Alzheimer's disease (AD), a leading cause of dementia worldwide, is a multifactorial neurodegenerative disorder characterized by amyloid-beta plaques, tauopathy, neuronal loss, neuro-inflammation, brain atrophy, and cognitive deficits. AD manifests as familial early-onset (FAD) with specific gene mutations or sporadic late-onset (LOAD) caused by various genetic and environmental factors. Numerous transgenic rodent models have been developed to understand AD pathology development and progression. The TgF344-AD rat model is a double transgenic model that carries two human gene mutations: APP with the Swedish mutation and PSEN-1 with delta exon 9 mutations. This model exhibits a complete repertoire of AD pathology in an age-dependent manner. This review summarizes multidisciplinary research insights gained from studying TgF344-AD rats in the context of AD pathology. We explore neuropathological findings; electrophysiological assessments revealing disrupted synaptic transmission, reduced spatial coding, network-level dysfunctions, and altered sleep architecture; behavioral studies highlighting impaired spatial memory; alterations in excitatory-inhibitory systems; and molecular and physiological changes in TgF344-AD rats emphasizing their age-related effects. Additionally, the impact of various interventions studied in the model is compiled, underscoring their role in bridging gaps in understanding AD pathogenesis. The TgF344-AD rat model offers significant potential in identifying biomarkers for early detection and therapeutic interventions, providing a robust platform for advancing translational AD research. Key words Alzheimer's disease, Transgenic AD models, TgF344-AD rats, Spatial coding.

• MeSH
• Alzheimerova nemoc * genetika   patologie   metabolismus   MeSH
• amyloidový prekurzorový protein beta genetika   metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• mozek patologie   metabolismus   MeSH
• potkani inbrední F344 MeSH
• potkani transgenní * MeSH
• presenilin-1 genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Magnetic resonance spectroscopic imaging (MRSI) enables the simultaneous noninvasive acquisition of MR spectra from multiple spatial locations inside the brain. Although 1H-MRSI is increasingly used in the human brain, it is not yet widely applied in the preclinical setting, mostly because of difficulties specifically related to very small nominal voxel size in the rat brain and low concentration of brain metabolites, resulting in low signal-to-noise ratio (SNR). In this context, we implemented a free induction decay 1H-MRSI sequence (1H-FID-MRSI) in the rat brain at 14.1 T. We combined the advantages of 1H-FID-MRSI with the ultra-high magnetic field to achieve higher SNR, coverage, and spatial resolution in the rat brain and developed a custom dedicated processing pipeline with a graphical user interface for Bruker 1H-FID-MRSI: MRS4Brain toolbox. LCModel fit, using the simulated metabolite basis set and in vivo measured MM, provided reliable fits for the data at acquisition delays of 1.30 ms. The resulting Cramér-Rao lower bounds were sufficiently low (< 30%) for eight metabolites of interest (total creatine, N-acetylaspartate, N-acetylaspartate + N-acetylaspartylglutamate, total choline, glutamine, glutamate, myo-inositol, and taurine), leading to highly reproducible metabolic maps. Similar spectral quality and metabolic maps were obtained with one and two averages, with slightly better contrast and brain coverage due to increased SNR in the latter case. Furthermore, the obtained metabolic maps were accurate enough to confirm the previously known brain regional distribution of some metabolites. The acquisitions proved high reproducibility over time. We demonstrated that the increased SNR and spectral resolution at 14.1 T can be translated into high spatial resolution in 1H-FID-MRSI of the rat brain in 13 min using the sequence and processing pipeline described herein. High-resolution 1H-FID-MRSI at 14.1 T provided robust, reproducible, and high-quality metabolic mapping of brain metabolites with minimal technical limitations.

