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Cognitive and behavioral alterations in neurodevelopmental and pharmacological animal models of schizophrenia
Malenínská, Kristýna ; Stuchlík, Aleš (advisor) ; Blahna, Karel (referee) ; Telenský, Petr (referee)
Establishing reliable animal models of psychiatric diseases such as schizophrenia is essential to better understand the neurobiological, behavioural and genetic basis of the disorder and to develop new drugs with greater therapeutic efficacy. These models allow the study of different aspects of schizophrenia, including positive, negative and cognitive symptoms similar to schizophrenia. All available animal models of schizophrenia can be divided into four different categories of induction: developmental, pharmacological, genetic and lesion-induced. However, none of these models perfectly replicates all aspects of schizophrenia in humans, and it is therefore necessary to precisely define the influence of each manipulation. This thesis focuses on the study of pharmacological and developmental animal models of schizophrenia, with an emphasis on examining the cognitive and behavioral changes associated with the disorder. Specifically, we investigated the pharmacological induction of schizophrenia- like symptoms by acute administration of MK-801, developmental models of two interventions combining the maternal immune response following poly(I:C) administration and subsequent stress of offspring in adolescence, and repeated prenatal and neonatal administration of lipopolysaccharide (LPS). In the...
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One-trial association task as a basic biological model of episodic memory in rats
Radostová, Dominika ; Stuchlík, Aleš (advisor) ; Horáček, Jiří (referee) ; Telenský, Petr (referee)
One-trial association task as a basic biological model of episodic memory in rats Abstract A very important structure in the animal and human brain is the hippocampus. The study one of its many functions, episodic memory, is facing with the limited possibilities of non-invasive methods. In this regard, animal models are helpful. In order to study the individual components of such a complex ability in detail, a new behavioral task testing the association of temporally close but separate stimuli was developed. The test animals were exposed to a sequence of a sound conditioned stimulus and an unconditioned electric shock, between which there was a delay of 2 seconds. 59% of the rats successfully learned the association as well as the correct escape reaction to solve the task. Based on the results, the so-called One-Trial Trace Escape Reaction task could be a very valuable tool for a more detailed understanding of animals' incidental one-trial learning important for episodic memory. Another important phenomenon investigated in this work is the development of new neurons in the hippocampus in adulthood and its influence on learning and flexibility. After blocking the animals' neurogenesis with the temozolomide, the animals' ability to learn to avoid an invisible sector in the active avoidance task was tested....
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Cognitive flexibility in selected animal models of psychiatric disorders
Janíková, Martina ; Stuchlík, Aleš (advisor) ; Rokyta, Richard (referee) ; Ježek, Karel (referee)
Cognitive flexibility is the ability to adjust thinking and behavior based on changing conditions. Cognitive rigidity has been described in a variety of psychiatric and neurodevelopmental disorders and has been suggested to contribute to symptom maintenance. Therefore, we aimed to study cognitive flexibility and other behavioral characteristics in several rodent models relevant to schizophrenia, obsessive-compulsive disorder, and autism spectrum disorder. In a two-hit mice model relevant to schizophrenia, we found the between-group difference in set- shifting and decreased number of parvalbumin interneurons in the hippocampus of stressed female mice. Interestingly, we found no impairment in any other behavioral task. In two pharmacological rat models relevant to OCD, we showed that sensitization to D2/D3 receptor agonist quinpirole and serotonin 1A/7 agonist 8-OH-DPAT produced severe spatial learning and memory impairment in the Active Allothetic Place Avoidance task. The impairment was so severe that the reversal couldn't be tested. Surprisingly, drugs decreasing glutamatergic neurotransmission, memantine and riluzole, further impaired the performance in both models, although no such effect was observed when they were applied alone. Lastly, we showed that the knockout of a collapsin response...
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Evolution of brain complexity and processing and cognitive capacity in selected vertebrates
Kverková, Kristina ; Němec, Pavel (advisor) ; Stuchlík, Aleš (referee) ; Iwaniuk, Andrew N. (referee)
Brain processing capacity has traditionally been inferred from data on brain size. However, recent studies have shown that similarly sized brains of distantly related species can differ markedly in the number and distribution of neurons, their basic computational units. There- fore, a finer-grained approach is needed to reveal the evolutionary paths to increased cogniti- ve capacity. This quantitative approach to the evolution of brain processing capacity at the cellular level is relatively new, since quick and reliable estimation of the number of neurons in whole brains or large brain regions has only become possible in the past 15 years or so with the introduction of the isotropic fractionator. This method of determining brain cellular com- position is applicable to a wide range of questions. We can assess intraspecific variation, both at the individual and population level, examine the effect of sex and age, and the study se- lection at the intraspecific level. At the other side of the spectrum, we can study large macro- evolutionary trends or try to isolate the effect of specific selective pressures by comparing more closely related and ecologically similar species. In this thesis, I explored variation in brain size and brain cellular composition across vertebrates at both intraspecies and...
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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 use of chemogenetic tools in the research of brain diseases
Neřoldová, Markéta ; Stuchlík, Aleš (advisor) ; Tabáková, Petra (referee)
Chemogenetics is a newly developed set of tools that allow for selective manipulation of cell activity. They consist of a receptor mutated irresponsive to endogenous ligands and a synthetic ligand that does not interact with the wild-type receptors. Many different types of these receptors and their respective ligands for inhibition or excitation of neuronal subpopulations were designed in the past few decades. It has been mainly the G-protein coupled receptors (GPCRs) selectively responding to clozapine-N-oxide (CNO), namely Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), that have been employed in research. Chemogenetics offer great possibilities since the activity of the receptors is reversible, inducible on demand by the ligand, and non-invasive. Also, specific groups or types of neurons can be selectively manipulated thanks to the delivery by viral vectors. Furthermore, the effect of the chemogenetic receptors on neurons lasts longer, and even chronic activation can be achieved. That can be useful for behavioural testing. The great advantage of chemogenetic tools is especially apparent in the case of the research of brain diseases since they can manipulate whole neuronal circuits and connections between different brain areas. Many psychiatric or other brain diseases...
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Activation of neuroglia after status epilepticus induced by intracerebroventricular application of 4-aminopyridine in the rat.
Uttl, Libor ; Otáhal, Jakub (advisor) ; Stuchlík, Aleš (referee)
Epilepsy is a chronic disease characterized by spontaneous epileptic seizures. One percent of the world population is affected by the epilepsy. The existence of proper models is crucial for study of distinct types of epilepsy. We decided to deeply describe the model of status epilepticus (SE) induction in an adult rat by the intracerebroventricular application of 4-aminopyridine (4-AP). For description of this model we used the histology and immunohistochemistry methods, the western blot analysis focused on the microglial activation markers, and the series of behavioral tests to reveal the functional influence of SE in chronical experiment (8 months). We described the ability of the 4-AP to induce SE in this model. After SE, neuron degeneration and microglial activation appeared. The areas of degenerated neurons strongly corresponded to the regions with activated microglias. By the western blotting we demonstrated the oxidative stress by an increase of 3-nitrotyrosine already 2 hours after SE. Microglial activation detected by the immunohistochemistry correlated to the observed increase in IL-1β and CD68 production after SE. Considering these results we verified the functional influence of the SE in chronical experiment. We did not observed any significant changes of cognitive and motoric functions...
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