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Vliv stresu na periferii a v CNS s ohledem na úlohu muskarinových receptorů
Název práce v češtině: Vliv stresu na periferii a v CNS s ohledem na úlohu muskarinových receptorů
Název v anglickém jazyce: The effects of stress on the periphery and in the central nervous system with respect to the role of muscarinic receptors
Klíčová slova: M2 muskarinové receptory, stres, biorytmus, CRH, integrační úloha hypotalamu
Klíčová slova anglicky: M2 muscarinic receptors, stress, biological rhytms, CRH, hypothalamic integration
Akademický rok vypsání: 2013/2014
Typ práce: disertační práce
Jazyk práce: čeština
Ústav: Fyziologický ústav 1. LF UK (11-00150)
Vedoucí / školitel: prof. MUDr. Jaromír Mysliveček, Ph.D., MBA
Řešitel: skrytý - zadáno a potvrzeno stud. odd.
Datum přihlášení: 04.08.2014
Datum zadání: 04.08.2014
Datum potvrzení stud. oddělením: 04.08.2014
Datum a čas obhajoby: 17.03.2022 10:00
Místo konání obhajoby: Fyziologický ústav 1. LF UK
Datum odevzdání elektronické podoby:14.02.2022
Datum proběhlé obhajoby: 17.03.2022
Předmět: Obhajoba dizertační práce (B90002)
Oponenti: prof. MUDr. Jitka Kuncová, Ph.D.
  doc. RNDr. Ján Bakoš, Ph.D.
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Předběžná náplň práce
Tato práce si klade za cíl analyzovat roli muskarinových M2 receptorů (M2MR) v organismu v situaci klidového stavu a ve stresu. Základní funkcí těchto receptorů na periferii je regulace srdeční frekvence, proto lze sledováním změn v srdeční frekvenci hodnotit aktivitu M2MR. V experimentech jsou sledovány změny u subjektů s exprimovanými M2MR a porovnávány s jedinci M2KO, kterým tyto receptory chybí. Srdeční frekvence je funkcí vztahu mezi sympatickým a parasympatickým autonomním tonem; výsledná frekvence je tedy určena interakcí adrenergních a cholinergních receptorů, které jsou spřaženy s G proteiny. Jejich aktivita je ovlivňována etážemi autonomního nervového systému (ANS) s nejvyššími kontrolními centry v hypothalamu, který funguje jako integrátor. Organismus reaguje na absenci M2MR snížením počtu adrenergních receptorů, srdeční frekvence v klidových podmínkách se výrazně nemění. Při stresu omezením volného pohybu (restraint stres) však dochází k rozdílům jak v průběhu stresové reakce, tak v postresovém období, kdy se projeví nedostatek kardioinhibičního vlivu parasympatického nervového systému. Předpokládalo se, že SF určuje vztah mezi adrenergními β (kardioexcitační) a cholinergními M2 (kardioinhibiční) receptory, ale u jedinců s M2KO se může projevit vliv nonM2MR po podání karbacholu (muskarinový agonista).
Ultradiánní srdeční rytmus je nadstavbou cirkadiánního rytmu, kde jsou struktury hypothalamu, konkrétně suprachiasmatické jádro (SCN), určujícím pacemakerem. Odpověď ANS může ovlivnit další hypotalamické funkce – cirkadiánní rytmus, endokrinní regulaci, metabolismus, termoregulaci, příjem potravy a tekutin a může evokovat změny chování a mít vliv na paměť. Proto předpokládáme, že stres by mohl ovlivnit i výše uvedené procesy. Součástí stresové odpovědi je i sekrece kortikotropin releasing hormonu (CRH), má vliv endokrinní na hypotalamo-hypofyzární osu (HPA) a nonHPA účinek jako neuromediátor. Zkoumali jsme vliv stresu na chování a krátkodobou paměť, vliv na dlouhodobou paměť je známý.
Princip dlouhodobé trvalé sympatické stimulace a snížení parasympatického tonu je známý při chronickém srdečním selhání, obstrukční spánkové apnoe nebo dlouhodobé katecholaminové terapii, což je patologická situace, kterou může stres akcentovat. Aferentní informace do hypotalamických center ovlivní celou řadu integračních funkcí hypothalamu (emoce, metabolismus, humorální regulace).
Předběžná náplň práce v anglickém jazyce
This work aims to analyze the role of muscarinic M2 receptors in an organism in the situation of resting state and stress. The core function of these receptors on the periphery is heart rate regulation, therefore, by monitoring the changes in heart rate M2 muscarinic receptor activity can be assessed. In the experiments monitored changes in subjects with expressed M2 muscarinic receptors are compared with M2KO subjects who lack these receptors. Heart rate is the function of the relationship between sympathetic tone and parasympathetic tone; thus, the resulting frequency is determined by the interaction of adrenergic and cholinergic receptors, either of which is attached to the G proteins. Their activity is influenced by the autonomic nervous system network levels with the highest controlling centres in the hypothalamus, which serves as an integrator. The organism responds to the absence of M2 muscarinic receptors by decreasing the number of adrenergic receptors, the heart rate in resting conditions does not change significantly. However, when stressed by restraint of free movement (restraint stress), there are differences both during the stress response and in the post-stress period when a lack of the counteracting influence of the parasympathetic nervous system becomes apparent. The relationship was also thought to be within adrenergic and cholinergic receptors, with M2KO subjects showing evidence of nonM2MR after administration of carbachol (muscarinic agonist).
Ultradian heart rate rhythm is superimposed to circadian rhythm, where hypothalamus structures, specifically the suprachiasmatic nucleus (SCN), are the defining pacemaker. The autonomic response may modify other hypothalamic functions - circadian rhythms, endocrine regulation, metabolism, thermoregulation, food, and fluid intake, and may evoke behavioural changes and have an influence on memory. Therefore, we assume that stress could also impact the above processes. Corticotropin-releasing hormone (CRH) is secreted as a part of the stress response, it works within endocrine system (hypothalamo-hypophyseal or HPA axis effect) and acts as a neuromediator (nonHPA effect). In subjects lacking CRH, we investigate the effect of restraint stress on behaviour and short-term memory, the impact on long-term memory trace has been known.
The principle of long-term sustained sympathetic stimulation and reduction of parasympathetic nervous system tone is known in chronic heart failure, obstructive sleep apnoea, or long-term catecholamine therapy, a situation that can be accentuated by stress. The afferent information to hypothalamic centres will affect a variety of integrative functions of the hypothalamus (emotions, metabolism, humoral regulation).
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