Curs 2 - somn

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SOMNUL = componenta esentiala a integritatii si functionarii normale a creierului si intregului organism al fiintelor umane si animale SOMNUL = stare activa a creierului, cu propriile sisteme de retele neuronale functionale si mecanisme de control a homeostaziei specifice extrem de complexe SOMNUL = componenta inseparabila a ciclurilor somn-veghe

Somnul = o stare fiziologica de intrerupere a activitatii de veghe constiente, cand creierul este relativmaireactivlastimul relativmaireactivlastimuliinterni iinternidecat decat la stimuli externi - alternanta somn-veghe are o ciclicitatepredictibila (diferentamajorafatadestari (diferentamajorafatadestarilepatologicede lepatologicedepierdereaconstien pierdereaconstientei) tei) - creierul isi scadegradualresponsivitatea scadegradualresponsivitateala la stimuli vizuali, auditivi si alti stimuli din mediu – mediu  – tranzitia  tranzitia catre somn (→stadiulIdesomnNREM) •

Proiectiile eferente ale FR trunchiului cerebral

1. rostral – rostral – spre creierul bazal anterior ( “forebrain”) 2. caudal – caudal  – spre  spre maduva spinarii 3. spre sistemele motorii & de reglare interna

Components of the consciousness system

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Somnul urmeaza un ritm circadian - cu periodicitate reglata genetic independent de un “ceas biologic intrinsec” ( in relatie cu factori -trigger externi: lumina, intuneric,orelezilei, modalitatiledeactivitate,orelemeselor, etc.) Cand fiinta umana este privata de acesti factori-cheie si supusa unui nivel constant de iluminare, ciclul somn-veghe se alungeste la cca. 24,5 ore

“Ceasul biologic principal” la mamifere – nc. suprachiasmatic rostral (sincronizeazaactivitatilediurne)

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LeziunidinSCN→pierdereaorganizariicircadiene

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Proiectii directe din retina

( SCN ) din

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la om, cel mai puternic agent de sincronizare: LUMINA

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alternanta lumina / intuneric: organizeaza ritmul biologic •

nevoia de adormire

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momentul trezirii

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Informatii aferente multiple de la caile celorlalti stimuli externi reglatori

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Interactiune coordonata intre circuitele neuronale de control ale:

h-talamusul

A. reglarii starii de veghe (stimuleazaactivareacorticala&trezireacomportamentala) •

nn. Ach-ergici din: TRUNCHI CEREBRAL si CREIERUL ANTERO-BAZAL

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nn. monoaminergici (NA, Hys-NH 2, 5-HT2 ) din: TRUNCHIUL CEREBRAL si HIPOTALAMUSUL POSTERIOR nn. orexigenici ( hipocretina ) din HIPOTALAMUSUL LATERAL

(distrugereaneuronilororexinici→narcolepsia!)

A. reglarii somnului •

inhibitia /disfacilitarea sistemelor de trezire prin:  –

cell. ARIA PREOPTICA VENTRAL-LATERALA ( VLPO ) »

 –

galanina, GABA

nc. PREOPTIC MEDIAN ( MnPN ) »

GABA

Neuronii preoptici se activeaza in timpul somnului si se proiecteaza in hipotalamusul posterior si trunchiul cerebral rostral ( → INHIBITIE ) (patterndedescarcarereciprocceluidinsistemeledeveghe) Both homeostatic factors (factor S) and circadian factors (factor C) interact to determine the timing and quality of sleep The propensity to fall asleep varies throughout the day and depends upon both time since the last sleep period (process S) and circadian factors (process C): -thelongerthetimesincethelastsleepperiod,thegreaterwillbe process S; -itspropensitywill bemodulated byprocessC The circadian pressure to sleep: - is greatest at ~2 am with a secondary peak at ~2 pm. - it is least at ~6 am and ~6 pm.