• MeSH
• krysa rodu rattus MeSH
• magnetická rezonanční tomografie metody   MeSH
• metabolom MeSH
• mozek * metabolismus   diagnostické zobrazování   MeSH
• poměr signál - šum MeSH
• potkani Sprague-Dawley MeSH
• potkani Wistar MeSH
• protonová magnetická rezonanční spektroskopie metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of ubiquitin-protein ligase E3A (UBE3A), resulting in marked changes in synaptic plasticity. In AS mice, a dysregulation of Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) was previously described. This has been convincingly validated through genetic rescue of prominent phenotypes in mouse cross-breeding experiments. Selective ligands that specifically stabilize the CaMKIIα central association (hub) domain and affect different conformational states in vitro are now available. Two of these ligands, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and (E)-2-(5-hydroxy-2-phenyl-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (Ph-HTBA), confer neuroprotection after ischemic stroke in mice where CaMKIIα is known to be dysregulated. Here, we sought to investigate whether pharmacological modulation with these prototypical CaMKIIα hub ligands presents a viable approach to alleviate AS symptoms. We performed an in vivo functional evaluation of AS mice treated for a total of 14 days with either HOCPCA or Ph-HTBA (7 days pre-treatment and 7 days of behavioural assessment). Both compounds were well-tolerated but unable to revert robust phenotypes of motor performance, anxiety, repetitive behaviour or seizures in AS mice. Biochemical experiments subsequently assessed CaMKIIα autophosphorylation in AS mouse brain tissue. Taken together our results indicate that pharmacological modulation of CaMKIIα via the selective hub ligands used here is not a viable treatment strategy in AS.

• MeSH
• Angelmanův syndrom * farmakoterapie   genetika   MeSH
• chování zvířat účinky léků   MeSH
• fenotyp * MeSH
• ligandy MeSH
• modely nemocí na zvířatech * MeSH
• mozek účinky léků   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neuroprotektivní látky farmakologie   MeSH
• proteinkinasa závislá na vápníku a kalmodulinu typ 2 * metabolismus   MeSH
• ubikvitinligasy metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Major depressive disorder (MDD) is a mental illness with a high worldwide prevalence and suboptimal pharmacological treatment, which necessitates the development of novel, more efficacious MDD medication. Nuclear magnetic resonance (NMR) can non-invasively provide insight into the neurochemical state of the brain using proton magnetic resonance spectroscopy (1H MRS), and an assessment of regional cerebral blood flow (rCBF) by perfusion imaging. These methods may provide valuable in vivo markers of the pathological processes underlying MDD. METHODS: This study examined the effects of the chronic antidepressant medication, citalopram, in a well-validated MDD model induced by bilateral olfactory bulbectomy (OB) in rats. 1H MRS was utilized to assess key metabolite ratios in the dorsal hippocampus and sensorimotor cortex bilaterally, and arterial spin labelling was employed to estimate rCBF in several additional brain regions. RESULTS: The 1H MRS data results suggest lower hippocampal Cho/tCr and lower cortical NAA/tCr levels as a characteristic of the OB phenotype. Spectroscopy revealed lower hippocampal Tau/tCr in citalopram-treated rats, indicating a potentially deleterious effect of the drug. However, the significant OB model-citalopram treatment interaction was observed using 1H MRS in hippocampal mI/tCr, Glx/tCr and Gln/tCr, indicating differential treatment effects in the OB and control groups. The perfusion data revealed higher rCBF in the whole brain, hippocampus and thalamus in the OB rats, while citalopram appeared to normalise it without affecting the control group. CONCLUSION: Collectively, 1H MRS and rCBF approaches demonstrated their capacity to capture an OB-induced phenotype and chronic antidepressant treatment effect in multiple brain regions.

• MeSH
• bulbus olfactorius metabolismus   chirurgie   účinky léků   MeSH
• citalopram * farmakologie   MeSH
• deprese farmakoterapie   metabolismus   MeSH
• depresivní porucha unipolární farmakoterapie   metabolismus   MeSH
• hipokampus metabolismus   účinky léků   MeSH
• krysa rodu rattus MeSH
• magnetická rezonanční spektroskopie metody   MeSH
• modely nemocí na zvířatech * MeSH
• mozek * metabolismus   účinky léků   MeSH
• mozkový krevní oběh * účinky léků   MeSH
• potkani Sprague-Dawley MeSH
• protonová magnetická rezonanční spektroskopie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

AIMS: Endoplasmic reticulum stress followed by the unfolded protein response is one of the cellular mechanisms contributing to the progression of α-synuclein pathology in Parkinson's disease and other Lewy body diseases. We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with α-synuclein pathology in human post-mortem brain tissue. METHODS: We analysed brain tissue from 45 subjects-14 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response-related proteins (Grp78, eIF2α) and endoplasmic reticulum stress-regulating neurotrophic factors (MANF, CDNF). RESULTS: We showed that regional levels of two endoplasmic reticulum-localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating α-synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2α was upregulated in the striatum of Lewy body disease patients and correlated with increased α-synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble α-synuclein levels. CONCLUSIONS: Our data suggest a strong but regionally specific change in Grp78 and eIF2α levels, which positively correlates with soluble α-synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble α-synuclein concentration and disease progression.

