Consciousness, sleep and systemic diseases of the nervous ...

Literature:

Dudel et al., Neurowissenschaft (Springer)

Reichert, Neurobiologie (Thieme)

Kandel et al., Principles of Neural Science (McGraw Hill)

Kahle, Taschenatlas der Anatomie, Band 3: Nervensystem und

Sinnesorgane (Thieme)

Greenstein and Greenstein, Color Atlas of Neuroscience (Thieme)

Sacks, Der Mann, der seine Frau mit einem Hut verwechselte (rororo)

Contents:

1. Consciousness and the arousal system

2. Sleep

3. Systemic diseases of the nervous system

Consciousness, sleep and systemic diseases of the

nervous system

Consciousness: „State of awareness“

Two features:

• subjectivity: own direct experience appears more „real“ than the

experience of others

• unity: experience comes as a unified whole

Consciousness may follow the decision-making process: Brain activity

could be determined in the prefrontal cortex up to 10s before the decision-

making process became conscious(Soon et al. (2008) Unconscious determinants of free decisions in the human brain.

Nat. Neurosci. 11:543–545)

But: shorter veto option - movement can be prevented up to a time of

200 ms(Schultze-Kraft et al. (2016) The point of no return in vetoing self-initiated

movements. PNAS 113: 1080–1085)

Consciousness and the arousal system

Lesions with „fractional loss of consciousness“

Somatosensoric neglect:

deficit in the self-image of

part of the body:

Loss of discrete part of self

awareness „The man who

fell out of

bed“


Lesions with complete loss of consciousness: coma

Patients who cannot make a purposeful response to stimulation

Persistent vegetative state: wake-sleep cycle after 1-2 weeks of coma -

appear wakeful, smile etc., but actions have no cognitive content

→ brain death: all brain function cease including brain stem reflexes

(but patients may still have responses on spinal cord level)

Mainly two reasons:

• bilateral impairment of cerebral hemispheres, e.g., caused by a

diffuse metabolic block

(hypoxia – inadequate oxygenation; ischemia – insufficient blood flow)

• lesions in the brain stem: arousal system („ARAS“)

Barbiturate-induced coma: Protection of brain during major surgery by

reducing metabolic rate of brain tissue


Central arousal system→ Consciousness is only present when ascending

reticular activating system (ARAS) sufficiently "shakes up" the cortex

Integrating system to coordinate brain activity

Consists of relatively few neurons that are

concentrated in certain nuclei and form

long and diffuse projections

Afferents from the spinal cord and various

parts of the brain

A single nerve cell of the ARAS can

modulate up to 100,000 postsynaptic

neurons

Through collateral networking, the specific content of the afferents is lost

But: afferents are not all equally effective: acoustic stimuli have a stronger effect

than visual ones, and pain stimuli have a stronger effect than mechanical stimuli.


- Cholinergic system

- Catecholaminergic system

(dopamine, epinephrine,

norepinephrine)

- Serotonergic system


General role:

- Coordination of autonomous functions

- Arousal system

- Modulation of pain

- Control of emotional behavior and mood

Characterized by specific types of neurotransmitters

→ individual distinguishable and specialized systems

(distinct chemoarchitectonic nuclear groups)

Cholinergic system

Many cholinergic neurons project from nuclei in the basal telencephalon and from

nuclei of the brain stem.

The brain stem nuclei strongly innervate the thalamus.

Basal nuclei innervate large regions of the neocortex and the limbic system (e.g.,

hippocampus).

Role in controlling general brain activity (arousal system) and wake/sleep states


Noradrenergic system

Most noradrenergic neurons are localized in Locus coeruleus.

L.c. is a small nucleus in the pons that consists of about 12,000 neurons.

Axonal projections of the L.c. are highly branched and project in almost every brain

region.

Synaptic endings are not directed but release norepinephrine in large postsynaptic

areas.

Evidence for overactivity of the noradrenergic system in mania (manic depressive

disorders)

Important role in controlling general brain activity (arousal system)

→ considered as „Sympathicus of the CNS“


Serotonergic neurons

Most serotonergic neurons are localized in the nine Raphe nuclei of the brain stem.

Serotonergic neurons project in almost every brain region.

Serotonergic neurons modulate arousal, emotional state and sleep cycles.

