Timpul si ritmurile biologice

Timpul intern / ritmurile biologice determinate de un pacemaker

circadian endogen, supus unei sincronizari zilnice cu timpul extern .
Cronobiologia este stiinta care studiaza ritmurile biologice.

Almost all organisms studied, from cyanobacteria to Homo

Sapiens, have intrinsic time-keeping systems that adjust
physiology and behavior to anticipate the daily cycles of light
and darkness.
Physiological processes that vary over the 24-hour day include
activity, alertness, hormone secretion, organ physiology, and
gene expression.
These variations are not just passive responses to a rhythmic
environment, but instead reflect an underlying biological
mechanism that can measure time on a 24-hour time scale.
This mechanism orchestrates physiology, to achieve
predictive, rather than reactive, homeostasis.

Circadian Timekeeping, in Fundamental Neuroscience, L. Squire

Ceasul biologic
Nucleul suprachiasmatic (NSC) din hipotalamus ceasul
biologic principal al organismului, care prin ritmicitatea
impulsurilor nervoase eliberate spontan, isi imprima
amprenta oscilatiilor sale asupra celorlalte sisteme
celulare cu activitate autonoma din organism,
sincronizandu-le, si astfel ajunge sa moduleze de la
secretia neuroendocrina la functii fiziologice complexe,
inclusiv functia cognitiva.
Oscilatorii celulari locali regleaza expresia genetica intr-o
maniera specifica fiecarui tip celular, contribuind la
fiziologia fiecarui organ si sistem.
10% din genom este transcris in mod ritmic, fiind
responsabil de exprimarea actorilor cheie in
metabolismul celular specific fiecarui tesut (Miller, 2007).

Ritmul circadian (RC)

Persista cu un ciclu de 24 ore in conditii de mediu constante (circa
diem)
Generat de un mecanism biologic intern de mentinere a timpului,
care prin evenimente moleculare ritmice controlate genetic
coordoneaza functiile celulare, sistemice si comportamentale (de
ex. ciclul somn-veghe).

Este in mod normal sincronizat cu ziua de 24 ore de catre stimulii

de mediu:
- Lumina photoentrainment
- Temperatura
- Concentratia hormonilor
- Disponibilitatea nutrientilor

Ritmuri biologice

Ritmul circadian (RC)

Exista o ierarhie a oscilatorilor circadieni autonomi care
oscileaza cu un ciclu de 24 ore.
NSC master clock coordoneaza oscilatiile din alte
tesuturi si regleaza comportamentul (celular si de sistem)
Mecanismul molecular care raspunde de oscilatiile
circadiene autonome celulare se bazeaza pe o bucla de
feedback autonoma care actioneaza la nivelul
transcriptiei-translatiei genice.

Nucleul suprachiasmatic (NSC) master pacemaker

Situat in hipotalamusul anterior, deasupra chiasmei optice
Constituit din 2 nuclei (stg + dr) a cate 10.000 neuroni fiecare, in
special GABAergici
Primeste aferente de la celulele ganglionare din retina care
contin melanopsina, printr-o cale monosinaptica tract retinohipotalamic (RHT)
Lezarea ambilor NSC produc aritmicitate
Trimite si primeste conexiuni de la glanda pineala, si raspunde
la secretia de melatonina a acesteia.

Glutamate-induced calcium influx into SCN neurons represents the first step in the
signal transduction pathway leading to entrainment.

Transcription and translation feedback loops constitute the

core clock mechanism
Transcription

mRNA

Translation

Clock gene 1
Inhibition (Per/Cry mediated repression)
Protein
(positive element)

Clock, Bmal1
(Transcription factors)

Delay (impose a cycle length of ~24 h)

Per/Cry accumulate

+
Transcription

Translation
mRNA

Clock gene 2

Protein
(negative element)

mRNA or
Protein level

Period (Per)
Cryptochrome (Cry)

Time

A general scheme of signal transduction mechanisms involved in circadian entrainment.

Diego A. Golombek, and Ruth E. Rosenstein Physiol Rev 2010;90:1063-1102

Glutamate activates NMDA-induced calcium influx which, together with other second messengers, triggers the activation of
diverse signal transduction cascades, including calmodulin kinase II (CaMKII) and neuronal nitric oxide synthase (nNOS)
activity, cAMP- and cGMP-dependent protein kinases, and mitogen-activated protein kinase (MAPK). Although the crosstalk between these diverse cascades is not currently well-known, it is plausible that a common mechanism involved in the
pathway is phosphorylation of cAMP response element binding protein (CREB). In turn, pCREB activates per1 and per2
transcription by binding to a CRE element in their promoter regions (these genes are also activated by Clock/Bmal binding
to E boxes). Solid lines represent mechanisms that have been described experimentally, and dashed lines indicate
possible additional links of the pathway.
http://physrev.physiology.org/content/90/3/1063

Nucleul suprachiasmatic (NSC / SCN) - conexiuni

Proiectiile din NSC sunt orientate in mare parte catre Hipotalamus creierul vegetativ, cu rol in integrarea functiei nervoase si endocrine.
Activitatea NSC depinde de conexiunile sale cu hipotalamusul, prin care
integreaza o varietate de informatii sensitive importante pentru organizarea
temporala a diferitelor functii reglate de hipotalamus.