• MeSH
• alfa-synuklein * metabolismus   MeSH
• biologické markery metabolismus   MeSH
• chaperon endoplazmatického retikula BiP * metabolismus   MeSH
• demence s Lewyho tělísky * patologie   metabolismus   MeSH
• eukaryotický iniciační faktor 2 * metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozek metabolismus   patologie   MeSH
• neurotrofní faktory metabolismus   MeSH
• proteiny teplotního šoku * metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální dráha UPR * fyziologie   MeSH
• stres endoplazmatického retikula fyziologie   MeSH
• upregulace * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Glial cells expressing neuron-glial antigen 2 (NG2), also known as oligodendrocyte progenitor cells (OPCs), play a critical role in maintaining brain health. However, their ability to differentiate after ischemic injury is poorly understood. The aim of this study was to investigate the properties and functions of NG2 glia in the ischemic brain. Using transgenic mice, we selectively labeled NG2-expressing cells and their progeny in both healthy brain and after focal cerebral ischemia (FCI). Using single-cell RNA sequencing, we classified the labeled glial cells into five distinct subpopulations based on their gene expression patterns. Additionally, we examined the membrane properties of these cells using the patch-clamp technique. Of the identified subpopulations, three were identified as OPCs, whereas the fourth subpopulation had characteristics indicative of cells likely to develop into oligodendrocytes. The fifth subpopulation of NG2 glia showed astrocytic markers and had similarities to neural progenitor cells. Interestingly, this subpopulation was present in both healthy and post-ischemic tissue; however, its gene expression profile changed after ischemia, with increased numbers of genes related to neurogenesis. Immunohistochemical analysis confirmed the temporal expression of neurogenic genes and showed an increased presence of NG2 cells positive for Purkinje cell protein-4 at the periphery of the ischemic lesion 12 days after FCI, as well as NeuN-positive NG2 cells 28 and 60 days after injury. These results suggest the potential development of neuron-like cells arising from NG2 glia in the ischemic tissue. Our study provides insights into the plasticity of NG2 glia and their capacity for neurogenesis after stroke.

• MeSH
• antigeny metabolismus   MeSH
• astrocyty metabolismus   MeSH
• ischemie mozku * metabolismus   MeSH
• mozek metabolismus   MeSH
• myši transgenní MeSH
• myši MeSH
• nervové kmenové buňky * metabolismus   MeSH
• neuroglie metabolismus   MeSH
• oligodendroglie metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Neonatal hypoxic-ischemic (HI) brain insult is a major cause of neonatal mortality and morbidity. To assess the underlying pathological mechanisms, we mapped the spatiotemporal changes in polyamine, amino acid, and neurotransmitter levels, following HI insult (by the Rice-Vannucci method) in the brains of seven-day-old rat pups. Matrix-assisted laser desorption/ionization mass spectrometry imaging of chemically modified small-molecule metabolites by 4-(anthracen-9-yl)-2-fluoro-1-methylpyridin-1-ium iodide revealed critical HI-related metabolomic changes of 22 metabolites in 14 rat brain subregions, much earlier than light microscopy detected signs of neuronal damage. For the first time, we demonstrated excessive polyamine oxidation and accumulation of 3-aminopropanal in HI neonatal brains, which was later accompanied by neuronal apoptosis enhanced by increases in glycine and norepinephrine in critically affected brain regions. Specifically, putrescine, cadaverine, and 3-aminopropanal increased significantly as early as 12 h postinsult, mainly in motor and somatosensory cortex, hippocampus, and midbrain, followed by an increase in norepinephrine 24 h postinsult, which was predominant in the caudate putamen, the region most vulnerable to HI. The decrease of γ-aminobutyric acid (GABA) and the continuous dysregulation of the GABAergic system together with low taurine levels up to 36 h sustained progressive neurodegenerative cellular processes. The molecular alterations presented here at the subregional rat brain level provided unprecedented insight into early metabolomic changes in HI-insulted neonatal brains, which may further aid in the identification of novel therapeutic targets for the treatment of neonatal HI encephalopathy.

