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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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The role of nociceptive synaptic transmission modulation
Heleš, Mário ; Paleček, Jiří (advisor) ; Rokyta, Richard (referee) ; Krůšek, Jan (referee)
Pain represents a major symptom in a multitude of medical conditions and can often become the main negative factor in a patient's low quality of life. The complex issue of pain management is further underscored by the reduced efficacy of conventional analgesics in conditions such as neuropathic pain. Neuropathic pain, unlike acute nociceptive pain, originates from damage to the peripheral or central nervous system and often develops into chronic pain syndrome. Most analgesics available today provide only limited and unsatisfactory analgesia in chronic neuropathic pain and are often associated with severe adverse effects. Modulation of nociceptive transmission in spinal cord dorsal horn (SCDH) stands out in recent research as a pivotal mechanism, especially in chronic pain development and maintenance. The major aim of this doctoral thesis was to investigate how pain-associated processes interfere with opioid-induced analgesia, with the main focus on the interaction between chemokine (C-C motif) ligand 2 (CCL2), transient receptor potential vanilloid type 1 (TRPV1), and μ-opioid receptor (MOR). To achieve a better insight into opioid signaling in SCDH we studied the following issues: (I.) How does CCL2 modulate MOR-mediated effects on nociceptive synaptic transmission in SCDH neurons and in vivo...
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Neuromodulation in heart failure
Naar, Jan ; Ošťádal, Petr (advisor) ; Rokyta, Richard (referee) ; Vízek, Martin (referee)
The prognosis of heart failure with reduced ejection fraction remains poor. Neurohumoral activation, including increased cardiac sympathetic nerve activity, plays an important role in the pathogenesis as well as disease progression. Recently, several neuromodulation strategies have been proposed that aim to directly affect the residual autonomic imbalance. Spinal cord stimulation is one of the proposed methods. In the clinical part of this project, we assessed the mid-term effect of spinal cord stimulation on cardiac sympathetic nerve activity and the acute effect on autonomic balance. In the total study population, we did not detect any changes in cardiac sympathetic nerve activity or heart rate variability. However, we observed that the patients with high baseline sympathetic nerve activity or low heart rate variability responded favourably to therapy, reflected in reduced cardiac sympathetic nerve activity and increased heart rate variability. Considering these results, we conducted an experimental study focused on the effect of acute severe heart failure on heart rate variability. In a porcine model of hypoxic myocardial dysfunction, we observed a significant reduction in heart rate variability in all parameters recorded. Our results indicate that spinal cord stimulation may improve autonomic...
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Experimental bridging of spinal cord injury with hydrogels
Hejčl, Aleš ; Syková, Eva (advisor) ; Rokyta, Richard (referee) ; Filip, Stanislav (referee)
Hydrogels are biomaterials used in the treatment of experimental spinal cord injury (SCI). In a model of acute SCI, we implanted hydrogels based on 2-hydroxyethylmethacrylate (HEMA) and hydroxypropylmethacryla-mide (HPMA). One month after implantation the hydrogels bridged the cavity, adhered well to the spinal cord and created permissive environment, infiltrated with blood vessels, axons and Schwann cells. Physical modifications (e.g. surface charge) of hydrogels may improve bridging of acute SCI. We implanted hydrogels based on HEMA with a surface charge in spinal cord hemisection and compared with a hydrogel without charge. Hydrogels with surface charge improved connective tissue adhesion and growth of axons compared to a hydrogel without charge. Biodegradable hydrogels may bridge a lesion followed by complete re-sorption. In a model of acute SCI we implanted hydrogels based on the copolymer of HPMA and etoxyethylmethacrylate (EOMA) degraded from the periphery, which was substituted with new tissue after 1 month, to the center, comprising amorphous residuals of the hydrogel. Delayed hydrogel implantation may improve bridging of spinal cord le-sion. We implanted hydrogels based on HEMA acutely or in a delayed fashion (after 7 days) in spinal cord transection. Delayed implantation re-duced the volume of...
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Astrocytic changes in a mouse model of Alzheimer's disease
Kulijewicz-Nawrot, Magdalena ; Syková, Eva (advisor) ; Rokyta, Richard (referee) ; Zach, Petr (referee)
1. SUMMARY: In this thesis we reported astrocytic atrophy characterized by a reduction in the surface area and volume of GFAP-positive glial cells in the prefrontal cortex of 3xTg-AD mice - an important morphological alteration starting far before any well known histopathological hallmark of AD. This change is present in parallel with homeostatic failure suggested by the decreased expression of GS. Those alterations can have drastic effects on brain connectivity and the biochemistry of the main neurotransmitters within the brain, such as glutamate and GABA. GFAP is implicated in a variety of processes, such as cell migration and proliferation, neurite outgrowth, astrocytic glutamate transporter expression (GLAST and GLT-1) and synaptic plasticity, so that every change can shift the astrocytes' role from physiology to pathology. In the case of affected GFAP-IR astrocytes, the withdrawal of processes from neurons and synapses can lead to a severe transmission crush, due to the uncontrolled spillover of the neurotransmitter from the synaptic cleft, inadequate metabolic support and the lack of a physiological barrier between the affected synapse and other synapses in its close vicinity. This will directly disturb the reciprocal connections between the affected brain regions, inluding the important structures...
