1,721,073 research outputs found
Silencing synapses: A route to understanding synapse degeneration in chronic neurodegenerative disease
No full textThe degeneration of pre-synaptic boutons in the stratum radiatum of the dorsal hippocampus is one of earliest components of neurodegeneration in several models of murine prion disease. We recently showed that blockade of synaptic transmission by infusion of botulinum neurotoxin A (BoNT/A) into the hippocampus several weeks prior to the onset of degeneration, had no detectable impact on the extent of the synaptic degeneration.1 We elaborate here on the rationale for these experiments and highlight why we believe that this negative result is interesting and important. We also discuss new observations that might provide insights into the molecular events that underlie synapse degeneration.</p
Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology
Full text linkBotulinum neurotoxins are metalloproteases that specifically cleave N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in synaptic terminals, resulting in a potent inhibition of vesicle fusion and transmitter release. The family comprises different serotypes (BoNT/A to BoNT/G). The natural target of these toxins is represented by the neuromuscular junction, where BoNTs block acetylcholine release. In this review, we describe the actions of botulinum toxins after direct delivery to the central nervous system (CNS), where BoNTs block exocytosis of several transmitters, with near-complete silencing of neural networks. The use of clostridial neurotoxins in the CNS has allowed us to investigate specifically the role of synaptic activity in different physiological and pathological processes. The silencing properties of BoNTs can be exploited for therapeutic purposes, for example to counteract pathological hyperactivity and seizures in epileptogenic brain foci, or to investigate the role of activity in degenerative diseases like prion disease. Altogether, clostridial neurotoxins and their derivatives hold promise as powerful tools for both the basic understanding of brain function and the dissection and treatment of activity-dependent pathogenic pathways
Pluripotent Stem Cells for Brain Repair: Protocols and Preclinical Applications in Cortical and Hippocampal Pathologies
Full text linkBrain injuries causing chronic sensory or motor deficit, such as stroke, are among the leading causes of disability worldwide, according to the World Health Organization; furthermore, they carry heavy social and economic burdens due to decreased quality of life and need of assistance. Given the limited effectiveness of rehabilitation, novel therapeutic strategies are required to enhance functional recovery. Since cell-based approaches have emerged as an intriguing and promising strategy to promote brain repair, many efforts have been made to study the functional integration of neurons derived from pluripotent stem cells (PSCs), or fetal neurons, after grafting into the damaged host tissue. PSCs hold great promises for their clinical applications, such as cellular replacement of damaged neural tissues with autologous neurons. They also offer the possibility to create in vitro models to assess the efficacy of drugs and therapies. Notwithstanding these potential applications, PSC-derived transplanted neurons have to match the precise sub-type, positional and functional identity of the lesioned neural tissue. Thus, the requirement of highly specific and efficient differentiation protocols of PSCs in neurons with appropriate neural identity constitutes the main challenge limiting the clinical use of stem cells in the near future. In this Review, we discuss the recent advances in the derivation of telencephalic (cortical and hippocampal) neurons from PSCs, assessing specificity and efficiency of the differentiation protocols, with particular emphasis on the genetic and molecular characterization of PSC-derived neurons. Second, we address the remaining challenges for cellular replacement therapies in cortical brain injuries, focusing on electrophysiological properties, functional integration and therapeutic effects of the transplanted neurons
A comparative morphometric analysis of the optic nerve in two cetacean species, the striped dolphin (Stenella coeruleoalba) and fin whale (Balaenoptera physalus)
No full textA comparative study was made on one Mysticete (the fin whale, Balaenoptera physalus) and one Odontocete species (the striped dolphin, Stenella coeruleoalba) by measuring several morphological characteristics seen in cross sections of the optic nerve. We found that the two cetacean nerves share a number of specializations that distinguish them from the optic nerve of terrestrial mammals. Fiber density is approximately two-fold lower than in land mammals. A corresponding increase in the cross-sectional area occupied by astrocytes is observed. A population of "giant" (up to 15 mum in diameter) optic axons is present in both the B. physalus and the S. coeruleoalba nerve. It is argued that these features probably reflect common adaptations to the constraints imposed by the aquatic environment. "Giant" optic axons might ensure short-latency detection of preys and other targets during navigation while the increased astroglial content might be related to the maintenance of neuronal function during periods of anaerobic metabolism under water
Synaptic Vesicles Dynamics in Neocortical Epilepsy
Full text linkNeuronal hyperexcitability often results from an unbalance between excitatory and inhibitory neurotransmission, but the synaptic alterations leading to enhanced seizure propensity are only partly understood. Taking advantage of a mouse model of neocortical epilepsy, we used a combination of photoconversion and electron microscopy to assess changes in synaptic vesicles pools in vivo. Our analyses reveal that epileptic networks show an early onset lengthening of active zones at inhibitory synapses, together with a delayed spatial reorganization of recycled vesicles at excitatory synapses. Proteomics of synaptic content indicate that specific proteins were increased in epileptic mice. Altogether, our data reveal a complex landscape of nanoscale changes affecting the epileptic synaptic release machinery. In particular, our findings show that an altered positioning of release-competent vesicles represent a novel signature of epileptic networks
Long term intake of barley beta-D-glucan attenuates glucose intolerance, mood disorders and cognitive decline in high-fat diet-induced obese mice exposed to chronic psychosocial stress
No full textHigh-fat diet (HFD)-induced obesity causes insulin resistance and increases vulnerability to chronic psychosocial stress-induced dysfunctions, including anxiety and mood disorders, cognitive decline and myocardial ischemia. The inhibition of class I histone deacetylases leads to metabolic homeostasis and dietary barley (1.3) beta-D-glucan (β-D-glucan), a water-soluble polysaccharide, increases levels of histone H4 acetylation. We tested whether the long-term intake of β-D-glucan prevents glucose intolerance, affective disorders and cognitive decline in stressed obese mice. 24 male mice C57BL/6 were fed three different diets for 18 wks: 1) standard diet (SD; 10% Kcal from fat; n=8), 2) HFD (58% Kcal from fat; n=8) or 3) HFD supplemented with 3% w/v β-D-glucan (HFD+BG; 58% Kcal from fat; n=8). From the 16th to the 18th wk all animals underwent to the resident-intruder stress test. Before and after chronic stress, the anxiety-related behaviour and the spatial working memory were evaluated by elevated plus-maze (PM; entries in open arms, %) and Y-maze test (YM; spontaneous alternation, %). At the end of the experiment, plasma brain derived neurotrophic factor (BDNF) and the hippocampal expression of tropomyosin-related kinase B (TrKB, the BDNF receptor) were evaluated because of their key role in energy balance and in the pathogenesis of affective and cognitive disorders. At the 16th wk, HFD’s body weight was increased compared to SD group (+36.6%, p<0.01), but the β-D-glucan supplementation prevented the HFD-induced weight gain. The glucose tolerance test area under the curve (AUC; 0–120 min) was higher in HFD than SD mice fasted (447.7 ± 55 vs 259.1 ± 23.4 mg/dL*min: p<0.001); although, it was lower (−25.8%, p<0.01) in the HFD+BG compared to HFD group. Compared to SD group, open arm activity at the16th week was lower in the HFD (−250%, p<0.001) than in the HFD+BG group (−55.5% p<0.05). After stress, the entries in open arms were absent in HFD mice and were further reduced (−75%, p<0.01) in SD animals, yet the open arm activity was unchanged in HFD+BG group. Spatial working memory after 16 wks. was similar in all groups, but after stress it was reduced only in HFD mice (−18.9%, p<0.01). Compared to SD, reduction of BDNF plasma levels was detected in HFD mice, but not in HFD+BG group (SD, 66 ± 22 pg/ml; HFD, 27 ± 11 pg/ml; HFD+BG, 78 ± 32 pg/ml, p<0.05). The hippocampal expression of TrKB in HFD+BG group was significantly higher than HFD mice (HFD+BG, 0.63 ± 0.13 a.u.; SD, 0.5± 0.1 a.u.; HFD, 0.44 ± 0.05 a.u., p<0.05). In conclusion, β-D-glucan intake attenuates glucose intolerance and improves the stress-induced response in obese mice through the upregulation of hippocampal BDNF/TrkB pathway. Our data provide a basis for developing a new nutraceutical approach for the protection against obesity/stress-related disorders
Thalamic inputs determine functionally distinct gamma bands in mouse primary visual cortex
No full textA triheptanoin-supplemented diet rescues hippocampal hyperexcitability and seizure susceptibility in FoxG1+/- mice
Full text linkThe Forkhead Box G1 (FOXG1) gene encodes a transcription factor with an essential role in the mammalian telencephalon development. FOXG1-related disorders, caused by deletions, intragenic mutations or duplications, are usually associated with severe intellectual disability, autistic features, and, in 87% of subjects, epileptiform manifestations. In at least a subset of the patients with FoxG1 mutations, seizures remain intractable, prompting the need for novel therapeutic options. To address this issue, we took advantage of a haploinsufficient animal model, the FoxG1+/- mouse. In vivo electrophysiological analyses of FoxG1+/- mice detected hippocampal hyperexcitability, which turned into overt seizures upon delivery of the proconvulsant kainic acid, as confirmed by behavioral observations. These alterations were associated with decreased expression of the chloride transporter KCC2. Next, we tested whether a triheptanoin-based anaplerotic diet could have an impact on the pathological phenotype of FoxG1+/- mice. This manipulation abated altered neural activity and normalized the enhanced susceptibility to proconvulsant-induced seizures, in addition to rescuing the altered expression of KCC2 and increasing the levels of the GABA transporter vGAT. In conclusion, our data show that FoxG1 haploinsufficiency causes dysfunction of hippocampal circuits and increases the susceptibility to a proconvulsant insult, and that these alterations are rescued by triheptanoin dietary treatment
Dispositivo automatizzato per la riabilitazione motoria e per la valutazione della funzionalità degli arti anteriori in modelli animali
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