scholarly journals Inferring and validating mechanistic models of neural microcircuits based on spike-train data

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Josef Ladenbauer ◽  
Sam McKenzie ◽  
Daniel Fine English ◽  
Olivier Hagens ◽  
Srdjan Ostojic
Keyword(s):  
Parameter Estimation ◽  
Spike Train ◽  
Synthetic Data ◽  
Ground Truth ◽  
Neuronal Population ◽  
Mechanistic Models ◽  
Population Activity ◽  
Comprehensive Evaluations

Abstract The interpretation of neuronal spike train recordings often relies on abstract statistical models that allow for principled parameter estimation and model selection but provide only limited insights into underlying microcircuits. In contrast, mechanistic models are useful to interpret microcircuit dynamics, but are rarely quantitatively matched to experimental data due to methodological challenges. Here we present analytical methods to efficiently fit spiking circuit models to single-trial spike trains. Using derived likelihood functions, we statistically infer the mean and variance of hidden inputs, neuronal adaptation properties and connectivity for coupled integrate-and-fire neurons. Comprehensive evaluations on synthetic data, validations using ground truth in-vitro and in-vivo recordings, and comparisons with existing techniques demonstrate that parameter estimation is very accurate and efficient, even for highly subsampled networks. Our methods bridge statistical, data-driven and theoretical, model-based neurosciences at the level of spiking circuits, for the purpose of a quantitative, mechanistic interpretation of recorded neuronal population activity.

scholarly journals Inferring and validating mechanistic models of neural microcircuits based on spike-train data

2018 ◽  
Author(s):  
Josef Ladenbauer ◽  
Sam McKenzie ◽  
Daniel Fine English ◽  
Olivier Hagens ◽  
Srdjan Ostojic
Keyword(s):  
Parameter Estimation ◽  
Spike Train ◽  
Synthetic Data ◽  
Ground Truth ◽  
Neuronal Population ◽  
Mechanistic Models ◽  
Population Activity ◽  
Comprehensive Evaluations

AbstractThe interpretation of neuronal spike train recordings often relies on abstract statistical models that allow for principled parameter estimation and model selection but provide only limited insights into underlying microcircuits. In contrast, mechanistic models are useful to interpret microcircuit dynamics, but are rarely quantitatively matched to experimental data due to methodological challenges. Here we present analytical methods to efficiently fit spiking circuit models to single-trial spike trains. Using derived likelihood functions, we statistically infer the mean and variance of hidden inputs, neuronal adaptation properties and connectivity for coupled integrate-and-fire neurons. Comprehensive evaluations on synthetic data, validations using ground truth in-vitro and in-vivo recordings, and comparisons with existing techniques demonstrate that parameter estimation is very accurate and efficient, even for highly subsampled networks. Our methods bridge statistical, data-driven and theoretical, model-based neurosciences at the level of spiking circuits, for the purpose of a quantitative, mechanistic interpretation of recorded neuronal population activity.

scholarly journals Neurokinin B regulates reproduction via inhibition of kisspeptin in a teleost, the striped bass

2017 ◽  
Vol 233 (2) ◽  
pp. 159-174 ◽  
Author(s):  
Nilli Zmora ◽  
Ten-Tsao Wong ◽  
John Stubblefield ◽  
Berta Levavi-Sivan ◽  
Yonathan Zohar
Keyword(s):  
Striped Bass ◽  
Brain Slices ◽  
Neuronal Population ◽  
Minor Effect ◽  
Pituitary Cells ◽  
Neurokinin B ◽  
A Minor ◽  
Lh Secretion

Kisspeptin and neurokinin B (NKB) are neuropeptides co-expressed in the mammalian hypothalamus and coordinately control GnRH signaling. We have found that Nkb and kisspeptin neurons are distinct in the teleost, striped bass (STB) and capitalized on this phenomenon to study the mode of action of Nkb and its related neuropeptide-F (Nkf), both of which are encoded by the tac3 gene. In vitro brain slices and in vivo administration studies revealed that Nkb/f consistently downregulated kiss2, whereas antagonist (AntD) administration restored this effect. Overall, a minor effect was noted on gnrh1 expression, whereas Gnrh1 content in the pituitaries was reduced after Nkb/f treatment and increased with AntD. Concomitantly, immunostaining demonstrated that hypothalamic Nkb neurons border and densely innervate the largest kiss2 neuronal population in the hypothalamus, which also coexpresses Nkb receptor. No expression of Nkb receptor or Nkb neuronal projections was detected near/in Gnrh1 soma in the preoptic area. At the level of the pituitary, however, the picture was more complex: both Nkb/f and AntD upregulated lhb and fshb expression and Lh secretion in vivo. Together with the stimulatory effect of Nkb/f on Lh/Fsh secretion from pituitary cells, in vitro, this may indicate an additional independent action of Nkb/f within the pituitary, in which the hypothalamic pathway is more dominant. The current study demonstrates that Nkb/f utilizes multiple pathways to regulate reproduction in the STB and that in the brain, Nkb mainly acts as a negative modulator of kiss2 to regulate the release of Gnrh1.