OREXINELE ( HIPOCRETINELE ) •

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Orexins or hypocretins, which are produced by a small group of neurons in the hypothalamus and whose actions are mediated by two types of receptors: OX1R and OX2R Orexinergic neurons are projected widely into a number of brainstem, cortical and limbic regions They have been related with the mechanisms that enable regulation of the sleep-wake cycle, the ingestion of food and drink, and some particular types of learning Further research will help to determine the functioning of orexinergic neurons and the interactionbetweenthesystemsthatregulateemotion,energetichomeostasisandthe rewardmechanisms, on the one hand, and the systemsthatregulatethesleep-wakecycleon theother 

STRUCTURA GENERALA A SOMNULUI •

2 componente fundamentale ale somnului:  –

 –

non-REM ( NREM ) •

Clasic: 4 stadii de profunzime: I, II ( somn superficial ), III, IV ( SWS )

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Clasificarea actuala AASM: N1, N2, N3

REM

Diferente majore NREM / REM: - circuite neuronale activate - relatia creier / mediul exterior si intern (controlul homeostaziei sistemice, activitatii motorii si receptivitatii informatiilor din afara SNC ) - tipul de activitate biochimica in metabolismul si comunicarea interneuronala * NREM: activitate mentala minima / absenta * REM: activitate corticala intensa - activitatea electrica a creierului →EEG

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Sleep is divided into a 90 minute cycle of NREM sleep and REM sleep

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This cycle is repeated 3-6 times during the night Generally, a night of sleep begins in NREM and progressesthroughdeeperNREMstages (stages2,3,and4usingtheclassicdefinitions , or stagesN2andN3usingtheupdated definitions) before the first episode of REM sleep occurs approximately 80 to 100 minutes later As the sleep cycle progresses through the night there is less stage N3 NREM sleep and more REM sleep (moreREMsleepontowardsmorning,whichexplainswhywhenyouawakenin themorning,yougenerallyawakenfromadream)  sleep is a very light stage of sleep with a low arousal threshold. It generally lasts for less than 10 minutes, at sleep onset. During this stage, the EEG shows alpha activity During stage voltage activity

, which accounts for 50 percent of total sleep time, the EEG shows low-

 –

 activity

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the advancement to Stage 2 begins when at least 0.5 second, on a

 and

that last

of electrical activity (hypnoticagentshavebeenshowntoincreasethedensityofsleepspindles) the

and

 –

, although they may

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reappear for short intervals

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The

is associated with the secretion of from basal forebrain neurones

(benzodiazepinesandbarbiturates,whichactthrough stimulationofGABAreceptorsintheCNS,inducesleep oranesthesia)

ARHITECTURA SOMNULUI •

An

signifies the and

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Progression to

can

identified 

 is defined as an

during Stages 3 and 4 ( N3 )

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uses the term

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and  for

for

:

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is used to indicate the

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In of 4-7 Hz

with frequencies of 8-13 Hz

marked with the advent of

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and

that range from

(deepsleep): EEG pattern of 20%-50% high-amplitude

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 with frequencies

11-16 Hz and

(>75 μV), low-frequency

(2 Hz)

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In starea de veghe: Ach, Hys-NH2, NA ( din trunchiul cerebral & hipotalamus ) au efect activator asupra neuronilor talamo-corticali, blocand hiperpolarizarea prin canalele de K+

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In stad.N2 NREM: inhibitia sincrona produsa de GABA: abundenta de fusuri de somn

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In somnul SWS ( NREM-N3 ):  –

scaderea Ach (→ dezinhibitia nc. reticular talamici ), prin reducerea depolarizarii SRAA ( in somnul precoce ) permite un raspuns de tip “burst -mode”dependent ++ de un prag scazut al canalelor lente de Ca ( descarcari de serii repetitive pe fond de hiperpolarizare )

REM •

A specific

within the : during SWS, these

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The

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REM sleep usually is not divided into stages

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For research purposes:

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also

can be partially attributed to a

 –

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seems to

tonic (parasympatheticallydrivenstate)REM sleep phasic (sympatheticallydrivenstate)REM sleep occurinclusters)

( with noeyemovements)