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Neurogenic pulmonary edema in rats with spinal cord injury
Šedý, Jiří ; Syková, Eva (advisor) ; Herget, Jan (referee) ; Rokyta, Richard (referee)
N urogenic puhnonary edema (NPE) is an acu te life-threatening complication of the c ntral nervous system (CNS) injury. Anesthetics can either promote or inhibit the NPE development. We examined the role of different concentrations of isoflurane anesthesia (1.5 - 3%) on the developmen t of NPE in rats with balloon compressed spinal cord. The development of NPE was examined in vivo and on histological sections of lung tissue. Neurological recovery in animals anesthetized with 1.5% or 3% isoflurane was monitored using BBB and pian tar tests for 7 weeks post-injury. The grade of the spinal gray and white matter sparing was evaluated using morphornetry. The r le of gradually developed spinal cord lesíon and spínal cord transection in the developmen t of NPE were evaluated also. NPE developed in all animals anesthetized with 1.5-2% isofluran . Almost 42% of animals died due to massive pulmonary bleeding and suffocation; X-ray imaging, pulmonary index and histological sections showed massive NPE. More than 71 % of animals anesthetized with 2.5-3% i oflu rane had no signs of NPE. Blood pressure rose more rapidly in animals from 1.5% group than in 3% group; this hypertensive reaction was caused by the sympathetic hyperactivi ty. Animals from 3% group recovered their motor and sensory func tions more rapidly than...
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název v anglickém jazyce není uveden
Pospíšilová, Eva ; Paleček, Jiří (advisor) ; Kršiak, Miloslav (referee) ; Rokyta, Richard (referee)
Tissue injury leads to increased sensitivity to noxious and innocuous stimuli due to mechanisms of peripheral sensitisation of primary nociceptors and central sensitization of neurons in the spinal dorsal horns. The subpopulation of capsaicin - sensitive sensory neurons plays an important role in this process. The capsaicin - sensitive neurons express capsaicin TRPV1 receptors (transient receptor potential 1) on their peripheral and central terminals, local high concentration capsaicin treatment can induce regional destruction of these endings. It is well estabilished that TRPV1 receptors play the key role in neural transmission of nociceptive information and its modulation. The aims of this study were to investigate the role of capsaicin - sensitive primary afferent fibers and the involvement of peripheral and central TRPV1 receptors in the development of hypersensitivity after surgical tissue trauma, to test the effect of high concentration capsaicin and the specific TRPV1 antagonist treatment on postoperative pain and to enlighten the function of central TRPV1 receptors in the neural mechanisms of nociception. Using behavioral testing methods, the responses to mechanical (Von Frey filaments) and thermal stimuli (radiant heat source) were tested on the rat plantar incision model of surgical pain...
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Changes of the eExtracellular space diffusion parameters during acute pathological states in the rodent brain and the role of AQP4 channels in cell swelling
Dmytrenko, Lesia ; Vargová, Lýdia (advisor) ; Druga, Rastislav (referee) ; Rokyta, Richard (referee)
1. SUMMARY The diffusion properties of the extracellular space (ECS), which govern the movement of neuroactive substances through its volume and thus extrasynaptic transmission, are profoundly affected in states associated with cell swelling. In this work we compared ECS diffusion parameter changes during acute cell swelling in vivo in models of pilocarpine-induced status epilepticus (SE) and ischemia/anoxia evoked by cardiac arrest. To elucidate mechanisms involving the aquaporin 4 (AQP4) water channel in pathological cell swelling, we used models of hypotonic stress and elevated K+ in coronal slices of genetically modified mice. The ECS diffusion parameters volume fraction ( = ECS volume/total tissue volume), tortuosity factor (2 = apparent diffusion coefficient/free diffusion coefficient) and non-specific uptake (k') were determined by the real-time iontophoretic method, which was the primary method used in my thesis work. Changes in the activity-related extracellular K+ concentration ([K+ ]e) were measured using ion-selective microelectrodes. The apparent diffusion coefficient of water (ADCW) was determined by diffusion-weighted MRI. In both models in vivo, ECS volume fraction and ADCW decreased; these changes were more profound and their time course was faster during terminal ischemia/anoxia in...
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