scholarly journals Minireview: Recent Progress in Gonadotropin-Releasing Hormone Neuronal Migration

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1159-1165 ◽  
Author(s):  
Stuart A. Tobet ◽  
Gerald A. Schwarting
Keyword(s):  
Basal Forebrain ◽  
Direct Evidence ◽  
Neuronal Population ◽  
External Factors ◽  
Reproductive Axis ◽  
Gnrh Neurons ◽  
Molecular Phenotypes ◽  
The Brain

Neurons that synthesize GnRH are critical brain regulators of the reproductive axis, yet they originate outside the brain and must migrate over long distances and varied environments to get to their appropriate positions during development. Many studies, past and present, are providing clues for the types of molecules encountered and movements expected along the migratory route. Recent studies provide real-time views of the behavior of GnRH neurons in the context of in vitro preparations that model those in vivo. Live images provide direct evidence of the changing behavior of GnRH neurons in their different environments, showing that GnRH neurons move with greater frequency and with more alterations in direction after they enter the brain. The heterogeneity of molecular phenotypes for GnRH neurons likely ensures that multiple external factors will be found that regulate the migration of different portions of the GnRH neuronal population at different steps along the route. Molecules distributed in gradients both in the peripheral olfactory system and basal forebrain may be particularly influential in directing the appropriate movement of GnRH neurons along their arduous migration. Molecules that mediate the adhesion of GnRH neurons to changing surfaces may also play critical roles. It is likely that the multiple external factors converge on selective signal transduction pathways to engage the mechanical mechanisms needed to modulate GnRH neuronal movement and ultimately migration.

scholarly journals Functional and structural properties of highly responsive somatosensory neurons in mouse barrel cortex

2019 ◽  
Author(s):  
C Barz ◽  
PM Garderes ◽  
D Ganea ◽  
S Reischauer ◽  
D Feldmeyer ◽  
...  
Keyword(s):  
Barrel Cortex ◽  
Fluorescent Protein ◽  
Network Connectivity ◽  
Vibrotactile Stimulation ◽  
Population Activity ◽  
Highly Active ◽  
Structural And Functional Properties ◽  
High Responders

SummarySparse population activity is a hallmark of supra-granular sensory neurons in neocortex. The mechanisms underlying sparseness are not well understood because a direct link between the neurons activated in vivo and their cellular properties investigated in vitro has been missing. We used two-photon calcium imaging to identify a subset of neurons in layer L2/3 (L2/3) of mouse primary somatosensory cortex that are highly active following principal whisker vibrotactile stimulation. These high responders were then tagged using photoconvertible green fluorescent protein for subsequent targeting in the brain slice using intracellular patch-clamp recordings and biocytin staining. This approach allowed us to investigate the structural and functional properties of high responders that distinguish them from less active control cells. Compared to less responsive L2/3 neurons, high responders displayed increased levels of stimulus-evoked and spontaneous activity, elevated noise and spontaneous pair-wise correlations, and stronger coupling to the population response. Intrinsic excitability was reduced in high responders, while other electrophysiological and morphological parameters were unchanged. Thus, the choice of which neurons participate in stimulus encoding may largely be determined by network connectivity rather than by cellular structure and function.

scholarly journals PTMProphet: Fast and Accurate Mass Modification Localization for the Trans-Proteomic Pipeline

2019 ◽  
Author(s):  
David D Shteynberg ◽  
Eric W Deutsch ◽  
David S Campbell ◽  
Michael R Hoopmann ◽  
Ulrike Kusebauch ◽  
...  
Keyword(s):  
Cell Biology ◽  
Software Tool ◽  
Ground Truth ◽  
Peptide Sequence ◽  
Bayesian Mixture ◽  
Downstream Analysis ◽  
Bayesian Mixture Models ◽  
Sequence Database Search

Spectral matching sequence database search engines commonly used on mass spectrometry-based proteomics experiments excel at identifying peptide sequence ions, and in addition, possible sequence ions carrying post-translational modifications (PTMs), but most do not provide confidence metrics for the exact localization of those PTMs when several possible sites are available. Localization is absolutely required for downstream molecular cell biology analysis of PTM function in vitro and in vivo. Therefore, we developed PTMProphet, a free and open-source software tool integrated into the Trans-Proteomic Pipeline, which reanalyzes identified spectra from any search engine for which pepXML output is available to provide localization confidence to enable appropriate further characterization of biologic events. Localization of any type of mass modification (e.g., phosphorylation) is supported. PTMProphet applies Bayesian mixture models to compute probabilities for each site/peptide spectrum match where a PTM has been identified. These probabilities can be combined to compute a global false localization rate at any threshold to guide downstream analysis. We describe the PTMProphet tool, its underlying algorithms and demonstrate its performance on ground-truth synthetic peptide reference datasets, one previously published small dataset, one new larger dataset, and also on a previously published phospho-enriched dataset where the correct sites of modification are unknown. Data have been deposited to ProteomeXchange with identifier PXD013210.

scholarly journals Ventral pallidal GABAergic neurons control wakefulness associated with motivation through the ventral tegmental pathway

2020 ◽  
Author(s):  
Ya-Dong Li ◽  
Yan-Jia Luo ◽  
Wei Xu ◽  
Jing Ge ◽  
Yoan Cherasse ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Gabaergic Neurons ◽  
Population Activity ◽  
Lateral Habenula ◽  
Optogenetic Stimulation ◽  
Ventral Tegmental ◽  
Stimulation Of

Abstract The ventral pallidum (VP) regulates motivation, drug addiction, and several behaviors that rely on heightened arousal. However, the role and underlying neural circuits of the VP in the control of wakefulness remain poorly understood. In the present study, we sought to elucidate the specific role of VP GABAergic neurons in controlling sleep–wake behaviors in mice. Fiber photometry revealed that the population activity of VP GABAergic neurons was increased during physiological transitions from non-rapid eye movement (non-REM, NREM) sleep to either wakefulness or REM sleep. Moreover, chemogenetic and optogenetic manipulations were leveraged to investigate a potential causal role of VP GABAergic neurons in initiating and/or maintaining arousal. In vivo optogenetic stimulation of VP GABAergic neurons innervating the ventral tegmental area (VTA) strongly promoted arousal via disinhibition of VTA dopaminergic neurons. Functional in vitro mapping revealed that VP GABAergic neurons, in principle, inhibited VTA GABAergic neurons but also inhibited VTA dopaminergic neurons. In addition, optogenetic stimulation of terminals of VP GABAergic neurons revealed that they promoted arousal by innervating the lateral hypothalamus, but not the mediodorsal thalamus or lateral habenula. The increased wakefulness chemogenetically evoked by VP GABAergic neuronal activation was completely abolished by pretreatment with dopaminergic D1 and D2/D3 receptor antagonists. Furthermore, activation of VP GABAergic neurons increased exploration time in both the open-field and light–dark box tests but did not modulate depression-like behaviors or food intake. Finally, chemogenetic inhibition of VP GABAergic neurons decreased arousal. Taken together, our findings indicate that VP GABAergic neurons are essential for arousal related to motivation.

scholarly journals Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

2016 ◽  
Vol 18 (5) ◽  
pp. 1082-1094 ◽  
Author(s):  
Daniel Scotcher ◽  
Christopher Jones ◽  
Maria Posada ◽  
Aleksandra Galetin ◽  
Amin Rostami-Hodjegan
Keyword(s):  
Mechanistic Models ◽  
Health And Disease ◽  
In Vivo Extrapolation

scholarly journals Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3022
Author(s):  
Maria Vizziello ◽  
Linda Borellini ◽  
Giulia Franco ◽  
Gianluca Ardolino
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Gene Mutations ◽  
Neuronal Population ◽  
In Vivo Models ◽  
Mitochondrial Homeostasis

The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.

scholarly journals Cannabinoids and Neurogenesis: The Promised Solution for Neurodegeneration?

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6313
Author(s):  
Andrea Valeri ◽  
Emanuela Mazzon
Keyword(s):  
Nervous System ◽  
Experimental Evidence ◽  
Neuronal Death ◽  
Synthetic Cannabinoids ◽  
Neuronal Population ◽  
Adult Brain ◽  
Analgesic Action ◽  
Beneficial Effects

The concept of neurons as irreplaceable cells does not hold true today. Experiments and evidence of neurogenesis, also, in the adult brain give hope that some compounds or drugs can enhance this process, helping to reverse the outcomes of diseases or traumas that once were thought to be everlasting. Cannabinoids, both from natural and artificial origins, already proved to have several beneficial effects (e.g., anti-inflammatory, anti-oxidants and analgesic action), but also capacity to increase neuronal population, by replacing the cells that were lost and/or regenerate a damaged nerve cell. Neurogenesis is a process which is not highly represented in literature as neuroprotection, though it is as important as prevention of nervous system damage, because it can represent a possible solution when neuronal death is already present, such as in neurodegenerative diseases. The aim of this review is to resume the experimental evidence of phyto- and synthetic cannabinoids effects on neurogenesis, both in vitro and in vivo, in order to elucidate if they possess also neurogenetic and neurorepairing properties.

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