( with eyemovementsthattendto

ThemostcommonlyusedmarkerofREMsleepphasicactivityinhumanbeingsistheburstsof rapideyemovements Muscle twitches and cardiorespiratory irregularities often accompany the sympathetically driven phasic REM bursts

1. The MENTAL ACTIVITY of human REM sleep is associated with DREAMING, based on vivid dream recall reported after approximately 80% of arousals from this state of sleep 2. Inhibition of spinal motor neurons by brainstem mechanisms mediates SUPPRESSION OF POSTURAL MOTOR TONUS in REM sleep (postsynapticinhibitionofmotorneuronsandmembranehyperpolarization;insubjectswith pontinedamage,REMwithoutatoniacanoccur – these patientsphysicallyenacttheeventsoftheir dreams) •

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A shorthanddefinitionofREMsleep:

Classic EEG features of REM sleep include high-frequency, irregular waveforms and the absenceofK-complexes,sleepspindles, and low-frequency waveforms The irregular waveforms unique to REM sleep have a “ sawtoothappearance” and are present in bursts lasting up to 5 seconds

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In terms of EEG readings, REM sleep mostcloselyresemblesthe wakingstate

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REM sleep is also characterized by:  –

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diminished or absent deep tendon reflexes

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irregular breathing in both frequency and tidal volume

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poikilothermia (cellsinthepreoptic/anteriorhypothalamuswhichcontrol thermoregulationceasefiring)

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penile tumescence

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increased variability in cardiac rhythm

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cerebral blood flow is also high during REM sleep

Neurotransmitters Simplistic Wake high monoaminergic high cholinergic orexin ( hypocretin ) NREM low monoaminergic low cholinergic REM low monaminergic high cholinergic Monoaminergic:dopamine,serotonin,norepinephrine,hystamine

PHYSIOLOGICAL CHANGES DURING SLEEP •

Cardiovascular

* During NREM, there is an overall reduction in heart rate, cardiac output and blood pressure ( “dip”), due to a general vasodilation

* During REM sleep, there are variations in blood pressure and heart rate, but overall  the rates are increased, especiallyduringthephasic eventsof REM sleep, probably due to a generalized vasoconstriction seen in the skeletal muscles during phasic REM sleep * Cardiac output is generally decreased during all sleep phases * Cerebral blood flow (CBF) increases above the level of resting wakefulness during tonic REM sleep and is even greater during phasic REM sleep * Cerebral metabolic rate, oxygen consumption and neuronal discharge rate are reduced during NREM sleep but increased above resting values during REM sleep •

system shows a general decrease in sympathetic tone and an increase in parasympathetic tone, except in phasic REM sleep.

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* Overall, there is slight hypercapnia, a decrease in total ventilation, and a decreased sensitivity to inspired CO 2 * During NREM there is a slight hypoventilation (relaxationofupper airwaymuscles,aswell asadecreaseinthefiringofinspiratoryneurons, whichshowadecreasedsensitivitytostimuli) * PCO2 levels raise while Po 2 levels fall * During NREM sleep, breathing is under chemical and mechanical feedback control * During REM there is an overall higher and variable respiratory rate ( it may be drivenbyhigher corticalcontrol , which may explain the variablerate)

NERVOUS SYSTEM DURING SLEEP •

During NREM sleep there is a reduced discharge rate and reduced brain metabolism (thereis anactiveinhibitionofthereticularactivatingsystem)

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During REM sleep, many parts of brain (visual cortex, limbic lobe) show increased firing rate and metabolism Brain transection studies have shown that the

and 

to generate the

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During NREM sleep, there is an increase in parasympathetic activity similar to relaxed wakefulness; sympathetic drives remain at about the same level as during relaxed wakefulness During tonic REM sleep, parasympathetic activity remains about the same as during NREM sleep, but sympathetic activity decreases, resulting in an overall predominance of parasympathetic activity However, during sympathetic activation is generally favored Overall, there is a