• MeSH
• krysa rodu rattus MeSH
• metabolomika MeSH
• mozek * metabolismus   MeSH
• mozková hypoxie a ischemie * metabolismus   patologie   MeSH
• neurony metabolismus   MeSH
• neurotransmiterové látky * metabolismus   MeSH
• novorozená zvířata * MeSH
• polyaminy * metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Tick-borne encephalitis virus (TBEV) targets the central nervous system (CNS), leading to potentially severe neurological complications. The neurovascular unit plays a fundamental role in the CNS and in the neuroinvasion of TBEV. However, the role of human brain pericytes, a key component of the neurovascular unit, during TBEV infection has not yet been elucidated. In this study, TBEV infection of the primary human brain perivascular pericytes was investigated with highly virulent Hypr strain and mildly virulent Neudoerfl strain. We used Luminex assay to measure cytokines/chemokines and growth factors. Both viral strains showed comparable replication kinetics, peaking at 3 days post infection (dpi). Intracellular viral RNA copies peaked at 6 dpi for Hypr and 3 dpi for Neudoerfl cultures. According to immunofluorescence staining, only small proportion of pericytes were infected (3% for Hypr and 2% for Neudoerfl), and no cytopathic effect was observed in the infected cells. In cell culture supernatants, IL-6 production was detected at 3 dpi, together with slight increases in IL-15 and IL-4, but IP-10, RANTES and MCP-1 were the main chemokines released after TBEV infection. These chemokines play key roles in both immune defense and immunopathology during TBE. This study suggests that pericytes are an important source of these signaling molecules during TBEV infection in the brain.

• MeSH
• chemokin CCL5 * metabolismus   MeSH
• chemokin CXCL10 * metabolismus   MeSH
• cytokiny metabolismus   MeSH
• klíšťová encefalitida * virologie   metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mozek * virologie   metabolismus   patologie   MeSH
• pericyty * virologie   metabolismus   MeSH
• replikace viru MeSH
• viry klíšťové encefalitidy * fyziologie   patogenita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

One element, potassium, can be identified as the connecting link in the research of Czech neurophysiologist Prof. František Vyskočil. It accompanied him from the first student experiments on the frog muscle (Solandt effect) via sodium-potassium pump and quantum and non-quantum release of neurotransmitters (e.g. acetylcholine) to the most appreciated work on the reversible leakage of K+ from brain neurons during the Leao ́s spreading cortical depression, often preceding migraine. He used a wide range of methods at the systemic, cellular and genetic levels. The electrophysiology and biochemistry of nerve-muscle contacts and synapses in the muscles and brain led to a range of interesting findings and discoveries on normal, denervated and hibernating laboratory mammals and in tissue cultures. Among others, he co-discovered the facilitating effects of catecholamines (adrenaline in particular) by end-plate synchronization of individual evoked quanta. This helps to understand the general effectiveness of nerve-muscle performance during actual stress. After the transition of the Czech Republic to capitalism, together with Dr. Josef Zicha from our Institute, he was an avid promoter of scientometry as an objective system of estimating a scientist ́s success in basic research (journal Vesmír, 69: 644-645, 1990 in Czech).

• MeSH
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• lidé MeSH
• mozek * fyziologie   metabolismus   MeSH
• neurony * metabolismus   fyziologie   MeSH
• neurovědy * MeSH
• žáby MeSH
• zvířata MeSH
• Check Tag
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• historické články MeSH
• přehledy MeSH

Auditory processing in mammals begins in the peripheral inner ear and extends to the auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay auditory information via the primary auditory neurons to cochlear nuclei. Information is subsequently processed in the superior olivary complex, lateral lemniscus, and inferior colliculus and projects to the auditory cortex via the medial geniculate body in the thalamus. Recent advances have provided valuable insights into the development and functioning of auditory structures, complementing our understanding of the physiological mechanisms underlying auditory processing. This comprehensive review explores the genetic mechanisms required for auditory system development from the peripheral cochlea to the auditory cortex. We highlight transcription factors and other genes with key recurring and interacting roles in guiding auditory system development and organization. Understanding these gene regulatory networks holds promise for developing novel therapeutic strategies for hearing disorders, benefiting millions globally.

• MeSH
• lidé MeSH
• mozek metabolismus   růst a vývoj   MeSH
• sluch * fyziologie   MeSH
• sluchová dráha * fyziologie   MeSH
• sluchové korové centrum metabolismus   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH