Minimal Models of Adapted Neuronal Response to In Vivo–Like Input Currents

2004 ◽  
Vol 16 (10) ◽  
pp. 2101-2124 ◽  
Author(s):  
Giancarlo La Camera ◽  
Alexander Rauch ◽  
Hans-R. Lüscher ◽  
Walter Senn ◽  
Stefano Fusi
Keyword(s):  
Pyramidal Neurons ◽  
Neuronal Response ◽  
Large Population ◽  
Time Varying ◽  
Minimal Models ◽  
Stationary Model ◽  
The Central Nervous System ◽  
Mechanisms Of Adaptation ◽  
Reversal Potentials

Rate models are often used to study the behavior of large networks of spiking neurons. Here we propose a procedure to derive rate models that take into account the fluctuations of the input current and firing-rate adaptation, two ubiquitous features in the central nervous system that have been previously overlooked in constructing rate models. The procedure is general and applies to any model of firing unit. As examples, we apply it to the leaky integrate-and-fire (IF) neuron, the leaky IF neuron with reversal potentials, and to the quadratic IF neuron. Two mechanisms of adaptation are considered, one due to an after hyperpolarization current and the other to an adapting threshold for spike emission. The parameters of these simple models can be tuned to match experimental data obtained from neocortical pyramidal neurons. Finally, we show how the stationary model can be used to predict the time-varying activity of a large population of adapting neurons.

scholarly journals Cell Depletion Due to Diphtheria Toxin Fragment A after Cre-Mediated Recombination

2004 ◽  
Vol 24 (17) ◽  
pp. 7636-7642 ◽  
Author(s):  
Damian Brockschnieder ◽  
Corinna Lappe-Siefke ◽  
Sandra Goebbels ◽  
Michael R. Boesl ◽  
Klaus-Armin Nave ◽  
...  
Keyword(s):  
Diphtheria Toxin ◽  
Pyramidal Neurons ◽  
De Novo ◽  
Transgenic Animals ◽  
Cell Loss ◽  
Toxin Gene ◽  
Cell Type ◽  
Conditional Expression ◽  
The Central Nervous System

ABSTRACT Abnormal cell loss is the common cause of a large number of developmental and degenerative diseases. To model such diseases in transgenic animals, we have developed a line of mice that allows the efficient depletion of virtually any cell type in vivo following somatic Cre-mediated gene recombination. By introducing the diphtheria toxin fragment A (DT-A) gene as a conditional expression construct (floxed lacZ-DT-A) into the ubiquitously expressed ROSA26 locus, we produced a line of mice that would permit cell-specific activation of the toxin gene. Following Cre-mediated recombination under the control of cell-type-specific promoters, lacZ gene expression was efficiently replaced by de novo transcription of the Cre-recombined DT-A gene. We provide proof of this principle, initially for cells of the central nervous system (pyramidal neurons and oligodendrocytes), the immune system (B cells), and liver tissue (hepatocytes), that the conditional expression of DT-A is functional in vivo, resulting in the generation of novel degenerative disease models.

scholarly journals Impact of functional synapse clusters on neuronal response selectivity

2019 ◽  
Author(s):  
Balázs B Ujfalussy ◽  
Judit K Makara
Keyword(s):  
Large Scale ◽  
Pyramidal Neurons ◽  
Neuronal Response ◽  
Cluster Formation ◽  
Biophysical Model ◽  
Functional Clustering ◽  
Synaptic Interactions ◽  
Nonlinear Amplification ◽  
Output Transformation

SummaryClustering of functionally similar synapses in dendrites is thought to affect input-output transformation by inducing dendritic nonlinearities. However, neither the in vivo impact of synaptic clusters on somatic membrane potential (sVm), nor the rules of cluster formation are elucidated. We developed a computational approach to measure the effect of functional synaptic clusters on sVm response of biophysical model CA1 and L2/3 pyramidal neurons to behaviorally relevant in vivo-like inputs. Large-scale dendritic spatial inhomogeneities in synaptic tuning properties did influence sVm, but small synaptic clusters appearing randomly with unstructured connectivity did not. With structured connectivity, ~10-20 synapses per cluster was optimal for clustering-based tuning, but larger responses were achieved by 2-fold potentiation of the same synapses. We further show that without nonlinear amplification of the effect of random clusters, action potential-based, global plasticity rules can not generate functional clustering. Our results suggest that clusters likely form via local synaptic interactions, and have to be moderately large to impact sVm responses.