 and

***RELATIA INERVATIEI CHOLINERGICE / STAREA VIGILA si SOMNUL / MEMORIA Eliberarea corticala a Ach:  –

crescuta in timpul starii de veghe

 –

maxima si exclusiva in somnul REM

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minima in somnul SWS

 Ach creste selectivitatea raspunsului neuronal la informatia noua, favorizand retinerea ei ( encodarea ) : influenta benefica asupra memoriei declarative ! reactivarea achizitiilor mnestice recente (“replay”) in circuitele hipocampice, NECESARA pentru transferul si integrarea lor in retelele celulare neocorticale ( corelate cu prezenta in std.2 NREM pe EEG a fusurilor de somn sioscilatiilor lente, mai abundente dupa procesul de “invatare declarativa” )  –

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activitatea NA in absenta activitatii Ach permite consoloidarea memoriei de lunga durata in retelele neocorticale, prin facilitarea activitatii metabolice celulare ( sinteze proteice: LTP de lunga durata ) reflecta activitatea neocorticala si talamica ( ncc. anteriori ): •

inversarea fluxului informational ( hipocamp → neocortex )

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necesita reducerea stimularii Ach si cortizolice (implicatiipentruAD, apneeadesomn,nerespectareaorelordesomn

* consolidarea memoriei procedurale * consolidarea memoriei declarative cu continut emotional bogat ! •

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Mecanisme asemanatoare ca pentru catre hipocamp a (  –

“replay” in

 –

participarea

, dar implica activarea de )

Proces fiziologic care permite unui organism sa realizeze o pe baza unei si sa raspunda astfel  din  decat cel in contextul caruia s-a realizat

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ameliorareafunctieiexecutive

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creativitatea

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introspectia

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performantaintelectualamaibuna

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performantecomportamentalemaibune

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simaiales

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( talamus, girus cingulat anterior, operculul parietal, complexul amigdalian ) – asociata cu activitate imaginativa vie ( visul ) si inhibitia quasi-totala cu mediul extern ( senzorial & comportamental, motor ) subiectul relateaza aspecte corelate explicit cu activitatea sa mnestica recenta ( corelatie cu activarea reg. parahipocampice in somnul NREM, implicata in codarea mnestica ) au

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concomitent cu

in si

,

Activitatea endocrina in cursul somnului

A. Activitatea hormonala

( in ansambu ) (ex.:prolactina)

B. Activitatea hormonala in relatie cu un

(ex.:STH/GH)

C. Activitatea hormonala

(ex.:ACTH,cortizol)

Activitatea hormonala depine de interactiunea a mai multi factori, care interactioneaza:

si

-

(frecventa<1/zi;

 )

(frecventa>1/zi;

 –

nivele scazute in conditii bazale, in starea de veghe

 –

cresteri usoare in cursul somnului

 )

relatie de tip circadian

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decalareaorelordesomn:decalareaciclurilorsecretoriidePRL

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modificareafusuluiorar:adaptarearitmuluiPRLnecesitaundecalajdetimp

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variatii mari intra- si interindividuale

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date contradictorii, functie de studii: •

concentratii crescute in timpul somnului

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peak secretor inainte de adormire, scadere progresiva in cursul somnului de noapte

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concentratie scazuta in cursul starii de veghe, in cursul zilei •

exceptie → episoadelesecretoriideclansatede: •

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barbati tineri: 3 episoade ( in medie ) in cursul somnului de noapte

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femei: variabilitate mai mare, influenta importanta a ciclului menstrual

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secretia totala dimnua cu inaintarea in varsta (sepastreazasecretiamaximain cursulsomnului,laoricevarsta!)

concentratia scade la trecerea din somnul NREM spre somnul REM

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fluctuatii in cursul ciclurilor NREM/ REM: •

declin la debutul fiecarei faze REM

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eliberare crescuta la trecerea din REM catre NREM, si la trezire

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oscilatii nocturne cu ritm de 90 min, dar independent de ciclurile de somn

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nivelele de aldosteron le reflectapecelede

cu un decalaj de cca. 20 min

( terapia anti-HTA ): profilulsecretoral

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aldosteronuluiurmeazadinamica •

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evolutie in mare masura paralela, dar

identica ( incepe relativ rapid in jurul orelor 04:00 a.m. )

 –

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secretia scade in cursul zilei →

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profilulsecretor

 –

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secretie ritmata de alternanta lumina / intuneric, dar

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secretie

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debutul secretiei continue:

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lipsa de interactiune cu somnul ( studiiputine )

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secretie neifluentata de ritmul somn/ veghe si fazele de somn

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Rezistenta la insulina si ritmul circadian

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influenta ciclurilor

si

:

 –

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Studii recente: •

toleranta la glucoza este ( orele 08:00 ),

( orele 20:00 )

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discordanta intre

si

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•

 –

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← ale activitatii neuronale in zone cerebrale interconectate intre ele la distanta, dar implicate in acelasi proces [ v. & activate de

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Fiecare  –

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 – asociat cu in particular: memoria, invatarea, functia executiva, atentia complexa Somnul permite sale prin intrerupereaachizitiilorcontinue

si

Somnul are  –

creativitate,capacitateadeintrospectie,functiaexecutiva

 –

 –

Peter Tripp - privare de somn 201 ore ( incinta de sticla in New York’s Times Square ) •

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pierdereprogresivaacapacitatiideadormi→deteriorarecognitiva progresiva→

Dupa exercitii de  –

→

( origine: nc.subcoeuleus, propagare: SRRA medial; tinta: GLU in creierul bazal anterior → proiectie in hipocamp, amigdala, cortex occipital ) -

~ corelata cu

 –

 –

 –

neuronii din hipocamp care au fost in REM

→ se reactiveaza

( “replay” al activitatii din starea de veghe ) concomitent cu  –

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disruptiaactivitatiiAchinREM→altereazaretentiainformatiilor 

sediul

 –

a informatiilor noi

al

 –

•

•

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carcteristicile electrofiziologice si biochimice  – asociate cu ambele procese, bidirectionale ale neuroplasticitatii: •

undeleascutitePGO

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sincronismultheta

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nivelulminimaldemonoaminebiogene(NAfaciliteazafen.feed-backin neocortex) (corelatcuact.thetainhipocamp,reducereatrimiteriide informatiidinhipocampspreneocortex) transcriptiacrescutaintraneuronalagenelorlegatedeplasticitate

mediu neuronal care permite  –

rol particular in consolidarea si modularea

cuun

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→ inhiba inducerea LTP si mentinerea informatiei

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( ore ) → in girusul dentat ( hipocampic )

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IRMf:

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undele lente permit a neuronilor implicati in procesul de invatare sau memorare ( encodare ) de o maniera accelerata si condensata in timp + concomitent permite si in sinapsele care au fost doar slab reactivate (→ stergerea altor informatii ) => (unelesuntstabilizate-LTP, alteledezactivate-LTD)

 –

=>

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Experimental: la trezire,

 dependente de zonele de , este

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generate de nc. reticular talamic → cell.corticale “oscileaza” in fusuri ( 11 -16 Hz ) nu apar in somn,devine

(

- deaparitiafusurilorde lasfarsitulfiecaruifusdesomn→

 ) (mediubiochimic~REM,dar

•

 )

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hipocampuldeterminaacelasitipde cortexulprefrontalinNREM-N2~inREM

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in

linistita din cursul somnului: , alaturi de cele vechi  –

 –

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 –

 –

 fusuriledesomn incetareaactivitatiicontinueNAurmatadedescarcarialeneuronilorNA,inacelasi timpcureactivareahipocampicasicorticala

↓  –



↓  –

permiteplasticitateasinapticabidirectionala(LTP/LTD)inariineocorticale – tinta

(activitateEEGtipdelta)

 –

 –

reactivareneuronalainfazacu

 –

 –

nivelAchscazut 

↓  –

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(nuseasociazacuactivarea genelordereactivitateprecoce,precuminLTPprecoce) poatereducefortacircuitelorcorticale,maiputinstimulateinreactivitareadelta