Neurons of myelencephalic Raphe nuclei project in the spinal cord and modulate

ascending pain transmission.

In primates: Serotonin inhibits aggressive behavior and increases social behavior.

Involved in mood disorders


- dopaminergic neurons in Ventral tegmentum that innervate in a very diffuse

manner the frontal cortex and the limbic system → reward system

Dopaminergic system

- dopaminergic neurons in Substantia nigra that innervate striatum

→ extrapyramidal system


Sleep

Two characteristics:

- Endogenously induced by a central oscillator

- Modulated by external timing cues („Zeitgeber“)

Circadian rhythms

Central oscillator:

lower vertebrates: Pineal body (Glandula

pinealis; „Zirbeldrüse“, „Epiphyse“)

– serves as light-sensitive organ

higher vertebrates: suprachiasmatic

nucleus (part of the hypothalamus;

contains about 10,000 neurons;

mechanism is unclear)

Sleep

Circadian rhythms: central oscillators

Studies in Drosophila point to complex transcriptional mechanism that determine the

time constant

Per („periodic“) gene: mutants show changed rhythms (e.g., per-long, per-short)

Periodic changes of the amount of per-mRNA and per-Protein

→ molecular feed-back loop

Per gene Per mRNA Per Protein

Modified

Per Protein

Dimerized

Per Protein

degradation

e.g.,

phosphorylation

degradation

transcription translation

Additional genes are involved: e.g., tim-, clk-, cyc-gene in Drosophila

Endogenous system has to be modulated:

- in lower vertebrates by light sensitive organ in the brain itself (pineal body) that

acts as a photoneuroendocrine organ

- in higher vertebrates by retinohypothalamic tract to the SCN and modulatory

input by activating systems of the brain stem

SCNeyeretinohypothalamic

tract

Brain stem

Activating

systems

Sleep

Circadian rhythms: modulators

Sleep

Circadian rhythms: modulators What sees the light?

- Eye is required for adjusting the system

- Blind (rodless and coneless mice) are still able to adjust rhythm

(Freedman et al. „Regulation of mammalian circadian behavior by non-rod, non-cone,

ocular photoreceptors“, Science 284:502-504(1999))

- Photoreceptors are much less sensitive and have different spectral

characteristics (lmax of 480 nm – rods: 498, cone: 508 nm)

- Melanopsin

expressing

retinal ganglion

cells

- KO-mice for this

opsin loose

ability to adjust

the system

Sleep


Output: suprachiasmatic nucleus connects to the pineal gland (pineal body)

Pineal body serves as a dark-active hormonal gland that secrets

melatonin (internal signal for „darkness“)

SCNPineal

gland

melatonin

eyeretinohypothalamic

tract

Brain stem

Activating

systems

Pituitary gland

Melatonin (N-acetly-5-methoxytryptamine)

Synthesized from the amino acid tryptophan

Melatonin synthesis and secretion shows a circadian rhythm that parallels the light-

dark circle (about 70% of melatonin secretion occurs during an 8h-period in the

night)

Secretion occurs passively and is a function of the synthesis

In rats, melatonin secretion can be abolished by denervation of the pineal body or by

continuous illumination (however circadian rhythm remains)

Sleep


Sleep

Actively induced and highly organized brain state with different phases

Behaviorially defined by 4 criteria:

• reduced motor activity

• decreased response to stimulation

• stereotypic posture

• relatively easy reversibility (→ coma)

Two distinct phases that cyclically alternate in a structured pattern:

Non-REM sleep:

• low neuronal activity

• low metabolic rate and brain temperature

• spinal reflexes and muscle tone is intact

• > 95% of daily output of growth hormone and sexual maturation hormones

REM sleep:

• discharge pattern of most neurons similar to wakefulness

• some neurons (e.g., in the pons) fire more intense than while awake

• brain temperature and metabolic rate rise

• inhibition of skeletal muscle tone

→ „paradoxical sleep“

Sleep

Humans usually fall asleep by entering non-REM sleep

Sleeper than moves into REM sleep

Cycle of non-REM and REM-phases is typically repeated 4-6 times

In successive cycles, duration of non-REM phases decrease while REM phases

increase

Sleep phases

Non-REM sleep can be further divided into 4 phases according to EEG

(electroencephalogram) recordings:

• Stage 1: transition from wakefuleness to the onset of sleep

• Stage 2: bursts of sinusoidal waves called sleep spindles (12-14 Hz)

• Stage 3, 4: high amplitude slow delta waves (0.5-2 Hz) which dominates in stage 4

Non-REM sleep: EEG recordings during the first hour of sleep

beta activity

theta waves

delta waves

SleepSleep phases

Function of sleep?

