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Drug addiction and perinatal stress
Kroupová, Anna ; Šlamberová, Romana (advisor) ; Valeš, Karel (referee) ; Stuchlík, Aleš (referee)
Introduction: Methamphetamine (MA) belongs to the psychostimulants with a central stimulating and anorectic effect. It has been found that MA is the most frequently abused drug of drug-addicted pregnant women. Drug abuse of mother can cause worsening maternal behavior and delayed offspring development. Prenatal application of MA can also lead to long- term changes in behavior, cognition and social interaction. It was also shown that maternal injections induce long-lasting effects on stress responsiveness in adult progeny. Stress and drug addiction are therefore closely connected. In children, perinatal stress is associated with cognitive, behavioral, physical and emotional problems as well as with autism. In adults, it is linked to depression and schizophrenia. In animals, perinatal stress reduces social play and social behavior, increases anxiety and impairs cognitive functions. Aim: The aim of this thesis was to determine the effect of perinatal factors such as prenatal MA/stress and/or early postnatal stress on sensorimotor development of pups and their mothers' behavior during lactation period, social behavior and oxytocin levels in juvenile age and subsequently on cognitive functions and behavior of exposed offspring in adulthood. For all behavioral tests of offspring, we monitor the possible...
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Effect of ketamine on light-induced changes in the circadian system
Kratina, Alex ; Bendová, Zdeňka (advisor) ; Valeš, Karel (referee)
The circadian system is controlled by the suprachiasmatic nuclei of the hypothalamus (SCN) and ensures optimal timing of physiological processes. Synchronization of this system with external light conditions is based on the activation of NMDA receptors during light exposure in the subjective night. Ketamine is a non-competitive antagonist of NMDA receptors used as a safe anesthetic, whose subanesthetic doses act as an antidepressant with a rapid onset of action, and increase proliferation in some parts of the brain. There are hypotheses about the possible effect of subanesthetic doses of ketamine on the circadian system, altough this effect has not yet been tested. This work aims to investigate the effect of a single subanesthetic dose of ketamine on the circadian system of the rat, especially on light-induced changes in locomotor activity and light-induced markers in the SCN and dentate gyrus, which represents one of the strongly proliferative areas of the brain. Our results show that ketamine decreases light pulse-induced c-FOS protein expression in the SCN at the onset of the subjective night, but increases this expression in the dentate gyrus under the same conditions. Reduction of c-FOS expression in the SCN correlates with the behavioral output of the circadian system and thus suppresses the...
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Impact of NMDA antagonists on neuroplasticity as a biological phenomenon
Kalivodová, Michaela ; Valeš, Karel (advisor) ; Krůšek, Jan (referee)
Neuroplasticity is a fundamental biological phenomenon that accompanies us throughout our lives, both in health and illness. By studying neuroplasticity, we can understand serious neurodegenerative diseases, help remodel the nervous system after damage, or make our actions more efficient in today's world. The first chapter of this thesis will discuss neuroplasticity in the physiological state, describing the development of nervous system, learning and memory, different types of neuroplasticity, and other ways to modify neurogenesis. The following chapter deals with the role of neuroplasticity in disease, its impairment in neuropsychiatric diseases. The most common ones will be described, such as depression, schizophrenia, Alzheimer's disease and Parkinson's disease. The next part of the thesis will discuss the molecular biology of NMDA receptor including structure, activation and excitotoxicity of the NMDA receptor, which is distinct from other receptors. Subsequently, selected NMDA antagonists competitive, non-competitive, uncompetitive, as well as glycine agonists and other selected natural modulators of the NMDA receptor will be described. Finally, this thesis will present the molecular and cellular mechanisms of the BDNF and mTOR pathways, knowledge of which provides a basis for further...
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The study of functional and pharmacological properties of glutamate receptors
Kysilov, Bohdan ; Vyklický, Ladislav (advisor) ; Valeš, Karel (referee) ; Novotný, Jiří (referee)
N-methyl-D-Aspartate receptors (NMDAR) are ionotropic glutamate receptors that are involved in the regulation of nearly every process in the brain. Therefore, even a subtle disturbance in NMDAR function may result in severe pathological consequences. Loss-of- function mutations in the NMDAR-encoding genes have been implicated in numerous neuropsychiatric disorders, including intellectual disability, developmental delay, schizophrenia, autism spectrum disorders, epilepsy, and movement disorders. Insufficient NMDAR function can be rectified by positive allosteric modulators, including neurosteroids; however, the mechanism underlying the potentiating effect of steroids is not well understood. By employing patch-clamp electrophysiology we assessed the effect of newly synthesized neurosteroid-like pregnane analogues on recombinant GluN1/GluN2B receptors. We demonstrated that compounds with short C3 residues, such as pregnanolone acetate (PA- Ace) and pregnanolone carboxylate (PA-Car), are negative modulators of NMDAR, whereas compounds with longer C3 residues, such as pregnanolone butyrate (PA-But) and epipregnanolone butyrate (EPA-But), are positive modulators of NMDARs. Furthermore, we revealed that EPA-But has a disuse-dependent positive allosteric effect, being similar in that regard to endogenous...
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Effects of allopregnanolon on motor functions of young laboratory rat.