scholarly journals Impact of functional synapse clusters on neuronal response selectivity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Balázs B. Ujfalussy ◽  
Judit K. Makara
Keyword(s):  
Pyramidal Neurons ◽  
Neuronal Response ◽  
Cluster Formation ◽  
Biophysical Model ◽  
Functional Clustering ◽  
State Dependent ◽  
Synaptic Interactions ◽  
Output Transformation ◽  
Random Connectivity

AbstractClustering of functionally similar synapses in dendrites is thought to affect neuronal input-output transformation by triggering local nonlinearities. However, neither the in vivo impact of synaptic clusters on somatic membrane potential (sVm), nor the rules of cluster formation are elucidated. We develop a computational approach to measure the effect of functional synaptic clusters on sVm response of biophysical model CA1 and L2/3 pyramidal neurons to in vivo-like inputs. We demonstrate that small synaptic clusters appearing with random connectivity do not influence sVm. With structured connectivity,  ~10–20 synapses/cluster are optimal for clustering-based tuning via state-dependent mechanisms, but larger selectivity is achieved by 2-fold potentiation of the same synapses. We further show that without nonlinear amplification of the effect of random clusters, action potential-based, global plasticity rules cannot generate functional clustering. Our results suggest that clusters likely form via local synaptic interactions, and have to be moderately large to impact sVm responses.

Novel Phytochemical Constituents and their Potential to Manage Diabetes

2020 ◽  
Vol 26 ◽  
Author(s):  
Shaik Ibrahim Khalivulla ◽  
Arifullah Mohammed ◽  
Kokkanti Mallikarjuna
Keyword(s):  
Natural Products ◽  
Large Population ◽  
World Health ◽  
In Vivo Studies ◽  
Antidiabetic Activity ◽  
Therapeutic Drug ◽  
Pharmacological Activities ◽  
Chemical Structures

Background: Diabetes is a chronic disease affecting a large population worldwide and stands as one of the major global health challenges to be tackled. According to World Health Organization, about 400 million are having diabetes worldwide and it is the seventh leading cause of deaths in 2016. Plant based natural products had been in use from ancient time as ethnomedicine for the treatment of several diseases including diabetes. As a result of that, there are several reports on plant based natural products displaying antidiabetic activity. In the current review, such antidiabetic potential compounds reported from all plant sources along with their chemical structures are collected, presented and discussed. This kind of reports are essential to pool the available information to one source followed by statistical analysis and screening to check the efficacy of all known compounds in a comparative sense. This kind of analysis can give rise to few numbers of potential compounds from hundreds, whom can further be screened through in vitro and in vivo studies, and human trails leading to the drug development. Methods: Phytochemicals along with their potential antidiabetic property were classified according to their basic chemical skeleton. The chemical structures of all the compounds with antidiabetic activities were elucidated in the present review. In addition to this, the distribution and their other remarkable pharmacological activities of each species is also included. Results: The scrutiny of literature led to identification of 44 plants with antidiabetic compounds (70) and other pharmacological activities. For the sake of information, the distribution of each species in the world is given. Many plant derivatives may exert antidiabetic properties by improving or mimicking the insulin production or action. Different classes of compounds including sulfur compounds (1-4), alkaloids (5-11), phenolic compounds (12-17), tannins (18-23), phenylpropanoids (24-27), xanthanoids (28-31), amino acid (32), stilbenoid (33), benzofuran (34), coumarin (35), flavonoids (36-49) and terpenoids (50-70) were found to be active potential compounds for antidiabetic activity. Of the 70 listed compounds, majorly 17 compounds are from triterpenoids, 13 flavonoids and 7 are from alkaloids. Among all the 44 plant species, maximum number (7) of compounds are reported from Lagerstroemia speciosa followed by Momordica charantia (6) and S. oblonga with 5 compounds. Conclusion: This is the first paper to summarize the established chemical structures of phytochemicals that have been successfully screened for antidiabetic potential and their mechanisms of inhibition. The reported compounds could be considered as potential lead molecules for the treatment of type-2 diabetes. Further, molecular and clinical trials are required to select and establish the therapeutic drug candidates.