Not completely clear: rats that have been deprived from sleep for 4-6 weeks die

Small animals generally sleep longer than larger ones (bats 20 hrs, elephants, 4-5 hrs)

Two main hypotheses:

1. The waking state causes a deficit in the neural

energy resources, which must be replenished

during sleep

2. Sleep has a key role in neuronal plasticity

Sleep

Posterior

hypothalamus

Midbrain reticular

formation

(Histaminergic neurons)

Anterior

hypothalamus

(GABA-ergic inhibitory

neurons)

Arou-

sal

state

Activation by heat

increases sleep

Destruction or blockage

increase sleep

Thalamus

Ventrolateral

Preoptic Nucleus

(VLPO):

sleep active

neurons

Regulation of sleep and wakefulness

Electrical stimulation of the ARAS promotes waking state

Sleep

Central VLPO

Extended VLPO

BrainstemHypothalamus Wakefulness Non REM REM

Cholinergic neurons

Monoaminergic neurons

+ +

+ + +

0 + +

0

Stabilization of the system through orexin/hypocretin neurons of the

lateral hypothalamus („flip-flop switch model“) → produces discrete

states with sharp transitions(Saper et al. (2005) Hypothalamic regulation of sleep and

circadian rhythms. Nature 437:1257-1263)

Regulation of sleep phases

Sleep

Muscle tonus is lost during REM sleep because motor neurons are actively

inhibited by circuitry in the pons and medulla

Starter: Activation of GABA-ergic

neurons from the pons

Inhibition of noradrenergic and

serotonergic neurons

Activation of cholinergic neurons

in the pons

Activation of glutamatergic

neurons in the pons

Activation of glycin-ergic neurons

in the medulla Inhibition of alpha-motoneurons

in the ventral horn

Regulation of muscle tonus during REM sleep

Sleep

Symptoms: Sudden loss of muscle tonus (cataplexy) while retaining full

consciousness; patients sometimes suddenly fall asleep

Analysis of dogs with narcolepsy: during cataplexy, neurons in the brain

stem fire which normally only fire during REM sleep

Dogs with narcolepsy walk around during REM sleep

Narcoleptic dogs show mutation in orexin/hypocretin receptor

Sleep disorders

Insomnia increase of aminergic activity

Narcolepsy decrease of aminergic activity

Parasomnia activation of the central motor pattern

generator; results in sleep walking, sleep talking, tooth grinding, etc.

Sleep

Systemic diseases of the nervous system

Psychotic diseases

prevalence: about 1%

genetic component

Sometimes associated with persecution mania

(„Verfolgungswahn“)

Schizophrenia


Schizophrenia

Dopamine system appears to be at least partially involved:

➢ Pharmacological treatment that decreases dopaminergic synaptic

transmission (e.g., antipsychotic drug haloperidol) improves state of

schizophrenic patients

➢ Drugs that increase dopamine concentration (L-DOPA and cocaine) lead to

Schizophrenia-like symptoms

➢ postmortem analysis revealed an increased number of dopaminergic

receptors in the limbic system

New generation of antipsychotic drugs revealed, that also high affinity binding to

serotonin 2A receptors occurs


(Unipolar) depression: unpleasant mood, inability to experience pleasure,

generalized loss of interest in the world

– potential life threatening: 15% of all patients with depression die from suicide

Bipolar depressive (manic depressive) disorders: alternating euphoria and

depression

Mood disorders (disorders of affect)

Evidence for participation of the serotonin-reuptake system in depression

Antidepressant drug „Prozac“ (in German: Fluctin) inhibits re-uptake of serotonin and

increases its availability

Genetic factors are important – appears to be polygenic (no specific gene yet

identified)

Consciousness, sleep and systemic diseases of the nervous ...

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