Neurons in anterior cingulate and prefrontal cortex (ACC/PFC) carry information about behaviorally relevant target stimuli. This information is believed to affect behavior by exerting a top-down attentional bias on stimulus selection. However, attention information may not necessarily be a biasing signal but could be a corollary signal that is not directly related to ongoing behavioral success, or it could reflect the monitoring of targets similar to an eligibility trace useful for later attentional adjustment. To test this suggestion we quantified how attention information relates to behavioral success in neurons recorded in multiple subfields in macaque ACC/PFC during a cued attention task. We found that attention cues activated three separable neuronal groups that encoded spatial attention information but were differently linked to behavioral success. A first group encoded attention targets on correct and error trials. This group spread across ACC/PFC and represented targets transiently after cue onset, irrespective of behavior. A second group encoded attention targets on correct trials only, closely predicting behavior. These neurons were not only prevalent in lateral prefrontal but also in anterior cingulate cortex. A third group encoded target locations only on error trials. This group was evident in ACC and PFC and was activated in error trials "as if" attention was shifted to the target location but without evidence for such behavior. These results show that only a portion of neuronaly available information about attention targets biases behavior. We speculate that additionally a unique neural subnetwork encodes counterfactual attention information.

• MeSH
• akční potenciály fyziologie   MeSH
• analýza rozptylu MeSH
• časové faktory MeSH
• cingulární gyrus cytologie   MeSH
• Macaca mulatta MeSH
• neurony klasifikace   fyziologie   MeSH
• podněty MeSH
• pozornost fyziologie   MeSH
• prefrontální mozková kůra cytologie   MeSH
• reakční čas fyziologie   MeSH
• světelná stimulace MeSH
• vnímání prostoru fyziologie   MeSH
• výběrové chování fyziologie   MeSH
• zkreslení výsledků (epidemiologie) MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Visual attention modulates the firing rate of neurons in many primate cortical areas. In V4, a cortical area in the ventral visual pathway, spatial attention has also been shown to reduce the tendency of neurons to fire closely separated spikes (burstiness). A recent model proposes that a single mechanism accounts for both the firing rate enhancement and the burstiness reduction in V4, but this has not been empirically tested. It is also unclear if the burstiness reduction by spatial attention is found in other visual areas and for other attentional types. We therefore recorded from single neurons in the medial superior temporal area (MST), a key motion-processing area along the dorsal visual pathway, of two rhesus monkeys while they performed a task engaging both spatial and feature-based attention. We show that in MST, spatial attention is associated with a clear reduction in burstiness that is independent of the concurrent enhancement of firing rate. In contrast, feature-based attention enhances firing rate but is not associated with a significant reduction in burstiness. These results establish burstiness reduction as a widespread effect of spatial attention. They also suggest that in contrast to the recently proposed model, the effects of spatial attention on burstiness and firing rate emerge from different mechanisms.

• MeSH
• biologické hodiny fyziologie   MeSH
• Macaca mulatta MeSH
• mozkové vlny fyziologie   MeSH
• nervová síť fyziologie   MeSH
• pozornost fyziologie   MeSH
• vnímání prostoru fyziologie   MeSH
• zraková pole fyziologie   MeSH
• zrakové korové centrum fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

AIM: We aimed to characterize the role of mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) overexpression in multiple sclerosis (MS) and to evaluate its use as a biomarker. Materials & methods: We estimated levels of 17β-HSD10, amyloid β 1-42, cyclophilin D, 17β-HSD10-cyclophilin D complexes or 17β-HSD10-parkin complexes in cerebrospinal fluid (CSF) samples. RESULTS: The increase in 17β-HSD10 levels or in 17β-HSD10-parkin complexes and links to leukocytes were found only in relapsing-remitting MS. The sensitivity of the biomarker was 64%, the specificity equaled 60-63% compared with controls. CONCLUSION: Increased CSF levels of 17β-HSD10 in later stages of MS could be interpreted via its upregulation in demyelinated neuronal axons. CSF levels of 17β-HSD10 are not the valuable biomarker for the early diagnosis or for the progression of MS.

• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy MeSH
• amyloidní beta-protein MeSH
• biologické markery MeSH
• dospělí MeSH
• lidé MeSH
• peptidové fragmenty MeSH
• roztroušená skleróza MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIM: We aimed to characterize the role of mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) overexpression in multiple sclerosis (MS) and to evaluate its use as a biomarker. Materials & methods: We estimated levels of 17β-HSD10, amyloid β 1-42, cyclophilin D, 17β-HSD10-cyclophilin D complexes or 17β-HSD10-parkin complexes in cerebrospinal fluid (CSF) samples. RESULTS: The increase in 17β-HSD10 levels or in 17β-HSD10-parkin complexes and links to leukocytes were found only in relapsing-remitting MS. The sensitivity of the biomarker was 64%, the specificity equaled 60-63% compared with controls. CONCLUSION: Increased CSF levels of 17β-HSD10 in later stages of MS could be interpreted via its upregulation in demyelinated neuronal axons. CSF levels of 17β-HSD10 are not the valuable biomarker for the early diagnosis or for the progression of MS.

• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy mozkomíšní mok   MeSH
• amyloidní beta-protein mozkomíšní mok   MeSH
• biologické markery mozkomíšní mok   MeSH
• dospělí MeSH
• lidé MeSH
• peptidové fragmenty mozkomíšní mok   MeSH
• roztroušená skleróza mozkomíšní mok   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Alzheimer's Disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by memory loss, disorientation, and gradual deterioration of intellectual capacity. Its etiology has not been elucidated yet. To date, only one therapeutic approach has been approved for the treatment of AD. The pharmacotherapy of AD has relied on noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist - memantine, and acetylcholinesterase (AChE) inhibitors (AChEIs) - tacrine, donepezil, rivastigmine and galantamine. Donepezil was able to ameliorate the symptoms related to AD mainly via AChE, but also through reduction of β-amyloid burden. This review presents the overview of donepezilrelated compounds as potential anti-AD drugs developed on the basis of cholinergic hypothesis to act as solely AChE and butyrylcholinesterase (BChE) inhibitors.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemie   farmakologie   terapeutické užití   MeSH
• donepezil chemie   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemie   farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by frequent noncancerous neoplasia in the brain, which can induce a range of severe neuropsychiatric symptoms in humans, resulting from out of control tissue growth. The causative spontaneous loss-of-function mutations have been also identified in rats. Herein, we studied histopathological and molecular changes in brain lesions of the Eker rat model carrying germline mutation of the tsc2 gene, predisposed to multiple neoplasias. Predominant subcortical tumors were analyzed, along with a rare form occurring within the pyriform lobe. The uniform composition of lesions supports the histochemical parity of malformations, with immunofluorescence data supporting their neuro-glial origin. Massive depletion of mature neurons and axonal loss were evident within lesions, with occasional necrotic foci implying advanced stage of pathology. Enrichment of mesenchymal-derived cell markers with hallmarks of neurogenesis and active microglia imply enhanced cell proliferation, with local immune response. The depletion of capillaries within the core was complemented by the formation of dense mesh of nascent vessels at the interface of neoplasia with healthy tissue, implying large-scale vascular remodeling. Taken as a whole, these findings present several novel features of brain tumors in Eker rat model, rendering it suitable for studies of the pathobiology and progression of primary brain tumors, with therapeutic interventions.

• MeSH
• astrocyty patologie   MeSH
• axony patologie   MeSH
• mikroglie patologie   MeSH
• mozek krevní zásobení   patologie   MeSH
• nádory mozku krevní zásobení   etiologie   patologie   MeSH
• neurony patologie   MeSH
• potkani Long-Evans MeSH
• remodelace cév * MeSH
• tuberin genetika   MeSH
• tuberózní skleróza komplikace   patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy. METHODS: At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18). RESULTS: Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3). CONCLUSIONS: These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

• MeSH
• autistická porucha * MeSH
• haploinsuficience MeSH
• krysa rodu rattus MeSH
• status epilepticus * MeSH
• TOR serin-threoninkinasy genetika   MeSH
• tuberin genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybridK1383, bearing two methylene tether between two basic scaffolds, was found to be very potenthAChE inhibitor (IC50= 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed onhAChE with the most active compound in the study,K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• aktivace enzymů účinky léků   MeSH
• Alzheimerova nemoc enzymologie   MeSH
• apigenin chemie   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• glukuronáty chemie   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• lidé MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• takrin analogy a deriváty   chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer's disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors-THA and (-)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.

• MeSH
• acetylcholinesterasa MeSH
• aktivace enzymů účinky léků   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• aminochinoliny chemická syntéza   chemie   farmakologie   MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• heterocyklické sloučeniny tetra- a více cyklické chemie   farmakologie   MeSH
• hydrolýza MeSH
• inhibiční koncentrace 50 MeSH
• katalytická doména MeSH
• lidé MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• objevování léků * MeSH
• permeabilita MeSH
• racionální návrh léčiv MeSH
• takrin analogy a deriváty   chemie   farmakologie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH