born factor in sleep regulation?

1. conjoined twins

2. “morning after the night before” phenomenon

3. dolphins & ducks

Morning After the Night Before Phenomenon

rise in blood-glucose levels between 2am to 8am

Do hormones/blood-born factor regulate sleep?

may play a role, but cannot be the only factor

How do we study the possible neural regulation of sleep?

sleep defined by cortical EEG activity; perform transections to “zero-in” on sleep centers in the brain; what is observed must be mediated by neural centers above the cut, what is missing must be mediated below the cut

With transections on sleep centers in the brain where are observed and missing phenomena mediated?

1. observed must be mediated by neural centers above the cut

2. missing must be mediated by neural centers below the cut

Encephale Isole

isolated brain; transection preparation; cut between medulla & spinal cord to remove all ascending inputs

How did the encephale isole evidence role for brain structures in sleep?

EEG alternates between sleep-like & wake-like activity, and also REM; therefore, all sleep stages mediated by brain structures

Cerveau Isole

isolated forebrain; transection preparation; cut between hindbrain & forebrain

Describe the EEG of the cerveau isole?

EEG exhibits constant SWS; forebrain can produce SWS on own; need hindbrain for REM & wake

The encephale isole is a cute between the ______ and the ______ ______, whereas the cerveau isole is a cut between the ______ and the ______.

1. medulla

2. spinal cord

3. hindbrain

4. forebrain

What occurs following a lesion to the reticular activating system?

persistent SWS

The reticular activating system produces electrical stimulation that ______ the cortex. It is a ______ system, meaning it is mediated by the NT ______.

1. activates

2. cholinergic

3. acetycholine

Describe the role of the reticular activating system in the arousal system.

electrical stimulation wakes up cortex

Describe the role of the medulla in the arousal system.

inhibits the reticular formation to turn off cortex

Midpontine Transection

brainstem is severed in the middle of the pons

How do we study the role of the arousal system in sleep?

we can either stimulate the reticular activating system or use a midpontine transection to prevent medulla inhibition

Describe the EEG following a midpontine transection.

forebrain exhibits prolonged waking EEG due to loss of medulla inhibition to the reticular activating system

What 2 other wake-active systems are proposed to have roles in neural regulation of sleep? What NT is each associated with?

1. raphe: serotonin

2. locus coeruleus: norepinephrine

4 pieces of evidence for the raphe & the locus coeruleus having roles in the neural regulation of sleep?

1. both project widely in cortex

2. both are active during wake

3. both are silent during REM sleep

4. antidepressants suppress REM (promote 5-HT & NE)

Does the arousal system play a role in the neural regulation of sleep?

likely yes, though not the only component

2 hypothalamic wake areas proposed to have roles in the neural regulation of sleep?

1. tuberomammillary nucleus

2. dorsolateral hypothalamus

Tuberomammillary Nucleus

hypothalamic wake area with histaminergic cells that project to the brain stem and forebrain

3 pieces of evidence for the role of the tuberomammillary nucleus in the neural regulation of sleep?

1. stimulation leads to wakefulness

2. blocking with antihistamines leads to drowsiness

3. people who died from encephalitis & had hypersomnia had lesions in this region

Dorsolateral Hypothalamus

hypothalamic wake area with hypocretin (orexin) that projects to many of the wake centers and the cortex to activate them

4 proposed components in regulating sleep?

1. circadian regulation

2. hormonal/blood-born factor

3. neural regulation

4. chemicals

What is the forebrain sleep center?

certain parts of the basal forebrain

Describe the 3 experiments that suggest a role for the basal forebrain in sleep regulation.

1. lesion: constant wake-like EEG

2. stimulation: SWS EEG

3. recording: most active during SWS & inactive during REM

3 roles of GABAergic neurons of the basal forebrain in sleep regulation?

1. suppress activity of many brain areas to produce SWS

2. inhibit histamine cells

3. inhibit RPO in the brainstem

General anesthetics mimic the roles of ______ neurons.

GABAergic

Ventrolateral Preoptic Area (VLPO)

sleep promoting region that releases GABA; inhibits the activity of wake-promoting regions

The VLPO releases ______ to inhibit the activity of wake-promoting regions such as the ______, ______, ______, &______.

1. TMN

2. raphe

3. LC

4. RAS

Describe 4 pieces of evidence for the VLPO having a role in sleep regulation.

1. stimulation induces sleep

2. lesioning suppresses REM & NREM

3. expresses c-Fos during sleep

4. people who died from encephalitis & had insomnia had lesions in this region

Sleep-Wake Switch

Alternating system between wake- and sleep-promoting regions; VLPO active during sleep; LC, TMN, raphe are active during wake, stabilized by orexin

The sleep-wake switch is stabilized by ______.

orexin

REM Active Areas

areas of the Pons ventral to the LC

2 REM active areas?

1. nucleus reticularis pontis oralis (RPO)

2. nucleus reticularis pontis caudalis (RPC)

4 pieces of evidence for the role of the REM active areas in sleep regulation?

1. stimulation induces REM sleep

2. recording shows highest activity during REM sleep

3. lesions to these areas eliminates REM

4. lesions below this area eliminates REM atonia (animals act out their dreams)

REM sleep is regulated by the ______ & ______ ______.

1. midbrain

2. pontine nuclei

2 REM-on cells? When are they most active?

1. cholinergic activity is high during wake & REM

2. RPO is normally active by acetylcholine, which induces sleep

3 REM-off cells? Where are these located?

1. serotonin: raphe

2. norepinephrine: LC

3. histaminergic: TMN

Activity of the ______ & ______ ______ inhibits muscle tone in antigravity muscles. Lesions to these areas prevents ______ and causes animals to act out their dreams.

1. RPO

2. medial medulla

3. atonia

Cataplexy

loss of muscle tone during waking

Cataplexy is due to inappropriate activity of the ______-______ cells.

REM-on

What turns the VLPO on in the sleep-wake switch?

a host of chemical signals in the body

5 chemicals which influence sleep?

1. prostaglandin D2

2. adenosine

3. melatonin

4. growth hormone

5. interleukin

Prostaglandin D2 & sleep?

when infused into the ventricles, it increases sleep propensity which looks like normal sleep on EEG; dose-dependent increase in both REM & NREM

2 pieces of evidence for the role of prostaglandin D2 in sleep regulation?

1. eliminating the receptor where PGD2 acts (DP1) eliminates the sleep promoting effect in mice

2. blocking the DP1 receptor with a drug decreases sleep

Where is PGD2 produced?

produced by support structures, oligodendrocytes, meninges, blood vessels, choroid plexus, & microglia

PGD2 is produced in accordance with a ______ ______ and is therefore higher during sleep.

circadian rhythm

PGD2 levels increase during ______ ______ and are 100-1000x higher than normal in people with ______ ______ ______.

1. sleep deprivation

2. African Sleeping Sickness

3 effects on mice lacking one of the synthesis enzymes for PGD2?

1. can’t show increases in PGD2 during sleep deprivation

2. no NREM rebound following SD

3. no rebound in receptor KOs either

PGD2 receptors are found in the ______ ______ near the ______ ______.

1. arachnoid membrane

2. basal forebrain

PGD2 is synthesized by ______ ______ in the brain, released into the ______, & activates receptors on the ______ ______ near the ______ ______.

1. support structures

2. CSF

3. arachnoid membrane

4. basal forebrain

Theory for Adenosine in Sleep Regulation

adenosine is a by-product of increased metabolism; metabolism is higher during wake than NREM; adenosine levels in some brain areas are high during wake; glucose levels are high during sleep

Adenosine ______ promote wakefulness; adenosine ______ induce sleep.

1. antagonists

2. agonists

2 adenosine agonists that promote sleep? Location & specific role in sleep? (hint: 2 of one type)

1. A2a: rostral BF; increases NREM

2. A1: rostral BF; decreases REM

3. A1: systemic/ICV; increase NREM power

Adenosine levels in the ______ ______ and the ______ increase with SD. They decrease with ______ ______.

1. basal forebrain

2. cortex

3. recovery sleep

Infusion of adenosine or its agonists to the basal forebrain decreases ______ & increases ______ (possibly ______ too).

1. wake

2. REM

3. SWS

Adenosine antagonists ______-______ increase wake & decrease sleep.

dose-dependently

2 ways adenosine alters cellular activity?

1. changes gene expression

2. changes cell firing

2 ways adenosine can change gene expression?

1. activate sleep-active VLPO

2. turn off wake-active TMN

2 ways adenosine can change cell firing?

1. adenosine agonist inhibits wake-active neurons in the BF

2. antagonist increases firing of these neurons

Effect of blocking production of adenosine receptors with antisense tech?

leads to increased wake following SD

Effect of eliminating the gene for adenosine receptors?

little to no effect

Effects of A1-R activation?

leads to more A1-R production

Melatonin

made in the pineal gland; release regulated by light & the circadian clock

Growth Hormone

released from the anterior pituitary gland during NREM sleep; regulated by the growth hormone releasing hormone (GHRH)

3 pieces of evidence for growth hormone in sleep?

1. administration of GH increases REM & possibly NREM

2. blocking GH decreases REM & NREM

3. GHRH alone can increase REM & NREM

Interleukins

sleep-inducing factor S causes the production of these, which induce SWS

______ ______ & ______ ______ ______ have similar effects to interleukins, suggesting they may be linked with illness.

1. interferon a2

2. tumor necrosis factor-a