Neuropharmacological Screening of Chiral and Non-chiral Phthalimide- Containing Compounds in Mice: in vivo and in silico Experiments

2019 ◽  
Vol 15 (1) ◽  
pp. 102-118 ◽  
Author(s):  
Carolina Campos-Rodríguez ◽  
José G. Trujillo-Ferrara ◽  
Ameyali Alvarez-Guerra ◽  
Irán M. Cumbres Vargas ◽  
Roberto I. Cuevas-Hernández ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
In Silico ◽  
Biological Properties ◽  
Chiral Molecules ◽  
Chiral Compounds ◽  
Plus Maze ◽  
In Silico Studies ◽  
The Central Nervous System

Background: Thalidomide, the first synthesized phthalimide, has demonstrated sedative- hypnotic and antiepileptic effects on the central nervous system. N-substituted phthalimides have an interesting chemical structure that confers important biological properties. Objective: Non-chiral (ortho and para bis-isoindoline-1,3-dione, phthaloylglycine) and chiral phthalimides (N-substituted with aspartate or glutamate) were synthesized and the sedative, anxiolytic and anticonvulsant effects were tested. Method: Homology modeling and molecular docking were employed to predict recognition of the analogues by hNMDA and mGlu receptors. The neuropharmacological activity was tested with the open field test and elevated plus maze (EPM). The compounds were tested in mouse models of acute convulsions induced either by pentylenetetrazol (PTZ; 90 mg/kg) or 4-aminopyridine (4-AP; 10 mg/kg). Results: The ortho and para non-chiral compounds at 562.3 and 316 mg/kg, respectively, decreased locomotor activity. Contrarily, the chiral compounds produced excitatory effects. Increased locomotor activity was found with S-TGLU and R-TGLU at 100, 316 and 562.3 mg/kg, and S-TASP at 316 and 562.3 mg/kg. These molecules showed no activity in the EPM test or PTZ model. In the 4-AP model, however, S-TGLU (237.1, 316 and 421.7 mg/kg) as well as S-TASP and R-TASP (316 mg/kg) lowered the convulsive and death rate. Conclusion: The chiral compounds exhibited a non-competitive NMDAR antagonist profile and the non-chiral molecules possessed selective sedative properties. The NMDAR exhibited stereoselectivity for S-TGLU while it is not a preference for the aspartic derivatives. The results appear to be supported by the in silico studies, which evidenced a high affinity of phthalimides for the hNMDAR and mGluR type 1.

scholarly journals Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes

2021 ◽  
Vol 22 (15) ◽  
pp. 7996
Author(s):  
Jordan D. Lewicky ◽  
Nya L. Fraleigh ◽  
Alexandrine L. Martel ◽  
Thi M.-D. Nguyen ◽  
Peter W. Schiller ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Delivery Systems ◽  
Kappa Opioid Receptor ◽  
Antagonist Activity ◽  
Peptide Analogue ◽  
Nanoparticle Delivery ◽  
The Central Nervous System ◽  
Metabolic Degradation ◽  
Distribution Studies

Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3–3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30–40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS.

scholarly journals Plant Species of Sub-Family Valerianaceae—A Review on Its Effect on the Central Nervous System

Plants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 846
Author(s):  
Gitishree Das ◽  
Han-Seung Shin ◽  
Rosa Tundis ◽  
Sandra Gonçalves ◽  
Ourlad Alzeus G. Tantengco ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plant Species ◽  
Current Knowledge ◽  
Biological Properties ◽  
In Vivo Studies ◽  
Food Species ◽  
The Central Nervous System ◽  
Preclinical And Clinical Studies

Valerianaceae, the sub-family of Caprifoliaceae, contains more than 300 species of annual and perennial herbs, worldwide distributed. Several species are used for their biological properties while some are used as food. Species from the genus Valeriana have been used for their antispasmodic, relaxing, and sedative properties, which have been mainly attributed to the presence of valepotriates, borneol derivatives, and isovalerenic acid. Among this genus, the most common and employed species is Valerianaofficinalis. Although valerian has been traditionally used as a mild sedative, research results are still controversial regarding the role of the different active compounds, the herbal preparations, and the dosage used. The present review is designed to summarize and critically describe the current knowledge on the different plant species belonging to Valerianaceae, their phytochemicals, their uses in the treatment of different diseases with particular emphasis on the effects on the central nervous system. The available information on this sub-family was collected from scientific databases up until year 2020. The following electronic databases were used: PubMed, Scopus, Sci Finder, Web of Science, Science Direct, NCBI, and Google Scholar. The search terms used for this review included Valerianaceae, Valeriana, Centranthus, Fedia, Patrinia, Nardostachys, Plectritis, and Valerianella, phytochemical composition, in vivo studies, Central Nervous System, neuroprotective, antidepressant, antinociceptive, anxiolytic, anxiety, preclinical and clinical studies.

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