Here in this well concealed spot,

almost to be covered with a thumb nail,
lies the very mainspring of primitive
existence vegetative, emotional,
reproductive - on which, with more or
less success, man has come to
superimpose a cortex of inhibitions.
(Cushing, 1929).

Hipotalamusul
-

parte a diencefalului (1% din vol. creierului !)

constituie un centru integrativ esential pentru supravietuire si reproducere

reglarea temperaturii, frecventa cardiaca, presiunea arteriala, osmolaritatea

sangelui, alimentatie, emotie/afect si comportament sexual.

Melatonin represents the key linkage-molecule between the SCN

and the peripheral biological clocks

sleep inducer
regulator of the circadian rhythm

NSC comunica informatie temporala oscilatorilor periferici,

sincronizandu-i si inducandu-le un ritm principal

retino-hypothalamic projections

Amplificarea sincronizarii oscilatiilor

Nucleul Suprachiasmatic (SCN)

inima sistemului prin care circula si se
manifesta ritmul circadian
24-hour rhythms are observed in:
- core body temperature,
- hormone concentrations (melatonin,
cortisol, TSH, oxytocin and others),
- subjective alertness,
- objective performance
- other physiologic functions

SCN is essential for driving the 24-hour blood-pressure rhythm in mammals

Kohsaka A, Endocrine Journal 2012, 59 (6), 447-456

The circadian clock is tightly coupled to the regulation of temporal energy homeostasis through highly
complex mechanisms: controls of gene transcription, protein translation, protein phosphorylation, protein
degradation, and epigenetic modifications that occur between circadian and metabolic components.
The circadian and metabolic crosstalk in cardiovascular tissues indicates that the diurnal rhythm of
cardiovascular function may be influenced by both circadian and metabolic signals that primarily arise
from environmental conditions.

Maternal rhythm of melatonin is one of the time signals to the fetus

(maternal melatonin is a Zeitgeber for the fetal SCN)
Circadian rhythms in the fetus. Mol Cell Endocrinol. 2012 Feb 5;349(1):68-75.
Sern-Ferr M, Mendez N, Abarzua-Catalan L, Vilches N, Valenzuela FJ, Reynolds HE, Llanos AJ, Rojas A,
Valenzuela GJ, Torres-Farfan C.

Throughout gestation, the close relationship between mothers and their

progeny ensures adequate development and a successful transition to
postnatal life. By living inside the maternal compartment, the fetus is inevitably
exposed to rhythms of the maternal internal milieu such as temperature;
rhythms originated by maternal food intake and maternal melatonin, one of
the few maternal hormones that cross the placenta unaltered.
We propose that the fetal suprachiasmatic nucleus (SCN) of the hypothalamus
and fetal organs are peripheral maternal circadian oscillators, entrained by
different maternal signals. Conceptually, the arrangement produces internal
temporal order during fetal life, inside the maternal compartment. Following
birth, it will allow for postnatal integration of the scattered fetal circadian clocks
into an adult-like circadian system commanded by the SCN. PMID: 21840372

Intrinsic rhythmicity of SCN cells:

Dispersed SCN cells in vitro exhibit circadian
rhythms in firing rate

Time (h)

Welsch et al, 1995

Can the SCN restore rhythms to an arrythmic animal?

Remove SCN
(Suprachiasmatic nucleus)

Arrhythmic patterns of
locomotion, feeding,
hormone secretion

Implant donor
SCN tissue
Return rhythms
of donor hamster

SCN lesions ablate circadian rhythms

Pineal NAT

SCNX

Moore and Klein, 1974

Circadian Phase Markers, for clinical use

Melatonin concentration

Drop in temp associated with stability

in sleep
Altered by activity, food intake, and
sleep
Three dips in temp:
3:00-5:00
13:00-16:00
20:00-24:00

Melatonin secretion very sensitive to

light exposure, needs to be obtained
under dim light conditions
Increase in levels around 20:00
Levels peak at approximately 3:00 and
begin to decrease
Lowest levels just before awakening

Disruptions in the circadian rhythm physiology

consequently can cause a number of circadian
rhythm sleep disorders.

Hypocretin/orexin regulates
arousal, wakefulness, and
appetite

The SCN projects to the ventrolateral preoptic area (VLPO), an area mediating sleep.
VLPO inhibits the arousal activity of the tuberomammillary nucleus during sleep.
The SCN provides an arousal-promoting input to the posterior hypothalamic area, particularly
to hypocretin/orexin neurons, which project upon the neocortex and subcortical arousal areas.

Circadian rhythm - Sleep-wake cycle

Along with the internal circadian control of the sleep-wake rhythm,
the amount of time spent awake and asleep/24 h is under a
homeostatic control sleep propensity increases with elapsed time
awake/dissipates with elapsed time asleep
Independent of internal time (circadian phase), in an adult:
- the max capacity to stay awake is around 16 h
- the max capacity to maintain a sleep efficiency of 90% is around 8 h

http://www.scienzagiovane.unibo.it/English/sleep/3-sleep-animals.html

Sleep - a highly conserved behaviour which offers advantages that

outweigh the disadvantage of becoming vulnerable during sleep
Why we sleep?
Role of sleep in preventing the waking brain of synaptic overload or cellular
stress, in regulating cortical synaptic plasticity.
Memory consolidation by increased strength of synaptic connections induced
by experiences during waking hours.
Cognitive abilities, behavioral performance, mood, immune defence, weight
control are altered in sleep deprivation
(documented voluntary sleeplessness w/o pharmacol stim. 264 h/11 days)
Restorative role, energy conservation, replenish glycogen brain levels, allow
low energy consume to keep the body warm during colder nights (minimum
body temp. at night to reduce heat loss) - thermoregulation. O2 consume
decreased during sleep.
Role REM sleep in early development

Still, the underlining basis for the sleep homeostatic function remains
uncertain

Consciousness
and the Sleeping Brain
Consciousness is a persons subjective awareness of both their
inner thinking and feeling and their external environment
Sleep:
Active process
Composed of two major states, identified by EEG recording

Non-REM Sleep (stages 1-4): Stages 3&4 are known as deep sleep
or Slow Wave Sleep
Rapid Eye Movement (REM) Sleep (stage 5) - high levels of brain
activity
Timing and state of sleep depend on
Length of time awake
Circadian time

EEG during the 5 stages of sleep

Stage 1: Lasts about 5 minutes

Stage 2: Lasts about 20 minutes,

characterized by sleep spindles, rapid
bursts of mental activity
Stage 3: Also known as transitional
sleep and is characterized by delta
waves, which are large, slow waves
Stage 4: Lasts about 30 minutes.
Parasympathetic nervous system is
active, as muscles relax, heartbeat
slows, blood pressure declines, and
digestion speeds up
Stage 5: REM (rapid eye movement
sleep) Characterized by very rapid
brain waves ; muscle atonia

Five Stages of Sleep

These 5 stages (the sleep cycle) repeat themselves about
every 90 minutes, with Stages 3 and 4 getting shorter with
each cycle, and REM and Stage 2 getting longer with each
cycle
REM sleep rebound effect is a significant increase in the
proportion of REM sleep following deprivation of REM sleep

Stage 5: REM (rapid eye movement sleep)

REM - paradoxical sleep: muscle atonia, but other body
systems, including the brain, are active, much like a waking
pattern
If awakened during REM sleep, people often report having
been dreaming
Most dreams are emotional and unpleasant, perhaps
because the visual cortex and frontal lobe are inactive
during REM sleep; the limbic system structures are
active, however, creating irrational imagery and
emotional experiences of our dream world.
REM sleep accounts for 2025% of total sleep time

Why do we sleep and dream?

Sleep deprivation results in:
Impaired concentration and a general bodily feeling of
weakness and discomfort
Suppression of the immune system, lessening ones ability
to fight off infection and disease
Increased vulnerability to accidents
Increased difficulty in concentrating

Why do we dream?
Explanations for dreaming :
Sigmund Freud proposed that dreams were disguised passages
for inner conflicts of our unconscious mind, a view not accepted
by modern sleep researchers
The activation-synthesis hypothesis contends that dreams are
merely the sleeping brains attempt to make sense of random
neural activity without the rational interpretation of the frontal
lobe

http://www.medscape.org/viewarticle/465494_2

Timing
Multiple input pathways to the circadian clock
transmit various kinds of timing information
Light
Activity and arousal
Multiple output pathways from the clock regulate
various overt circadian rhythms
Sleep-wake cycles
Body temperature rhythms
Hormone rhythms

Robust, well-synchronized
circadian rhythms promote
health, well-being, and
optimal performance.

Timing is everything!