Krejčí, Lukáš ; Mareš, Pavel (advisor) ; Valeš, Karel (referee)
Allopregnanolone is a typical representative of neurosteroids. It can be formed by de novo synthesis directly in the CNS or as a metabolite of progesterone. It is an allosteric modulator of GABAA receptors, due to which it has anxiolytic, sedative and anticonvulsant effects. This work investigates the effect of allopregnanolone (ALLO) on the locomotor skills of laboratory rat pups. The results will serve as a reference study for the work of Tereza Košťálová (2020), who investigated the newly discovered neuroactive steroid pregnanolone pyroglutamate (PPG). This exogenous steroid, synthesized at the Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic (IOCB PRAGUE), offers potential use in the treatment of epilepsy. Our goal was to perform the same battery of motor tests after the application of allopregnanolone as a comparison, to what extent and in what way these two substances acutely affect the motor performance of the rat pup. The theoretical part of the thesis describes the physiological mechanisms of neurosteroids in the human body and their potential in the treatment of serious diseases, especially epilepsy. Next, the ontogenetic development of the rat's motor skills is described and compared to humans. The methodology describes the selection and...
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Mouse models for Angelman syndrome: generation and characterization
Syding, Linn Amanda ; Sedláček, Radislav (advisor) ; Vyklický, Ladislav (referee) ; Valeš, Karel (referee)
Angelman syndrome (AS) is a neurodevelopmental disease found in 1 to 10,000 to 40,000 births, exhibiting an equal gender ratio. Key characteristics of the disease include an ataxic gait with tremor, severe mental retardation, profound speech impairment and seizures. Behavioral deficits such as increased anxiety and autism spectrum disorder features is found in affected individuals as well. The disease stems from the imprinted region 15q11.2-13q where genes are either maternally or paternally expressed as a result of parent-of-origin specific expression of the alleles. There are four main genetic etiologies causing AS namely, i) a large deletion ranging from 4-6 Mb on the maternally inherited allele including imprinted and bi-allelically expressed genes, ii) maternal deletion of the Ubitiquin ligase E3 (UBE3A) gene, iii) paternal uniparental disomy and iv) imprinting defect leading to inappropriate methylation of the locus. So far, there is no cure for AS rather the symptoms are ameliorated using a multidisciplinary approach. The goal of the doctoral study was to further decipher the role of Ube3a and Gabra5 using two mouse models to gain more knowledge about the involvement of these two genes for future therapeutic interventions in for Angelman syndrome. One model generated was a full gene deletion...
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Drug abuse and perinatal stress
Kroupová, Anna ; Šlamberová, Romana (advisor) ; Stuchlík, Aleš (referee) ; Valeš, Karel (referee)
Introduction: Methamphetamine (MA) belongs to the psychostimulants with a central stimulating and anorectic effect. It has been found that MA is the most frequently abused drug of drug-addicted pregnant women. Drug abuse of mother can cause worsening maternal behavior and delayed offspring development. Prenatal application of MA can also lead to long- term changes in behavior, cognition and social interaction. It was also shown that maternal injections induce long-lasting effects on stress responsiveness in adult progeny. Stress and drug addiction are therefore closely connected. In children, perinatal stress is associated with cognitive, behavioral, physical and emotional problems as well as with autism. In adults, it is linked to depression and schizophrenia. In animals, perinatal stress reduces social play and social behavior, increases anxiety and impairs cognitive functions. Aim: The aim of this thesis was to determine the effect of perinatal factors such as prenatal MA/stress and/or early postnatal stress on sensorimotor development of pups and their mothers' behavior during lactation period, social behavior and oxytocin levels in juvenile age and subsequently on cognitive functions and behavior of exposed offspring in adulthood. For all behavioral tests of offspring, we monitor the possible...
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The role of intestinal microbiota in the development of Alzheimer's dementia
Hakenová, Kristina ; Valeš, Karel (advisor) ; Vodička, Martin (referee)
Preserving health at a higher age depends on the function of biological homeostatic systems (neural endocrine and immune activities), where the biological interaction between these systems and the intestinal microflora plays a key role. One of the most serious diseases associated with aging is Alzheimer's dementia (AD) and it is the most common cause of dementia in the world. This disease is accompanied by cognitive impairment associated with accumulation of amyloid plaques and neurofibrillary fibres in brain tissue. Naturally, biological changes occur during the process of aging, resulting in reduced functional capacity of the organism, accompanied by an increased risk of inflammatoryprocesses involved in the etiology of several chronic, pathologies, including neurodegenerative processes. These modulatory processes are associated with oxidative stress and intestinal dysbiosis. It is already well documented in the scientific literature that significant changes in the composition of intestinal microbiota occur in aging. These changes can lead to several biological changes, including increased permeability of the intestinal barrier, thereby causing the increased penetration of many biologically active substances into the body. This may be a risk factor for the development of inflammation in both...
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Automated monitoring of behaviour as a new paradigm in the research of depressive disorder
Revayová, Anna ; Valeš, Karel (advisor) ; Kubik-Zahorodna, Agnieszka (referee)
The rapid antidepressant effect of ketamine changed the direction of the research of potential antidepressants and its effect was also evaluated in this thesis. However, the main focus of this thesis is a new methodological approach to the research of depressive disorder. The main interest lies with the evaluation of automated monitoring of behaviour in this research. The first aim of this thesis was to evaluate the antidepressant effect of ketamine in the forced swimming test using software enabling automated monitoring of behaviour. The second aim was to meassure the change in phosphorylated Mammalian target of rapamycin (mTOR), using Enzyme-Linked ImmunoSorbent Assay (ELISA). The last, but the most important aim of this thesis was to implement the utilization of Phenotyper boxes in the automated behavioural evaluation of the olfactory bulbectomy model of depressive disorder and also evaluate the effect of ketamine in this model. Ketamine did not show an antidepressant effect in forced swimming test, however this observation could be influenced by chosen dose and mouse strain. Sensitivity of the test to chosen experimental protocol shows insufficient validity of this test. Observed change in level of phosphorylated mTOR corresponded with the behavioural results. Data collected from Phenotyper...
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